ABILIFY MAINTENA

CLASSES

Antidepressant Augmentation Agents

Partial Dopamine Receptor Agonist Antipsychotics

BOXED WARNING

Children, suicidal ideation

Safety and efficacy of oral aripiprazole has been demonstrated in pediatric patients 6 years of age or older for selected indications. Injectable formulations of aripiprazole are not approved for any indication in pediatric patients less than 18 years of age. Because oral aripiprazole is approved for the adjunct treatment of major depression in adults, a boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of aripiprazole may be necessary in patients with emerging suicidality or worsening depression.

Dementia, geriatric, stroke

Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and the use of aripiprazole in this population should be avoided if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. Although clinical experience has not identified differences in responses between elderly and younger patients receiving aripiprazole, a low starting dose is recommended for the elderly. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when aripiprazole is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction (GDR), or rationale for continued use. Refer to the OBRA guidelines for complete information.

DEA CLASS

Rx

DESCRIPTION

Oral and parenteral atypical antipsychotic of the dopamine system stabilizers class

Used orally in adults for schizophrenia, bipolar I disorder, and as an adjunct for major depression; short-acting injection used for agitation; distinct extended-release IM injections are used for maintenance of selected indications; used orally in pediatric patients for schizophrenia, bipolar I disorder, Tourette's syndrome, or irritability due to autism

As with all antipsychotics, boxed warning for increased mortality risk in elderly patients with dementia-related psychosis

COMMON BRAND NAMES

Abilify, Abilify Discmelt, Abilify Maintena, Abilify Mycite, Aristada

HOW SUPPLIED

Abilify Discmelt/Aripiprazole Oral Tab Orally Dis: 10mg, 15mg

Abilify Maintena Intramuscular Inj Pwd F/Susp ER: 300mg, 400mg

Abilify/Abilify Mycite/Aripiprazole Oral Tab: 2mg, 5mg, 10mg, 15mg, 20mg, 30mg

Abilify/Aripiprazole Oral Sol: 1mg, 1mL

Aristada Intramuscular Inj Susp ER: 1.6mL, 2.4mL, 3.2mL, 3.9mL, 441mg, 662mg, 675mg, 882mg, 1064mg

DOSAGE & INDICATIONS

For the treatment of schizophrenia.

Oral dosage (immediate-release oral dosage forms, tablets, orally disentegrating tablets, oral solution)

Adults

The recommended starting and target dose is 10 mg to 15 mg PO once daily. Effective dosage range: 10 mg/day to 30 mg/day. However, dosages greater than 10 mg to 15 mg/day PO were not more effective than the initial doses in clinical trials. Titrate no more frequently than every 2 weeks, the time needed to achieve steady state. Max: 30 mg/day PO. ORAL SOLUTION DOSING: The oral solution of aripiprazole can be substituted for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose to achieve a favorable clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose). SWITCHING FROM OTHER ANTIPSYCHOTICS: In 1 study, the following regimens were safe and effective: 1) initiation with simultaneous discontinuation of the current antipsychotic monotherapy; 2) immediate initiation with a 2-week taper of the current antipsychotic; or 3) a 2-week up-titration of aripiprazole while simultaneously tapering the current antipsychotic. Adverse events were comparable across treatment groups and time-limited. While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate.

Adolescents

Initially, 2 mg PO once daily. After 2 days increase to 5 mg PO once daily, and after 2 more days increase to the target dose of 10 mg PO once daily. Then, titrate in 5 mg increments, usually every 2 weeks to allow assessment of effectiveness and tolerability. Up to 30 mg/day has been studied; however, this dose does not appear to be more effective than the 10 mg/day dose. Max: 30 mg/day PO. ORAL SOLUTION DOSING: The oral solution of aripiprazole can be substituted for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose to achieve a favorable clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

Oral dosage (aripiprazole tablet with sensor, Abilify Mycite)

Adults

The recommended starting and target dose is 10 mg to 15 mg PO once daily. In general, do not increase the dose before 2 weeks. The maximum daily dose is 30 mg/day; however dosages greater than 15 mg/day have not been shown to have more clinically meaningful benefit. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial dose to one-half of the usual dose, then titrate to achieve a favorable clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose). While immediate discontinuation of the previous antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate. It should be noted that the use of Abilify Mycite to track drug ingestion in "real-time" or during an emergent event is not recommended because detection may be delayed or not occur. SWITCHING FROM OTHER ANTIPSYCHOTICS: In 1 study, the following regimens were safe and effective: 1) initiation with simultaneous discontinuation of the current antipsychotic monotherapy; 2) immediate initiation with a 2-week taper of the current antipsychotic; or 3) a 2-week up-titration of aripiprazole while simultaneously tapering the current antipsychotic. Adverse events were comparable across treatment groups and time-limited.

Intramuscular dosage (monthly extended-release injectable suspension; i.e. Abilify Maintena)

Adults

Initially, Abilify Maintena 400 mg IM once monthly, with maintenance dose administered no sooner than 26 days after the previous injection. At initiation, oral aripiprazole (10 mg to 20 mg per day) or other oral antipsychotic should be continued for 14 consecutive days to maintain therapeutic concentrations during initiation of IM aripiprazole therapy. Clinical trials have shown efficacy of the extended-release injection for both maintenance treatment of schizophrenia and in treating acutely relapsed adult patients. Once stabilized, may reduce to 300 mg IM once monthly based upon tolerability. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), the recommended starting and maintenance dose of Abilify Maintena is 300 mg/month IM as a single injection. In patients who are CYP2D6 PMs and receiving a CYP3A4 inhibitor for more than 14 days, the Abilify Maintena dose should be adjusted to 200 mg/month IM. MISSED DOSES: 1) If the second or third dose is missed and more than 4 weeks but less than 5 weeks have elapsed since the last injection: Administer the injection as soon as possible. 2) If the second or third dose is missed and more than 5 weeks have elapsed since the last injection: Restart concomitant oral aripiprazole for 14 days with the next administered injection. 3) If the fourth or subsequent dose is missed and greater than 4 weeks but less than 6 weeks have elapsed since the last injection: Administer the injection as soon as possible. 4) If the fourth or subsequent dose is missed and more than 6 weeks have elapsed since the last injection: restart concomitant oral aripiprazole for 14 days with the next administered injection.

Intramuscular dosage (extended-release aripiprazole lauroxil injectable suspension; i.e., Aristada)

Adults, including Geriatric Adults up to 65 years of age

Establish tolerability with oral aripiprazole prior to initiating treatment with IM Aristada in patients who have never received aripiprazole. Due to the long half-life of aripiprazole, it may take up to 2 weeks to fully evaluate tolerability. THERE ARE TWO OPTIONS FOR INITIATING TREATMENT WITH ARISTADA. INITIATION OPTION ONE: Administer one IM injection of Aristada Initio 675 mg in the deltoid or gluteal muscle AND give 1 dose of oral aripiprazole (30 mg PO) in conjunction with the first IM Aristada injection. Aristada may be administered on the same day as the Aristada Initio single use IM injection or up to 10 days thereafter; avoid injecting both Aristada Initio and Aristada concurrently into the same deltoid or gluteal muscle. INITIATION OPTION TWO: Continue oral aripiprazole for 21 consecutive days in conjunction with the first IM Aristada injection. Depending on the individual needs of the patient, Aristada can be initiated at an IM dose of 441 mg, 662 mg, or 882 mg monthly, 882 mg administered every 6 weeks, or 1,064 mg administered every 2 months. The dose and dosing interval may be adjusted as needed, taking into account the pharmacokinetics and prolonged-release characteristics of Aristada. ARISTADA DOSE FOR PATIENTS STABILIZED ON ORAL ARIPIPRAZOLE AS FOLLOWS: 10 mg/day PO (Aristada 441 mg/month IM); 15 mg/day PO (Aristada 662 mg/month IM, 882 mg IM every 6 weeks, or 1,064 mg IM every 2 months); and 20 mg/day or higher PO (Aristada 882 mg/month IM). CONVERSION FROM ABILIFY MAINTENA EXTENDED-RELEASE IM INJECTION: Abilify Maintena doses of 300 mg, 450 mg, 600 mg, and 724 mg correspond to 441 mg, 662 mg, 882 mg, and 1,064 mg respectively, of Aristada. The 441 mg dose may be administered in the deltoid or gluteal muscle, whereas all other doses and dosing regimens (662 mg monthly, 882 mg monthly, 882 mg every 6 weeks, or 1,064 mg every 2 months) should be administered in the gluteal muscle. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers who are receiving a strong CYP3A4 inhibitor for more than 2 weeks, reduce the Aristada dose to 441 mg/month from 662 mg/month, 882 mg every month to 6 weeks, or 1,064 mg every 2 months. No dosage adjustment is needed in patients taking 441 mg of Aristada, if tolerated. EARLY DOSING: If early dosing is needed, the injection should not be given earlier than 14 days after the previous injection. MISSED DOSES: 1) For patients who miss a dose while receiving 441 mg/month IM: If it has been 6 weeks or less since the missed dose, no oral supplementation is required. If it has been more than 6 weeks but not more than 7 weeks since the missed dose, supplement with 7 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada. If it has been more than 7 weeks since the missed dose, supplement with 21 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada. 2) For patients who miss a dose while receiving 662 mg/month, 882 mg/month, or 882 mg every 6 weeks IM: If it has been 8 weeks or less since the missed dose, no oral supplementation is required. If it has been more than 8 weeks but not more than 12 weeks since the missed dose, supplement with 7 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada. If it has been more than 12 weeks since the missed dose, supplement with 21 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada. 3) For patients who miss a dose while receiving 1,064 mg IM every 2 months: If it has been 10 weeks or less since the missed dose, no oral supplementation is required. If it has been more than 10 weeks but not more than 12 weeks since the missed dose, supplement with 7 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada. If it has been more than 12 weeks since the missed dose, supplement with 21 days of oral aripiprazole at the same dose of oral aripiprazole as when the patient began Aristada.

Intramuscular dosage (extended-release aripiprazole lauroxil injection for single dose use; e.g., Aristada Initio ONLY)

Adults, including Geriatric Adults up to 65 years of age

SINGLE DOSE ADMINISTRATION ONLY: Administer one 675 mg IM injection of Aristada Initio with one 30 mg dose of oral aripiprazole in conjunction with the first Aristada injection or up to 10 days thereafter. Aristada Initio may also be used as a single dose to re-initiate Aristada following a missed dose of Aristada; however, Aristada Initio is not for repeated dosing. Aristada Initio may be injected in either the deltoid or gluteal muscle and must be administered by a healthcare professional. Avoid injecting both Aristada Initio and Aristada into the same deltoid or gluteal muscle concurrently. For aripiprazole-naive patients, establish tolerability with oral aripiprazole prior to initiating treatment with Aristada Initio. Assessment of tolerability to the oral formulation may take up to 2 weeks due to the long half-life of the drug. Aristada Initio is not interchangeable with Aristada due to different pharmacokinetics. Avoid use in known CYP2D6 poor metabolizers. Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions.

For the acute treatment of mania and mixed episodes and maintenance treatment of bipolar disorder (Bipolar I Disorder).

Oral dosage (immediate-release oral dosage forms, tablets, orally disentegrating tablets, oral solution)

Adults

INITIAL MONOTHERAPY DOSING FOR ACUTE OR MAINTENANCE TREATMENT: 15 mg/day PO. INITIAL DOSING FOR ACUTE OR MAINTENANCE TREATMENT AS ADJUNCT THERAPY TO LITHIUM OR VALPROATE: 10 to 15 mg/day PO. The recommended target dose as monotherapy or adjunct therapy to lithium or valproate is 15 mg/day. May titrate if needed/tolerated. Use the lowest effective dose. Max: 30 mg/day PO. Periodically reassess the need for continued maintenance therapy. Maintenance studies with aripiprazole as monotherapy or adjunct therapy showed a significant delay in relapse to manic episodes, but not depressive episodes, compared to placebo. ORAL SOLUTION DOSING: The oral solution can be substituted for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose according to clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

Children and Adolescents 10 years and older

ACUTE OR MAINTENANCE THERAPY: Initially, 2 mg PO once daily. Titrate to 5 mg once daily after 2 days, and then titrate to a target dose of 10 mg/day after an additional 2 days. Subsequent increases should occur in increments of 5 mg/day. Use lowest effective dose. Max: 30 mg/day PO. Periodically reassess the need for continued maintenance therapy. ORAL SOLUTION DOSING: The oral solution can be substituted for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose according to clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

Oral dosage (oral tablet with sensor; e.g., Abilify Mycite)

Adults

INITIAL MONOTHERAPY DOSE FOR ACUTE OR MAINTENANCE THERAPY: 15 mg/day PO. INITIAL DOSE FOR ACUTE OR MAINTENANCE TREATMENT AS ADJUNCT TREATMENT TO LITHIUM OR VALPROATE: 10 to 15 mg/day PO. The recommended target dose as monotherapy or adjunct therapy to lithium or valproate is 15 mg/day. May titrate if needed/tolerated. Use lowest effective dose. Max: 30 mg/day PO. Maintenance studies with aripiprazole as monotherapy or adjunct therapy showed a significant delay in relapse to manic episodes, but not depressive episodes, compared to placebo. Periodically reassess the need for continued therapy. It should be noted that the use of Abilify Mycite to track drug ingestion in "real-time" or during an emergent event is not recommended because detection may be delayed or not occur. ORAL SOLUTION DOSING: Substitute for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose according to clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

Intramuscular dosage (monthly extended-release intramuscular suspension; i.e., Abilify Maintena)

Adults

FOR MAINTENANCE TREATMENT: The initial and maintenance dose is 400 mg IM once monthly, with subsequent maintenance doses administered no sooner than 26 days after the previous injection. At initiation, oral aripiprazole (10 mg to 20 mg per day) or other oral antipsychotic should be continued for 14 consecutive days to maintain therapeutic concentrations during initiation of IM aripiprazole therapy. Once stabilized, may reduce to 300 mg IM once monthly in patients experiencing adverse effects. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), the recommended starting and maintenance dose of Abilify Maintena is 300 mg/month IM as a single injection. In patients who are CYP2D6 PMs and receiving a CYP3A4 inhibitor for more than 14 days, the Abilify Maintena dose should be adjusted to 200 mg/month IM. MISSED DOSES: 1) If the second or third dose is missed and more than 4 weeks but less than 5 weeks have elapsed since the last injection: Administer the injection as soon as possible. 2) If the second or third dose is missed and more than 5 weeks have elapsed since the last injection: Restart concomitant oral aripiprazole for 14 days with the next administered injection. 3) If the fourth or subsequent dose is missed and greater than 4 weeks but less than 6 weeks have elapsed since the last injection: Administer the injection as soon as possible. 4) If the fourth or subsequent dose is missed and more than 6 weeks have elapsed since the last injection: restart concomitant oral aripiprazole for 14 days with the next administered injection. LIMITATIONS OF USE: Abilify Maintena is not FDA approved for the treatment of acute manic or mixed episodes.

For the treatment of agitation associated with schizophrenia or bipolar mania.

Intramuscular dosage (injection solution)

Adults

9.75 mg IM as a single dose. A lower dosage of 5.25 mg IM may be used if clinically warranted such as patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs). Subsequent administration may be considered if necessary; however, the efficacy of repeated dosages and the safety of administration more frequently than every 2 hours have not been established in controlled clinical trials. Maximum cumulative dose: 30 mg/day IM. Total daily doses greater than 30 mg have not been adequately studied. Single doses of 15 mg were not found superior to 9.75 mg in clinical trials. Patients requiring long-term treatment with aripiprazole should be changed to oral administration of the drug as soon as possible.

For the adjunctive treatment of major depression.

Oral dosage

Adults

Initially, 2 mg to 5 mg PO once daily as an adjunct to previously established antidepressant treatment. Adjust dose in increments of up to 5 mg at intervals of no less than 1 week each. The effective dose range is 2 mg/day to 15 mg/day PO. Periodically reassess to determine the need for continued treatment. It should be noted that the use of Abilify Mycite (aripiprazole tablets with sensor) to track drug ingestion in "real-time" or during an emergent event is not recommended because detection may be delayed or not occur. NOTE: No dosage adjustments are needed in patients with major depressive disorder receiving adjunct aripiprazole within this dose range with concomitant CYP modulators or for patients who are CYP2D6 poor metabolizers.

For the short-term treatment of irritability associated with autistic disorder.

Oral dosage

Children and Adolescents 6 years and older

Initially, 2 mg PO once daily. Increase dose to 5 mg PO once daily after 1 week. Further titration should occur in increments of 5 mg/day at intervals of no less than 1 week. Recommended dose range: 5 mg to 10 mg PO once daily. Individualize regimen based upon response and tolerability. Max: 15 mg/day PO. Periodically reassess to determine the need for continued treatment. Short-term efficacy was established in 2 placebo-controlled trials (8 week duration). In a maintenance trial, patients were initially stabilized with aripiprazole (2 mg/day to 15 mg/day) for 12 weeks (stabilization defined as greater than 25% improvement on the ABC-I subscale, and a CGI-I rating of much improved or very much improved). In the second phase of the maintenance trial (stabilized patients randomized to receive aripiprazole or placebo for an additional 16 weeks, n = 85), long-term efficacy was not established. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers ( CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose to achieve a favorable clinical response. In patients classified as CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

For the treatment of Tourette's syndrome or chronic tic disorders†.

NOTE: The FDA has designated aripiprazole as an orphan drug for this indication.

Oral dosage

Children and Adolescents 6 years and older

WEIGHING AT LEAST 50 KG: Initially, 2 mg PO once daily. After 2 days, increase to 5 mg PO once daily. Then, after 5 more days, increase to the target dose of 10 mg PO once daily. Increase gradually by 5 mg/day increments at weekly intervals as needed to achieve optimal control. Max: 20 mg/day PO. WEIGHING LESS THAN 50 KG: Initially, 2 mg PO once daily. After 2 days, increase dose to 5 mg PO once daily. Increase gradually at weekly intervals as needed. Max: 10 mg/day PO. In all patients, periodically reassess the need for continued maintenance treatment. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary during treatment with aripiprazole; review drug interactions. In CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust to favorable clinical response. In CYP2D6 PMs who are receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose). The American Academy of Neurology states that aripiprazole is probably more likely than placebo to reduce tic severity in patients with Tourette's syndrome or chronic tic disorders; however, there is insufficient evidence to determine the efficacy of aripiprazole relative to other antipsychotics used to treat tics.

For the treatment of severe behavioral or psychological symptoms of dementia† (BPSD)†.

Oral dosage

Geriatric Adults

Initially, 2 mg or 5 mg PO once daily, with gradual titration of the daily dose according to response and tolerance, usually by no more than 5 mg/day every week. Maximum suggested dose: 10 mg/day PO. A 2011 off-label use of review by the Agency for Healthcare Research and Quality (AHRQ) stated aripiprazole is efficacious for behavioral symptoms of dementia and for agitation. Antipsychotics are not FDA-approved for this indication and the labeling of all antipsychotics contains a boxed warning noting an increased risk of death in geriatric patients being treated for behavioral problems associated with dementia. The federal Omnibus Budget Reconciliation Act (OBRA) regulates the use of antipsychotics in long-term care facility (LTCF) residents with dementia-related behavioral symptoms. OBRA Max: 10 mg/day PO in residents meeting the OBRA criteria for treatment, except when documentation is provided showing that higher doses are necessary to maintain or improve the resident's functional status. In addition, the facility must attempt a gradual dose reduction (GDR) in 2 separate quarters, at least 1 month apart, within the first year of admission to the facility or after the facility has initiated an antipsychotic, unless clinically contraindicated. After the first year, a GDR must be attempted annually unless clinically contraindicated. The GDR may be considered clinically contraindicated if the target symptoms returned or worsened after the most recent GDR attempt within the facility and the physician has documented justification for why attempting additional dose reductions at that time would likely impair the resident's function or increase distressed behavior. ORAL SOLUTION DOSING: The oral solution can be substituted for the tablet on a mg-per-mg basis, up to 25 mg. Patients receiving 30 mg tablets should receive 25 mg of the solution due to enhanced absorption of the solution at higher dosages. ADJUSTMENTS: Coadministration of certain drugs may need to be avoided or dosage adjustments may be necessary; review drug interactions. In patients classified as CYP2D6 poor metabolizers (CYP2D6 PMs), reduce the initial oral aripiprazole dose to one-half of the usual dose, then adjust the dose to achieve a favorable clinical response. In patients classified as CYP2D6 PMs who are also receiving a strong CYP3A4 inhibitor, reduce the oral aripiprazole dose to one-quarter of the usual dose. When the CYP3A4 inhibitor is withdrawn, increase to the original dose (i.e., one-half of the usual dose).

†Indicates off-label use

MAXIMUM DOSAGE

Adults

30 mg/day PO tablets and 25 mg/day PO oral solution; 30 mg/day immediate-release IM; 400 mg/month extended-release IM (Abilify Maintena); 882 mg/month extended-release IM (Aristada); 675 mg IM single-dose administration (Aristada Initio).

Geriatric

30 mg/day PO tablets and 25 mg/day PO oral solution; 30 mg/day immediate-release IM; 400 mg/month extended-release IM (Abilify Maintena); 882 mg/month extended-release IM (Aristada) and 675 mg IM single-dose administration (Aristada Initio) but safety and efficacy of Aristada and Aristada Initio have not established in geriatric adults over 65 years of age.

Adolescents

Weight greater than or equal to 50 kg: 30 mg/day PO for schizophrenia and bipolar disorder; 15 mg/day PO for autism; 20 mg/day PO for Tourette's syndrome; safety and efficacy of the immediate-release (Abilify) and extended-release IM injections (Abilify Maintena, Aristada, Aristada Initio) have not been established.

Weight less than 50 kg: 30 mg/day PO for schizophrenia and bipolar disorder; 15 mg/day PO for autism; 10 mg/day PO for Tourette's syndrome; safety and efficacy of the immediate-release (Abilify) and extended-release IM injections (Abilify Maintena, Aristada, Aristada Initio) have not been established.

Children

Greater than or equal to 10 years and weighing greater than or equal to 50 kg: 30 mg/day PO for bipolar disorder; 15 mg/day PO for autism; 20 mg/day PO for Tourette's syndrome; not indicated for schizophrenia.

Greater than or equal to 10 years and weighing less than 50 kg: 30 mg/day PO for bipolar disorder; 15 mg/day PO for autism; 10 mg/day PO for Tourette's syndrome; not indicated for schizophrenia.

6 to 9 years weighing greater than or equal to 50 kg: 15 mg/day PO for autism; 20 mg/day PO for Tourette's syndrome; not indicated for bipolar disorder or schizophrenia.

6 to 9 years weighing less than 50 kg: 15 mg/day PO for autism; 10 mg/day PO for Tourette's syndrome; not indicated for bipolar disorder or schizophrenia.

Less than 6 years: Safety and efficacy have not been established.

Infants

Not indicated.

Neonates

Not indicated.

DOSING CONSIDERATIONS

Hepatic Impairment

No dosage adjustment for oral or parenteral aripiprazole is required on the basis of a patient’s hepatic function (mild to severe hepatic impairment, Child-Pugh score between 5 and 15).

Renal Impairment

No dosage adjustment for oral or parenteral aripiprazole is required on the basis of a patient’s renal function (mild to severe renal impairment, glomerular filtration rate between 15 and 90 mL/minute).

Intermittent hemodialysis

Hemodialysis is unlikely to be effective in removing aripiprazole since the drug is highly bound to plasma proteins.

ADMINISTRATION

Oral Administration

Oral Solid Formulations

Oral immediate release tablets (e.g., Abilify):

May be administered without regard to meals.

Orally disintegrating tablets (e.g., Abilify DiscMelt):

Do not open the blister until ready to administer.

Do not push the tablet through the foil because this could damage the tablet.

Place the tablet on the tongue and allow to dissolve. Tablet disintegration occurs rapidly in saliva.

Do not take with liquid unless it is necessary to do so. Do not divide the tablets in half.

May be administered without regard to meals.

Oral tablets with sensor (e.g., Abilify Mycite):

General instructions:

Prior to patient use, the healthcare provider should facilitate the use of the product and its components (patch, application, portal) and ensure the patient is capable and willing to use smartphones and apps.

Before using any component of the system, instruct patients to download the Mycite app and follow all of the instructions for use and ensure that the app is compatible with the specific smartphone of the patient.

The system includes a web-based portal for healthcare providers and caregivers.

Advise patients that if their smartphone is lost, impaired, or disabled, some information collected by the system may be lost. If the patient's device is lost or disabled, the Mycite patch should be changed immediately and connected to a new mobile device using their current account information. Information previously synced to the patient's account will be available.

Mycite tablets:

May administer without regard to meals.

Swallow tablets whole; do not divide, crush, or chew.

The tablets are embedded with an Ingestible Event Marker (IEM) intended to track drug ingestion in conjunction with a wearable sensor (Mycite patch) and smartphone app.

Although most ingestion will be detected within 30 minutes, it may take up to two hours for the smartphone app and web portal to detect ingestion of the tablet. If the tablet is not detected after ingestion, do not repeat the dose.

It is not recommended to use the tablets to track drug ingestion in "real-time" or during an emergency because detection may be delayed or not occur.

Mycite patch:

The patch detects the signal from the IEM sensor embedded in the tablet after ingestion and transmits data to a smartphone.

Apply only when instructed by the Mycite smartphone application (Mycite app) to the left side of the body just above the lower edge of the rib cage.

Ensure that the app is paired with the patch prior to use. The status of the patch is indicated by a status icon in the app to inform the user that the patch is properly adhered and fully functioning.

Do not place the patch where the skin is scraped, cracked, inflamed, or irritated, or in an area that overlaps the most recently removed patch.

Do not remove the patch when showering, swimming, or exercising.

Change the patch weekly or sooner if needed. The app will prompt you to change the patch and will direct you to apply and remove the patch correctly.

Remove the patch when having an MRI and replace it with a new one as soon as possible. If there is skin irritation, remove the patch.

Oral Liquid Formulations

Oral solution:

Administer using a calibrated oral measuring device.

May be administered without regard to meals.

Storage: Opened bottles of aripiprazole oral solution can be used for up to 6 months after opening, but not beyond the expiration date on the bottle.

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit.

Intramuscular Administration

Immediate-release intramuscular injection solution (i.e. Abilify short-acting injection):

For intramuscular (IM) use only. Do NOT administer intravenously or subcutaneously.

Available as a ready-to-use injectable solution.

Inject slowly and deeply into muscle mass.

Wait at least 2 hours between doses.

Discard any unused portion.

Extended-release intramuscular injection (i.e., Abilify Maintena) Single-Use Vial Preparation, Reconstitution, and Administration:

-Preparation of adapter-syringe assembly:

For intramuscular (IM) use only. Do NOT administer intravenously or subcutaneously.

Remove cover from vial adapter package. Do not remove vial adapter from package. Using vial adapter package to handle the vial adapter, attach the prepackaged luer lock syringe to the vial adapter.

Use the luer lock syringe to remove the vial adapter from the package and discard the vial adapter package. Do not touch the spike tip of the adapter at any time.

-Reconstitution and Dose preparation of single-use Vial for suspension:

Use appropriate aseptic technique and reconstitute at room temperature.

The lyophilized powder should be suspended with the 5 mL vial of Sterile Water for Injection supplied in the kit.

For the 400-mg vial, reconstitute with 1.9 mL of Sterile Water for Injection. For a 300-mg vial, reconstitute with 1.5 mL of Sterile Water for Injection.

Using the syringe with pre-attached hypodermic safety needle, withdraw pre-determined Sterile Water volume into the syringe.

Discard residual water that remains in the 5 mL vial of Sterile Water for Injection after reconstitution.

After slowly injecting the Sterile Water for Injection into the vial of lyophilized powder, withdraw air equal to pressure in the vial. Remove needle from the vial.

Engage the needle safety device using a one-handed technique. Gently press the sheath against a flat surface until the needle is firmly engaged in the needle protection sheath. Visually confirm that the needle is fully engaged into the needle protection sheath, and discard.

Shake the reconstituted vial vigorously for 30 seconds. The reconstituted suspension should be uniform, homogenous, opaque, and milky white in color.

Determine the recommended volume for injection.

Using the 400 mg reconstituted vial: 400 mg = 2 mL, 300 mg = 1.5 mL, 200 mg = 1 mL, 160 mg = 0.8 mL.

Using the 300 mg reconstituted vial: 300 mg = 1.5 mL, 200 mg = 1 mL, 160 mg = 0.8 mL.

Wipe top of the reconstituted vial with a sterile alcohol swab. Place and hold the reconstituted vial on a hard surface.

Attach the adapter-syringe assembly to vial by holding the outside of the adapter and pushing adapter's spike firmly through the rubber stopper until the adapter snaps in place.

Slowly withdraw recommended volume into the luer lock syringe. NOTE: A small amount of excess product will remain in the vial.

Detach the luer lock syringe containing the suspension from the vial. Attach syringe to the appropriate needle.

For deltoid administration, use the 23 gauge, 1-inch needle in non-obese patients and the 22 gauge, 1.5-inch needle in obese patients.

For gluteal administration, use the 22 gauge, 1.5-inch needle in non-obese patients and the 21 gauge, 2-inch needle in obese patients.

Ensure needle is firmly seated on safety device with a push and clockwise twist; pull the needle cap straight from the needle.

-Dose Administration and Disposal once prepared from Vial:

For once-monthly deep intramuscular gluteal or deltoid injection by a healthcare professional only. Do NOT administer by any other route.

For single-use only. Discard any unused portion.

Use immediately after reconstitution and preparation of the syringe.

Slowly inject the recommended volume as a single deep IM injection into the gluteal or deltoid muscle.

Do NOT massage the injection site.

After the injection, engage the needle safety device using a one-handed technique. Gently press the sheath against a flat surface until the needle is firmly engaged in the needle protection sheath. Appropriately dispose of the vials, adapter, needles, and syringe.

Do not re-use any components of the kit.

For subsequent injections, rotate sites of injection between the two gluteal or deltoid muscles.

If not injected immediately, keep vial at room temperature and shake vigorously for at least 60 seconds to re-suspend before preparing the syringe for injection. Do not store suspension in a syringe.

Refer to the Administration Instructions section of the official product labeling for detailed visual aids which accompany the written instructions.

Extended-release intramuscular injection (i.e., Abilify Maintena) Pre-Filled Dual Chamber Syringe Preparation, Reconstitution, Administration, and Disposal:

For once-monthly deep intramuscular gluteal or deltoid injection by a healthcare professional only. Do NOT administer by any other route.

For single-use only. Discard any unused portion.

Use immediately after reconstitution and preparation of the pre-filled syringe.

Use appropriate aseptic technique and reconstitute at room temperature.

Push plunger rod slightly to engage threads. Then, rotate plunger rod until the rod stops rotating to release diluent.

After plunger rod is at complete stop, middle stopper will be at the indicator line.

Vertically shake the syringe vigorously for 20 seconds until the drug is uniformly milky-white. The reconstituted suspension should be opaque and milky white in color.

To inject, twist and pull off Over-cap and Tip-cap. Select the appropriate needle.

For deltoid administration, use the 23 gauge, 1-inch needle in non-obese patients and the 22 gauge, 1.5-inch needle in obese patients.

For gluteal administration, use the 22 gauge, 1.5-inch needle in non-obese patients and the 21 gauge, 2-inch needle in obese patients.

While holding needle cap, ensure the needle is firmly seated on the safety device with a push; twist clockwise until snugly fitted. Pull needle-cap straight up.

Hold syringe upright and advance plunger rod slowly to expel the air until the suspension fills the needle base. If it's not possible to advance the plunger rod to expel the air, check that the plunger rod is rotated to a complete stop.

Slowly inject as a single deep IM injection into the gluteal or deltoid muscle.

Do not massage the injection site.

After the injection, engage the needle safety device and safely discard all kit components.

For subsequent injections, rotate sites of injection between the two gluteal or deltoid muscles.

Refer to the Administration Instructions section of the official product labeling for detailed visual aids which accompany the written instructions.

Extended-release aripiprazole lauroxil intramuscular injection (i.e., Aristada)

-General Administration Guidelines:

For administration as a long-acting intramuscular injection by a healthcare professional. Do NOT administer by any other route.

Prior to administering Aristada, establish tolerability with oral aripiprazole in patients who have never taken aripiprazole. Due to the half-life of oral aripiprazole, it may take up to 2 weeks to fully assess tolerability.

The 441 mg dose may be administered in the deltoid or gluteal muscle, whereas all other doses (662 mg, 882 mg, and 1,064 mg) should be administered in the gluteal muscle.

When initiating Aristada in conjunction with a single dose of Aristada Initio 675 mg, avoid injecting both Aristada Initio and Aristada concurrently into the same deltoid or gluteal muscle.

The dose and dosing interval may be adjusted, taking into account the pharmacokinetics and prolonged-release characteristics of Aristada.

If early dosing is needed, the injection should not be given any earlier than 14 days after the previous injection. If the patient misses their scheduled dose, refer to the dosing and administration recommendations for patients which are determined by the length of time since the last injection.

-Extended-release aripiprazole lauroxil injection (i.e., Aristada) Pre-filled Syringe Preparation, Administration, and Disposal:

The kit contains a pre-filled syringe with Aristada sterile aqueous suspension and 2 or 3 safety needles depending upon the dose.

Tap the syringe at least 10 times to dislodge any material which may have settled and shake vigorously for at least 30 seconds to ensure uniform suspension.

If the syringe is not used within 15 minutes, shake again for 30 seconds.

Select the injection needle based on injection site and dosage, as follows. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.

441 mg dose: Deltoid (21 gauge, 1-inch or 20 gauge, 1.5-inch), or Gluteal (20 gauge, 1.5-inch or 20 gauge, 2-inch).

662 mg dose: Gluteal (20 gauge, 1.5-inch or 20 gauge, 2-inch).

882 mg dose: Gluteal (20 gauge, 1.5-inch or 20 gauge, 2-inch).

1,064 mg dose: Gluteal (20 gauge, 1.5-inch or 20 gauge, 2-inch).

Attach the injection needle to the syringe securely with a clockwise twisting motion. Do NOT over-tighten, since this may lead to needle hub cracking.

Prime the syringe to remove air.

Bring the syringe into an upright position and tap the syringe to bring air to the top. Remove air by depressing the plunger rod. A few drops of suspension will be released.

Administer the entire contents of the syringe IM. Do not inject by any other route. Inject in a rapid and continuous manner (less than 10 seconds).

Cover the needle by pressing the safety device, and dispose of used and unused items in an appropriate waste container.

Refer to the Administration Instructions section of the official product labeling for detailed visual aids which accompany the written instructions.

Single-dose extended-release aripiprazole lauroxil intramuscular injection (i.e., Aristada Initio) Pre-filled Syringe Preparation, Administration, and Disposal:

Aristada Initio is not interchangeable with Aristada due to differing pharmacokinetics.

For use as a single intramuscular dose in the deltoid or gluteal muscle in patients initiating Aristada or after a missed dose of Aristada. Do not inject by any other route.

The kit contains a syringe with a sterile suspension of 675 mg/2.4 mL of Aristada Initio and 3 safety needles (a 2-inch 20 gauge needle with yellow needle hub, a 1.5-inch 20 gauge needle with yellow needle hub, and a 1-inch 21 gauge needle with a green needle hub).

This product should only be administered by a healthcare professional.

Avoid injecting Aristada Initio and Aristada concurrently into the same deltoid or gluteal muscle.

Tap the syringe at least 10 times to dislodge any settled material and vigorously shake the syringe for at least 30 seconds to ensure a uniform suspension.

If the syringe is not used within 15 minutes, shake again for 30 seconds.

Select needle size based on injection site. For patients with a larger amount of subcutaneous tissue overlaying the injection site muscle, use the longer of the needles provided.

Deltoid: 21 gauge, 1-inch or 20 gauge, 1.5-inch.

Gluteal: 20 gauge 1.5-inch or 20 gauge, 2-inch.

Attach the injection needle to the syringe securely with a clockwise twisting motion. Do NOT overtighten, since this could lead to needle hub cracking.

Prime the syringe to remove air by bringing syringe into upright position and tapping, then depress the plunger rod to remove air until a few drops are released. Small air bubbles in the syringe are normal.

Inject IM in a rapid and continuous manner. Product requires a rapid injection; do not hesitate.

Dispose of the needle. Cover the needle by pressing the safety device. Dispose of used and unused items in a proper waste container.

Refer to the Administration Instructions section of the official product labeling for detailed visual aids which accompany the written instructions.

STORAGE

Abilify:

- Store at 77 degrees F; excursions permitted to 59-86 degrees F

Abilify Discmelt:

- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

Abilify Maintena:

- Discard unused portion. Do not store for later use.

- Store at 77 degrees F; excursions permitted to 59-86 degrees F

Abilify Mycite:

- Avoid excessive humidity

- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

Aristada:

- Do not freeze

- Store between 68 to 77 degrees F, excursions permitted 59 to 86 degrees F

CONTRAINDICATIONS / PRECAUTIONS

General Information

Some reports suggest that a false positive urine drug screen may occur for amphetamines in patients who have ingested aripiprazole. Caution should be exercised when interpreting positive urine drug screens, and confirmation by alternative tests such as gas chromatography/mass spectrometry should be considered.

Bipolar disorder, mania

All effective antidepressants can transform depression into mania or hypomania in predisposed individuals. It is generally believed (though not established in controlled trials) that treating such an episode with an antidepressant alone may increase the likelihood of precipitation of a mixed/manic episode in patients at risk for bipolar disorder. If a patient develops manic symptoms, aripiprazole should be withheld and appropriate therapy initiated to treat the manic symptoms. Additionally, depression may be the presenting symptom of a mixed/manic episode of bipolar disorder. Patients with depression or comorbid depression in the setting of other psychiatric illness being treated with antidepressants should be observed for clinical worsening and suicidality, especially during the initial few months of a course of drug therapy, or at times of dose changes. Caregivers should be advised to closely observe the patient on a daily basis and to communicate immediately with the prescriber the emergence of agitation, irritability, unusual changes in moods or behavior, or suicidality.

Cerebrovascular disease, seizure disorder, seizures

In clinical trials with aripiprazole, seizures occurred in a small number of adult (0.1%) and pediatric (0.3%) patients. In addition, seizures occurred in 0.2% and 0% of patients receiving intramuscular aripiprazole and placebo, respectively, during clinical trials. For this reason, aripiprazole should be used with caution in patients with a seizure disorder or with conditions that may lower the seizure threshold (e.g. cerebrovascular disease). Conditions that lower the seizure threshold may be more prevalent in a population of 65 years or older.

Apheresis, AV block, bradycardia, cardiomyopathy, celiac disease, females, fever, heart failure, human immunodeficiency virus (HIV) infection, hyperparathyroidism, hypocalcemia, hypokalemia, hypomagnesemia, hypotension, hypothyroidism, hypovolemia, long QT syndrome, myocardial infarction, orthostatic hypotension, pheochromocytoma, QT prolongation, rheumatoid arthritis, sickle cell disease, sleep deprivation, syncope, systemic lupus erythematosus (SLE)

Aripiprazole can cause orthostatic hypotension associated with dizziness and, in rare cases, syncope; therefore, caution is advisable in patients with cardiac disease, cerebrovascular disease, pre-existing hypotension, or conditions that may predispose patients to hypotension (e.g., hypovolemia, dehydrated state, antihypertensive therapy). Orthostatic hypotension from antipsychotic use could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate orthostasis. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. In rare instances, QT prolongation has been reported during therapeutic use of aripiprazole and following overdose. Some drugs that prolong the QT interval have been associated with torsade de pointes (TdP), a life-threatening arrhythmia. Aripiprazole is considered a drug with a possible risk of TdP. Use aripiprazole with caution in patients with conditions that may increase the risk of QT prolongation including congenital long QT syndrome, bradycardia, AV block, heart failure, stress-related cardiomyopathy, myocardial infarction, cerebrovascular accident, hypomagnesemia, hypokalemia, hypocalcemia, or in patients receiving medications known to prolong the QT interval or cause electrolyte imbalances. Females, people 65 years and older, patients with sleep deprivation, pheochromocytoma, sickle cell disease, hypothyroidism, hyperparathyroidism, abnormally low body temperature, systemic inflammation (e.g., human immunodeficiency virus (HIV) infection, fever, and some autoimmune diseases including rheumatoid arthritis, systemic lupus erythematosus (SLE), and celiac disease) and patients undergoing apheresis procedures (e.g., plasmapheresis [plasma exchange], cytapheresis) may also be at increased risk for QT prolongation. It is advisable to correct electrolyte imbalances prior to initiation of aripiprazole. Because QT prolongation can occur following an overdose, an electrocardiogram should be obtained in cases of overdose.

Agranulocytosis, hematological disease, leukopenia, neutropenia

Aripiprazole should be used with caution in patients with hematological disease. Hematologic effects including leukopenia, neutropenia, and agranulocytosis have been associated with antipsychotic use. A history of drug-induced leukopenia or neutropenia or pre-existing low white blood cell (WBC) count may increase the likelihood of developing hematologic effects during treatment with an antipsychotic medication. Patients with a history of clinically significant low WBC count or drug-induced leukopenia/neutropenia should have frequent complete blood count (CBC) assessments during the first few months of treatment. Discontinuation of the antipsychotic should be considered if a clinically significant decline in WBC occurs in the absence of an identifiable cause. Patients with clinically significant neutropenia should be closely monitored for fever and infection, and appropriate medical intervention should be instituted if necessary. Aripiprazole should be discontinued in patients with severe neutropenia (ANC < 1000/mm3); ongoing medical care is recommended until the symptoms resolve.

Coadministration with other CNS depressants, driving or operating machinery, ethanol ingestion

Somnolence (including sedation/drowsiness) was a commonly reported adverse effect in clinical trials (11% of patients on oral aripiprazole, 8% of patients on placebo). Somnolence was also reported in 9% of patients receiving intramuscular aripiprazole versus 6% of those receiving placebo during clinical trials. In addition, somnolence has been reported more frequently in pediatric patients receiving oral aripiprazole (21%) than placebo (5%) during clinical trials. Somnolence from antipsychotic use could lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with conditions, diseases, or concurrent medication use that could exacerbate somnolence. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Because aripiprazole may have the potential to impair judgment, thinking, or motor skills, patients should be cautioned about driving or operating machinery or other hazardous tasks until they are reasonably certain that aripiprazole therapy does not affect them adversely. Given the primary CNS effects of aripiprazole, caution should be used during coadministration with other CNS depressants and alcohol. Ethanol ingestion may further impair cognitive and motor skills and patients should generally be advised to avoid use of alcoholic beverages.

Dysphagia

Patients with dysphagia or who are at risk for aspiration pneumonia should be closely monitored while receiving aripiprazole. Antipsychotic drug use has been associated with esophageal dysmotility and aspiration of gastric contents, which may increase the incidence of aspiration pneumonia in certain patient populations, such as patients with advanced Alzheimer's disease.

Children, suicidal ideation

Safety and efficacy of oral aripiprazole has been demonstrated in pediatric patients 6 years of age or older for selected indications. Injectable formulations of aripiprazole are not approved for any indication in pediatric patients less than 18 years of age. Because oral aripiprazole is approved for the adjunct treatment of major depression in adults, a boxed warning in the product label describes the risk of suicidality and suicidal ideation in children, adolescent, and young adult patients receiving antidepressants. In a pooled analysis of placebo-controlled trials of antidepressants (n = 4,500 pediatrics and 77,000 adults), there was an increased risk for suicidal thoughts and behaviors in patients 24 years of age and younger receiving an antidepressant versus placebo, with considerable variation in the risk of suicidality among drugs. The difference in absolute risk of suicidal thoughts and behaviors across different indications was highest in those with major depression. The need for an antidepressant in children, adolescents, or young adults for any use must be weighed against the risk of suicidality; it is unknown if this risk extends to long-term use. All patients should be monitored for symptom worsening or suicidality, especially at treatment initiation or after dose changes. Caregivers and/or patients should immediately notify the prescriber of changes in behavior or suicidal ideation. A change to the treatment regimen or discontinuation of aripiprazole may be necessary in patients with emerging suicidality or worsening depression.

Impulse control symptoms

Postmarketing reports suggest that patients can experience intense compulsive urges, particularly for gambling, and the inability to control these urges while taking aripiprazole. Less frequently reported impulse control symptoms include eating or binge-eating, shopping, and sexual actions. In some cases, these uncontrollable urges stop when the medicine is discontinued or the dose is reduced. Healthcare providers should inform patients and caregivers of the risk of impulse control symptoms when prescribing aripiprazole. Because patients may not recognize these behavioral changes as abnormal, healthcare providers should specifically ask patients about any new or increasing urges or compulsions while they are being treated with aripiprazole. Healthcare providers should closely monitor for new or worsening uncontrollable urges in patients at higher risk for impulse-control problems (e.g., personal or family history of obsessive-compulsive disorder, impulse control disorder, bipolar disorder, impulsive personality, alcoholism, drug abuse, or other addictive behaviors). It should be noted that impulse control symptoms can also be associated with the underlying disorder. A reduction in dose or discontinuation of the medicine should be considered if such urges develop since they may result in harm to the patient or others.

Diabetes mellitus, hyperglycemia

Aripiprazole, like other atypical antipsychotic agents, may cause metabolic changes. Increased blood sugar or diabetes, dyslipidemia, and weight gain may occur during therapy. While all of the drugs in the atypical antipsychotic class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Metabolic changes may increase cardiovascular or cerebrovascular risk over time. Metabolic changes are of particular concern patients with pre-existing risk factors, such as diabetes mellitus. Hyperglycemia, sometimes associated with diabetic ketoacidosis, hyperosmolar coma, or death, has been reported in patients treated with atypical antipsychotics. All patients treated with atypical antipsychotics, including aripiprazole, should be monitored for symptoms of hyperglycemia (e.g., polydipsia, polyuria, polyphagia, weakness). Patients with established diabetes mellitus who are started on atypical antipsychotics should be monitored regularly for worsening of glucose control. Patients with risk factors for diabetes mellitus (e.g., obese patients, family history of diabetes) should undergo fasting blood glucose testing at the beginning of treatment. Patients who develop symptoms of hyperglycemia during treatment should undergo fasting blood glucose testing. In some cases, hyperglycemia has resolved when the antipsychotic was discontinued; however, some patients required continuation of antidiabetic agents despite discontinuation of the suspect drug. Patients with diabetes should be advised that each mL of aripiprazole oral solution contains 400 mg of sucrose and 200 mg of fructose.

Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity

Aripiprazole, like other atypical antipsychotic agents, may cause metabolic changes. Increased blood sugar, dyslipidemia (increased cholesterol and/or triglycerides), and weight gain may occur during therapy. While all of the drugs in the atypical antipsychotic class have been shown to produce some metabolic changes, each drug has its own specific risk profile. Metabolic changes may increase cardiovascular or cerebrovascular risk over time. Metabolic changes are of particular concern patients with pre-existing risk factors, such as diabetes, obesity, or hyperlipidemia (e.g., hypercholesterolemia or hypertriglyceridemia). All patients should be informed of the importance of maintaining a nutritionally balanced diet during treatment with an antipsychotic. Clinical monitoring of weight and serum lipid profiles is recommended during aripiprazole treatment. When treating pediatric patients, weight gain should be assessed against the expected normal growth rate.

Tardive dyskinesia

Tardive dyskinesia is a syndrome of potentially irreversible, involuntary, dyskinetic movements that may develop in patients treated with antipsychotics. Regular evaluation for movement disorders is recommended (e.g., AIMS, DISCUS). Factors associated with a greater susceptibility to tardive dyskinesia include an age above 55 years, female gender, white or African ethnicity, presence of a mood disorder, intellectual disability, CNS injury, prior or current akathisia, significant parkinsonism, or acute dystonic reaction. The rate of tardive dyskinesia in adults treated with a first generation antipsychotic appears to be at least 3 times that observed with second generation antipsychotics. The risk of developing tardive dyskinesia and the likelihood that it will become irreversible are believed to increase as the duration of treatment and the total cumulative dose of antipsychotics administered to the patient increase. However, the syndrome can develop, although much less commonly, after relatively brief periods at low doses or may arise after drug discontinuation. Antipsychotics may suppress the signs and symptoms of tardive dyskinesia and thereby mask the underlying process; however, the syndrome may also remit partially or completely if the antipsychotic is withdrawn. The effect that symptomatic suppression has upon the long-term course of the syndrome is unknown. If signs and symptoms of tardive dyskinesia appear, aripiprazole discontinuation should be considered. However, some patients may require treatment despite the presence of the syndrome.

Neurological disease, Parkinson's disease

Antipsychotics can cause motor and sensory instability, which may lead to falls with the potential for fractures and other injuries. A fall risk assessment should be completed when initiating an antipsychotic in patients with diseases (e.g., neurological disease), conditions, or concurrent medication use that could exacerbate motor and sensory instability. A fall risk assessment should be completed recurrently in at-risk patients on long-term antipsychotic therapy. Pseudoparkinsonism was reported infrequently during clinical trial evaluation of aripiprazole; therefore, the drug should be used with caution in patients with Parkinson's disease because of the possible development of extrapyramidal symptoms. However, atypical antipsychotics like aripiprazole are less likely to interfere with treatments for Parkinson's disease than traditional antipsychotic agents.

Ambient temperature increase, dehydration, hyperthermia, hypothermia, strenuous exercise

Antipsychotics have been reported to disrupt the body's ability to reduce core body temperature presumably through effects in the hypothalamus, and they predispose patients to hyperthermia. Patients receiving aripiprazole should be advised of conditions that contribute to an elevation in core body temperature (e.g., strenuous exercise, ambient temperature increase, or dehydration). A less frequently described alteration in thermoregulatory processes reported with both conventional and atypical antipsychotics is hypothermia. Thermoregulation is multi-factorial; however, the dopaminergic system appears to have a primary role, and serotonin may also have modulatory activity (5-HT2a receptors). Most cases of hypothermia associated with antipsychotics have occurred in conjunction with other potential precipitating factors such as hypothyroidism, sepsis, organic brain injury, or environmental temperature. Hypothermia appears to occur more frequently during initiation of antipsychotic therapy or after dose increases.

Poor metabolizers

Aristada Initio (single dose extended-release intramuscular injection) should be avoided in known CYP2D6 poor metabolizers (CYP2D6 PMs). Dosage adjustments of all other formulations of aripiprazole (e.g., Abilify, Abilify Mycite, Abilify Maintena, Aristada) are recommended in known CYP2D6 PMs due to high aripiprazole concentrations. Approximately 8% of Caucasians and 3% to 8% of Black/African Americans cannot metabolize CYP2D6 substrates and are classified as CYP2D6 PMs.

Abrupt discontinuation

When discontinuing treatment with antipsychotic or antidepressant treatment, the clinician should recognize that abrupt discontinuation of immediate-release dose forms in some patients can cause adverse symptoms. While immediate discontinuation of an antipsychotic treatment may be acceptable for some patients, more gradual discontinuation may be most appropriate for others. With extended-release injections, rate-limited elimination of aripiprazole occurs following any given dose.

Dementia, geriatric, stroke

Antipsychotics are not approved for the treatment of dementia-related psychosis in geriatric patients and the use of aripiprazole in this population should be avoided if possible due to an increase in morbidity and mortality in elderly patients with dementia receiving antipsychotics. Deaths have typically resulted from heart failure, sudden death, or infections (primarily pneumonia). An increased incidence of cerebrovascular adverse events (e.g., stroke, transient ischemic attack), including fatal events, has also been reported. Although clinical experience has not identified differences in responses between elderly and younger patients receiving aripiprazole, a low starting dose is recommended for the elderly. The Beers Criteria consider antipsychotics to be potentially inappropriate medications (PIMs) in elderly patients except for treating schizophrenia, bipolar disorder, and nausea/vomiting during chemotherapy. The Beers panel recommends avoiding antipsychotics in geriatric patients with delirium, dementia, or Parkinson's disease. Non-pharmacological strategies are first-line options for treating delirium- or dementia-related behavioral problems unless they have failed or are not possible and the patient is a substantial threat to self or others. If antipsychotic use is necessary in geriatrics with a history of falls or fractures, consider reducing the use of other CNS depressants and implement other fall risk strategies. Due to the potential for antipsychotic-induced hyponatremia and SIADH, sodium levels should be closely monitored when aripiprazole is initiated and after dose changes. According to the federal Omnibus Budget Reconciliation Act (OBRA) regulations in residents of long-term care facilities, antipsychotic therapy should only be initiated in a patient with behavioral or psychological symptoms of dementia (BPSD) when the patient is a danger to self or others or has symptoms due to mania or psychosis. For acute conditions persisting beyond 7 days, appropriate non-pharmacologic interventions must be attempted, unless clinically contraindicated and documented. OBRA provides general dosing guidance for antipsychotic treatment of BPSD. Antipsychotics are subject to periodic review for effectiveness, medical necessity, gradual dose reduction (GDR), or rationale for continued use. Refer to the OBRA guidelines for complete information.

Neonates, pregnancy, pregnancy testing

Aripiprazole is recommended for use during pregnancy only when the benefits to the mother outweigh the potential risks to the fetus. Animal studies have shown evidence of developmental toxicity, including possible teratogenicity, and an increase in stillbirths. Neonates exposed to antipsychotics during the third trimester of pregnancy are at risk for extrapyramidal and/or withdrawal symptoms following delivery. There have been reports of agitation, hypertonia, hypotonia, tremor, somnolence, respiratory distress and feeding disorder in these neonates. These complications have varied in severity and have ranged from self-limited to those requiring intensive care unit support and prolonged hospitalization. Neonates exhibiting signs or symptoms of extrapyramidal effects or withdrawal should be carefully monitored. The knowledge about long-term neurobehavioral effects in offspring is limited for all antipsychotic agents and requires further investigation. According to the American Psychiatric Association treatment guidelines for schizophrenia, consider pregnancy testing in women of childbearing potential prior to initiation of an antipsychotic. The National Pregnancy Registry for Psychiatric Medications is dedicated to evaluating the safety of psychiatric medications that may be taken by women during pregnancy to treat a wide range of mood, anxiety, or psychiatric disorders. The primary goal of this Registry is to determine the frequency of major malformations, such as heart defects, cleft lip, or neural tube defects, in babies exposed to various psychiatric drugs during pregnancy. While the research concentrates on atypical antipsychotics and antidepressant use, pregnant women using other psychiatric medications are encouraged to register. For more information, contact the registry at https://womensmentalhealth.org/clinical-and-research-programs/pregnancyregistry or by phone 1-866-961-2388. It is not known if antipsychotics, through their effect on prolactin, would affect labor or obstetric delivery.

Breast-feeding

According to the manufacturer, a decision should be made to discontinue breast-feeding or discontinue aripiprazole, taking into account the importance of drug therapy to the mother. Aripiprazole is excreted into human breast milk. Milk to plasma ratios of approximately 0.18 to 0.2 have been reported. However, there is a variation of about 11-fold in the relative infant dose of this drug (0.7% to 8.3%). In addition, aripiprazole can accumulate in an infant because of the long elimination half-life of the drug (approximately 75 hours) and the immature hepatic and renal functions of the developing infant. Due to individual variability in response to antipsychotics, it may be prudent to continue the existing regimen if ongoing treatment is deemed necessary during breast-feeding. However, because there is a lack of experience with aripiprazole during breast-feeding, other agents may be preferred especially while nursing a newborn or preterm infant. Alternate medications for consideration include atypical agents such as olanzapine or quetiapine. Data related to the safety of antipsychotics during breast-feeding are limited and chronic administration of any antipsychotic during breast-feeding should be avoided if possible. Regardless of the antipsychotic used, the nursing infant should be closely monitored for excessive drowsiness, lethargy, and developmental delays. Combination treatment with antipsychotics may increase the risk of these adverse events. Consider the benefits of breast-feeding, the risk of potential infant drug exposure, and the risk of an untreated or inadequately treated condition. If a breast-feeding infant experiences an adverse effect related to a maternally ingested drug, healthcare providers are encouraged to report the adverse effect to the FDA.

Phenylketonuria

Aripiprazole orally disintegrating tablets (i.e., Abilify Discmelt) should be used cautiously in patients with phenylketonuria, as the tablets contain aspartame, a source of phenylalanine. Each 10 mg orally disintegrating tablet contains 1.12 mg of phenylalanine and each 15 mg orally disintegrating tablet contains 1.68 mg of phenylalanine.

Magnetic resonance imaging (MRI)

Patients should be instructed to remove the Mycite topical patch, which is used with the aripiprazole tablet with sensor (Abilify Mycite tablet), before undergoing magnetic resonance imaging (MRI) and replace with a new patch as directed as soon as possible after the MRI. Metal components contained in the backing of some patch systems can overheat during an MRI scan and cause skin burns in the area where the patch is adhered. If there is skin irritation that occurs with the patch at anytime, instruct patients to remove the patch and notify their healthcare prescriber.

Ensure correct formulation selection

Medication errors, including substitution and dispensing errors, may occur when selecting between the distinct extended-release aripiprazole lauroxil intramuscular injections, Aristada and Aristada Initio. Dosing and medication errors may also possibly occur with Abilify Maintena injections (aripiprazole extended-release injections). Prescribers and health care professionals administering the drug should ensure correct formulation selection during prescribing and before administration. The various injections have distinct properties. For example, Aristada Initio is for single administration in contrast to Aristada which is a maintenance injection administered monthly, every 6 weeks, or every 8 weeks. Do not substitute Aristada Initio for Aristada since these products have different pharmacokinetic profiles.[60196]

ADVERSE REACTIONS

Severe

bradycardia / Rapid / 0.1-0.9

seizures / Delayed / 0-0.2

rhabdomyolysis / Delayed / 0-0.1

myocardial infarction / Delayed / 0-0.1

AV block / Early / 0-0.1

cardiac arrest / Early / 0-0.1

atrial fibrillation / Early / 0-0.1

atrial flutter / Early / 0-0.1

suicidal ideation / Delayed / Incidence not known

stroke / Early / Incidence not known

diabetic ketoacidosis / Delayed / Incidence not known

agranulocytosis / Delayed / Incidence not known

torsade de pointes / Rapid / Incidence not known

toxic epidermal necrolysis / Delayed / Incidence not known

anaphylactoid reactions / Rapid / Incidence not known

angioedema / Rapid / Incidence not known

Stevens-Johnson syndrome / Delayed / Incidence not known

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) / Delayed / Incidence not known

laryngospasm / Rapid / Incidence not known

tardive dyskinesia / Delayed / Incidence not known

neuroleptic malignant syndrome / Delayed / Incidence not known

SIADH / Delayed / Incidence not known

water intoxication / Delayed / Incidence not known

serotonin syndrome / Delayed / Incidence not known

Moderate

hyperglycemia / Delayed / 0-17.6

constipation / Delayed / 2.0-11.0

blurred vision / Early / 3.0-8.0

urinary incontinence / Early / 1.0-5.0

sinus tachycardia / Rapid / 2.0-2.0

myoclonia / Delayed / 0.1-1.0

peripheral edema / Delayed / 0-1.0

orthostatic hypotension / Delayed / 0.2-1.0

hyponatremia / Delayed / 0-1.0

memory impairment / Delayed / 0.1-0.9

delirium / Early / 0.1-0.9

hypotension / Rapid / 0.1-0.9

urinary retention / Early / 0.1-0.9

hypoglycemia / Early / 0.1-0.9

myasthenia / Delayed / 0.1-0.9

photophobia / Early / 0.1-0.9

dyspnea / Early / 0.1-0.9

elevated hepatic enzymes / Delayed / 0.1-0.9

chest pain (unspecified) / Early / 0.1-0.9

hypertension / Early / 0.1-0.9

palpitations / Early / 0.1-0.9

hypokalemia / Delayed / 0.1-0.9

impotence (erectile dysfunction) / Delayed / 0.1-0.9

complex sleep-related behaviors / Early / 0-0.1

hyperthermia / Delayed / 0-0.1

thrombocytopenia / Delayed / 0-0.1

jaundice / Delayed / 0-0.1

hepatitis / Delayed / 0-0.1

hyperbilirubinemia / Delayed / 0-0.1

angina / Early / 0-0.1

QT prolongation / Rapid / 0-0.1

priapism / Early / 0-0.1

hyperprolactinemia / Delayed / 0-0.1

confusion / Early / Incidence not known

impaired cognition / Early / Incidence not known

mania / Early / Incidence not known

impulse control symptoms / Delayed / Incidence not known

depression / Delayed / Incidence not known

dysphagia / Delayed / Incidence not known

fecal incontinence / Early / Incidence not known

diabetes mellitus / Delayed / Incidence not known

hypertriglyceridemia / Delayed / Incidence not known

hyperlipidemia / Delayed / Incidence not known

hypercholesterolemia / Delayed / Incidence not known

leukopenia / Delayed / Incidence not known

neutropenia / Delayed / Incidence not known

Mild

headache / Early / 0-27.0

weight gain / Delayed / 2.2-26.3

drowsiness / Early / 3.0-23.0

agitation / Early / 19.0-19.0

insomnia / Early / 0-18.0

fatigue / Early / 2.0-17.0

anxiety / Delayed / 17.0-17.0

nausea / Early / 8.0-15.0

vomiting / Early / 3.0-14.0

dizziness / Early / 3.0-10.0

dyspepsia / Early / 9.0-9.0

fever / Early / 4.0-9.0

pharyngitis / Delayed / 3.0-9.0

appetite stimulation / Delayed / 3.0-7.0

restlessness / Early / 1.0-6.0

hypersalivation / Early / 4.0-6.0

lethargy / Early / 3.0-5.0

xerostomia / Early / 5.0-5.0

dental pain / Delayed / 4.0-4.0

diarrhea / Early / 4.0-4.0

arthralgia / Delayed / 1.0-4.0

musculoskeletal pain / Early / 1.0-4.0

abdominal pain / Early / 3.0-3.0

cough / Delayed / 3.0-3.0

irritability / Delayed / 2.0-2.0

myalgia / Early / 2.0-2.0

epistaxis / Delayed / 2.0-2.0

rash / Early / 0.1-2.0

pruritus / Rapid / 0.1-1.0

libido decrease / Delayed / 0.1-0.9

gastroesophageal reflux / Delayed / 0.1-0.9

nocturia / Early / 0.1-0.9

nasal congestion / Early / 0.1-0.9

hyperhidrosis / Delayed / 0.1-0.9

photosensitivity / Delayed / 0.1-0.9

hirsutism / Delayed / 0.1-0.9

alopecia / Delayed / 0.1-0.9

syncope / Early / 0.2-0.5

somnambulism / Early / 0-0.1

libido increase / Delayed / 0-0.1

diplopia / Early / 0-0.1

orgasm dysfunction / Delayed / 0-0.1

mastalgia / Delayed / 0-0.1

gynecomastia / Delayed / 0-0.1

menstrual irregularity / Delayed / 0-0.1

amenorrhea / Delayed / 0-0.1

asthenia / Delayed / 1.0

weight loss / Delayed / 1.0

anorexia / Delayed / 1.0

injection site reaction / Rapid / 1.0

psychomotor impairment / Early / Incidence not known

hypothermia / Delayed / Incidence not known

hiccups / Early / Incidence not known

urticaria / Rapid / Incidence not known

skin irritation / Early / Incidence not known

polydipsia / Early / Incidence not known

DRUG INTERACTIONS

Abarelix: (Major) Abarelix carries an established risk for QT prolongation. Prescribers need to weigh the potential benefits and risks of abarelix use in patients with prolonged QT syndrome or in patients taking other drugs that may prolong the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Abiraterone: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a moderate CYP2D6 inhibitor such as abiraterone. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 inhibitor and abiraterone should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 inhibitor and abiraterone for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a moderate CYP2D6 inhibitor alone.

Acarbose: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Acebutolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Acetaminophen; Butalbital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Acetaminophen; Butalbital; Caffeine: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Acetaminophen; Butalbital; Caffeine; Codeine: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination. (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Acetaminophen; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Acetaminophen; Codeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Acetaminophen; Dextromethorphan; Doxylamine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.

Acetaminophen; Dichloralphenazone; Isometheptene: (Moderate) Drugs that can cause CNS depression, including dichloralphenazone, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness if used concomitantly with atypical antipsychotics.

Acetaminophen; Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Acetaminophen; Oxycodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Acetaminophen; Pentazocine: (Moderate) Coadministration of pentazocine with atypical antipsychotics may result in additive respiratory and CNS depression and anticholinergic effects, such as urinary retention and constipation. Use pentazocine with caution in any patient receiving medication with CNS depressant and/or anticholinergic activity.

Acetaminophen; Tramadol: (Moderate) Concomitant use of tramadol with aripiprazole may cause excessive sedation, somnolence, and increased risk of seizure. Limit the use of tramadol with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and seizures.

Aclidinium; Formoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Acrivastine; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Albiglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Albuterol: (Minor) Use caution if administering aripiprazole with other drugs that may cause QT prolongation, including the short-acting beta-agonists (SABAs). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. SABAs may rarely cause adverse cardiovascular effects such as QT prolongation, usually at higher doses and/or when associated with hypokalemia.

Albuterol; Ipratropium: (Minor) Use caution if administering aripiprazole with other drugs that may cause QT prolongation, including the short-acting beta-agonists (SABAs). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. SABAs may rarely cause adverse cardiovascular effects such as QT prolongation, usually at higher doses and/or when associated with hypokalemia.

Aldesleukin, IL-2: (Moderate) Because aripiprazole is metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as aldesleukin, IL-2. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions, particularly CNS effects. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Alfentanil: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Alfuzosin: (Moderate) Use caution when administering alfuzosin with aripiprazole due to the potential for QT prolongation. Alfuzosin may prolong the QT interval in a dose-dependent manner. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Aliskiren; Amlodipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Aliskiren; Amlodipine; Hydrochlorothiazide, HCTZ: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Alogliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Alogliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Alogliptin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Alpha-glucosidase Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Alprazolam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Amifampridine: (Major) Carefully consider the need for concomitant treatment with atypical antipsychotics and amifampridine, as coadministration may increase the risk of seizures. If coadministration occurs, closely monitor patients for seizure activity. Seizures have been observed in patients without a history of seizures taking amifampridine at recommended doses. Atypical antipsychotics may increase the risk of seizures.

Amiodarone: (Major) Because both amiodarone and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as amiodarone. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of mild to moderate CYP3A4 and CYP2D6 inhibitors.

Amisulpride: (Major) Monitor ECGs for QT prolongation when amisulpride is administered with aripiprazole. Amisulpride causes dose- and concentration- dependent QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Amitriptyline: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Amitriptyline; Chlordiazepoxide: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Amlodipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Atorvastatin: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Benazepril: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Celecoxib: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as celexocib. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Hydrochlorothiazide, HCTZ; Olmesartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Hydrochlorothiazide, HCTZ; Valsartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Olmesartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Telmisartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amlodipine; Valsartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Amobarbital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Amoxapine: (Moderate) Use caution during co-administration of amoxapine and aripiprazole. Amoxapine exhibits some antipsychotic activity and may increase the risk of tardive dyskinesia or neuroleptic malignant syndrome (NMS) when antipsychotics are given concurrently. CNS effects, orthostatic hypotension, anticholinergic effects, and lowering of seizure threshold are potential problems with the combined use of amoxapine and antipsychotics.

Amoxicillin; Clarithromycin; Lansoprazole: (Major) Because both clarithromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Amoxicillin; Clarithromycin; Omeprazole: (Major) Because both clarithromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Amprenavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as amprenavir. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Anagrelide: (Moderate) Caution is advised if aripiprazole is administered with anagrelide. Torsades de pointes (TdP) and ventricular tachycardia have been reported with anagrelide. In addition, dose-related increases in mean QTc and heart rate were observed in healthy subjects. A cardiovascular examination, including an ECG, should be obtained in all patients prior to initiating anagrelide therapy. Monitor patients during anagrelide therapy for cardiovascular effects and evaluate as necessary. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.

Angiotensin II receptor antagonists: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Angiotensin-converting enzyme inhibitors: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Apalutamide: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as apalutamide, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When apalutamide is discontinued, the aripiprazole dose in adults should be reduced to the original dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with apalutamide when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with apalutamide, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if apalutamide is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Apomorphine: (Moderate) Use apomorphine and aripiprazole with caution due to a risk for QT prolongation and sedation. Apomorphine and aripiprazole may decrease the effectiveness of each other due to opposing effects on dopamine. Additive CNS effects are also possible. Dose-related QTc prolongation is associated with therapeutic apomorphine exposure. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In general, atypical antipsychotics are less likely to interfere with Parkinson's disease treatments than traditional antipsychotics. Monitor for movement disorders, unusual changes in moods or behavior, sedation, fast, irregular heartbeat, and diminished effectiveness of either agent during coadministration.

Aprepitant, Fosaprepitant: (Moderate) Caution is recommended during coadministration of aripiprazole, a partial CYP3A4 substrate, and aprepitant. A 3-day course of oral aprepitant with another CYP3A4 substrate resulted in an increased AUC of the substrate during the initial days following treatment (e.g., 4 days), then the substrate AUC declined between Days 8 and 15. Single doses of oral aprepitant or IV fosaprepitant have demonstrated weak CYP3A4 inhibition that is not considered clinically relevant. If these agents are coadministered, the patient should be carefully monitored for aripiprazole-related adverse reactions such as QT prolongation or torsade de pointes (TdP). In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Arformoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Armodafinil: (Moderate) In vitro data indicate that armodafinil is an inducer of CYP3A4/5 isoenzymes. Decreased blood levels of aripiprazole are expected when the drug is coadministered with inducers of CYP3A4, such as armodafinil. A dosage adjustment of aripiprazole may be necessary when these drugs are used concomitantly, and conversely, when armodafinil is discontinued in a patient taking aripiprazole. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Arsenic Trioxide: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. If possible, drugs that are known to prolong the QT interval should be discontinued prior to initiating arsenic trioxide therapy. QT prolongation should be expected with the administration of arsenic trioxide. Torsade de pointes (TdP) and complete atrioventricular block have been reported.

Artemether; Lumefantrine: (Major) Because both artemether; lumefantrine and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving potent inhibitors of CYP2D6 such as lumefantrine. Adults receiving 300 mg or 400 mg of Abilify Maintena should have a dose reduction to 200 mg or 300 mg, respectively, during coadministration of a potent CYP2D6 inhibitor if used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.

Asenapine: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Asenapine is an atypical antipsychotics with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.

Aspirin, ASA; Butalbital; Caffeine: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Aspirin, ASA; Butalbital; Caffeine; Codeine: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination. (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Aspirin, ASA; Caffeine; Dihydrocodeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Aspirin, ASA; Carisoprodol; Codeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Aspirin, ASA; Oxycodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Atazanavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as atazanavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Atazanavir; Cobicistat: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as atazanavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified. (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Atenolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Atenolol; Chlorthalidone: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Atomoxetine: (Moderate) Use caution when administering atomoxetine and aripiprazole concurrently. QT prolongation has occurred during therapeutic use and following overdose for both aripiprazole and atomoxetine.

Atropine; Difenoxin: (Moderate) Concurrent administration of diphenoxylate/difenoxin with aripiprazole can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.

Atropine; Diphenoxylate: (Moderate) Concurrent administration of diphenoxylate/difenoxin with aripiprazole can potentiate the CNS-depressant effects of diphenoxylate/difenoxin. Use caution during coadministration.

Atropine; Hyoscyamine; Phenobarbital; Scopolamine: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Azithromycin: (Major) Avoid coadministration of azithromycin with aripiprazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. QT prolongation and torsade de pointes (TdP) have been spontaneously reported during azithromycin postmarketing surveillance. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Barbiturates: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Bedaquiline: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Bedaquiline has been reported to prolong the QT interval. Prior to initiating bedaquiline, obtain serum electrolyte concentrations and a baseline ECG. An ECG should also be performed at least 2, 12, and 24 weeks after starting bedaquiline therapy. Coadministration with other QT prolonging drugs may result in additive or synergistic prolongation of the QT interval.

Belladonna Alkaloids; Ergotamine; Phenobarbital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Belladonna; Opium: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Bendroflumethiazide; Nadolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Benzhydrocodone; Acetaminophen: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Benzodiazepines: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Berotralstat: (Major) Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients receiving berotralstat. Monitor for aripiprazole-related adverse reactions during concurrent use of berotralstat. Adults receiving berotralstat for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of moderate CYP2D6/CYP3A4 inhibitors. Aripiprazole is a substrate for CYP2D6 and CYP3A4; berotralstat is a moderate CYP2D6 and moderate CYP3A4 inhibitor.

Beta-adrenergic blockers: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Betaxolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Bexarotene: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as bexarotene may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Bicalutamide: (Major) Monitor for aripiprazole-related adverse reactions during concurrent use of bicalutamide. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP2D6 inhibitor. Adults receiving a combination of a CYP2D6 inhibitor and bicalutamide for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor alone. Aripiprazole is a substrate for CYP2D6 and CYP3A4; bicalutamide is a weak CYP3A4 inhibitor.

Bismuth Subcitrate Potassium; Metronidazole; Tetracycline: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include aripiprazole.

Bismuth Subsalicylate; Metronidazole; Tetracycline: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include aripiprazole.

Bisoprolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Bisoprolol; Hydrochlorothiazide, HCTZ: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Boceprevir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as boceprevir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. Patients receiving a strong CYP3A4 inhibitor for more than 14 days should have their Aristada dose reduced to the next lower strength. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada injection who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In patients receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Bosentan: (Moderate) Bosentan is an inducer of CYP3A4, and may decrease plasma concentrations of drugs metabolized by this enzyme including aripiprazole. If bosentan and aripiprazole are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in oral aripiprazole dosage may be needed in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a moderate CYP3A4 inducer such as bosentan.

Brexpiprazole: (Contraindicated) Concurrent use of brexpiprazole and aripiprazole should be avoided. Aripiprazole and brexpiprazole are both atypical antipsychotics of the dopamine system stabilizer subclass and have similar mechanisms of action. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use.

Brimonidine; Timolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Bromocriptine: (Moderate) The effectiveness of bromocriptine may be reduced by most of the atypical antipsychotics, via their action as dopamine antagonists. Monitor the patient for reduced response to bromocriptine. The atypical antipsychotics elevate prolactin to various degrees. Atypical antipsychotics may also aggravate diabetes mellitus and cause metabolic changes including hyperglycemia; use caution if bromocriptine is taken for diabetes. If bromocriptine is taken for diabetes, monitor for worsening glycemic control.

Brompheniramine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Dextromethorphan; Guaifenesin: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Dextromethorphan; Phenylephrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Brompheniramine; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Budesonide; Formoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Budesonide; Glycopyrrolate; Formoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Buprenorphine: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of aripiprazole and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of aripiprazole and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.

Buprenorphine; Naloxone: (Major) Due to the potential for QT prolongation and additive CNS depressant effects, cautious use and close monitoring are advisable if concurrent use of aripiprazole and buprenorphine is necessary. Buprenorphine has been associated with QT prolongation and has a possible risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. FDA-approved labeling for some buprenorphine products recommend avoiding use with Class 1A and Class III antiarrhythmic medications while other labels recommend avoiding use with any drug that has the potential to prolong the QT interval. If concurrent use of aripiprazole and buprenorphine is necessary, consider a dose reduction of one or both drugs. Hypotension, profound sedation, coma, respiratory depression, or death may occur during co-administration of buprenorphine and other CNS depressants. Prior to concurrent use of buprenorphine in patients taking a CNS depressant, assess the level of tolerance to CNS depression that has developed, the duration of use, and the patient's overall response to treatment. Evaluate the patient's use of alcohol or illicit drugs. It is recommended that the injectable buprenorphine dose be halved for patients who receive other drugs with CNS depressant effects; for the buprenorphine transdermal patch, start with the 5 mcg/hour patch. Monitor patients for sedation or respiratory depression.

Bupropion: (Major) Because aripiprazole is partially metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP2D6 such as bupropion. Closely monitor for evidence of aripiprazole adverse events. Additionally, bupropion is associated with a dose-related risk of seizure; antipsychotics may increase this risk. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if a strong CYP2D6 inhibitor is used for more than 14 days. Adults receiving 662 mg or 882 mg of Aristada every 4 weeks should have their Aristada dose reduced to the next lower strength if a strong CYP2D6 inhibitor is used for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.

Bupropion; Naltrexone: (Major) Because aripiprazole is partially metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP2D6 such as bupropion. Closely monitor for evidence of aripiprazole adverse events. Additionally, bupropion is associated with a dose-related risk of seizure; antipsychotics may increase this risk. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if a strong CYP2D6 inhibitor is used for more than 14 days. Adults receiving 662 mg or 882 mg of Aristada every 4 weeks should have their Aristada dose reduced to the next lower strength if a strong CYP2D6 inhibitor is used for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.

Buspirone: (Moderate) The combination of buspirone and CNS depressants like the antipsychotics can increase the risk for drowsiness, sedation, and dizziness.

Butabarbital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Butorphanol: (Moderate) Concomitant use of butorphanol with other CNS depressants, such as aripiprazole, can potentiate the effects of butorphanol on respiratory depression, CNS depression, and sedation.

Cabergoline: (Moderate) Cabergoline should not be coadministered with aripiprazole due to mutually antagonistic effects on dopaminergic function. The dopamine antagonist action of aripiprazole may diminish the prolactin-lowering ability of cabergoline while the dopamine agonist effects of cabergoline may exacerbate a psychotic disorder, reducing the effectiveness of antipsychotics such as aripiprazole.

Cabotegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with aripiprazole as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Canagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Canagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Cannabidiol: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cannabidiol and aripiprazole. Concurrent use may result in additive CNS depression.

Carbamazepine: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as carbamazepine, is added to aripiprazole therapy. Concurrent use of carbamazepine (200 mg twice daily) and aripiprazole (30 mg/day) resulted in a decrease in Cmax and AUC values of aripiprazole and its active metabolite by about 70%. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is discontinued, the oral aripiprazole dose should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a strong CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dose adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Carbetapentane; Chlorpheniramine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Chlorpheniramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Diphenhydramine; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Guaifenesin: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Guaifenesin; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Phenylephrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Phenylephrine; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbetapentane; Pseudoephedrine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics.

Carbetapentane; Pyrilamine: (Moderate) Drowsiness has been reported during administration of carbetapentane. An enhanced CNS depressant effect may occur when carbetapentane with other CNS depressants including atypical antipsychotics. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbidopa; Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Carbidopa; Levodopa; Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease. (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Carbinoxamine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbinoxamine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbinoxamine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression. (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbinoxamine; Phenylephrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Carbinoxamine; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Cariprazine: (Moderate) The risk of adverse effects may be increased during concurrent use of cariprazine with other antipsychotics, such as aripiprazole. Similar to other antipsychotics, cariprazine administration has been associated with drowsiness, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. The incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, but the risk appears to be increased.

Carteolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Carvedilol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Celecoxib: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as celexocib. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Cenobamate: (Moderate) Monitor for excessive sedation and somnolence during coadministration of cenobamate and aripiprazole. Concurrent use may result in additive CNS depression.

Central-acting adrenergic agents: (Minor) Due to aripiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.

Ceritinib: (Major) Avoid use of aripiprazole with ceritinib if possible due to the risk of QT prolongation. Ceritinib causes concentration-dependent QT prolongation. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose. If concurrent use is unavoidable, periodically monitor ECGs and electrolytes; an interruption of ceritinib therapy, dose reduction, or discontinuation of therapy may be necessary if QT prolongation occurs. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as ceritinib. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if ceritinib is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of ceritinib for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving ceritinib or patients receiving a combination of ceritinib and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving ceritinib should have a dose reduction to 200 mg/month IM. Patients receiving a combination of ceritinib and a CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving ceritinib for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and ceritinib for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and ceritinib because the dose of Aristada Initio cannot be modified.

Cetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.

Cetirizine; Pseudoephedrine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.

Cetrorelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to any of the gonadotropin-releasing hormone (GnRH) analogs including cetrorelix.

Charcoal: (Major) Aripiprazole absorption is reduced when activated charcoal is coadministered within an hour of a 15 mg dosage, resulting in a decrease in aripiprazole AUC and Cmax by roughly 50%. Concomitant administration of aripiprazole with activated charcoal is not recommended. However, administration of activated charcoal may be appropriate in certain aripiprazole overdose situations.

Chlophedianol; Dexchlorpheniramine; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Chloramphenicol: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as chloramphenicol. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Chlorcyclizine: (Moderate) Additive CNS effects like drowsiness may be seen when combining sedating H1-blockers with atypical antipsychotics.

Chlordiazepoxide: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Chlordiazepoxide; Clidinium: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Chloroquine: (Major) Avoid coadministration of chloroquine with aripiprazole due to the increased risk of QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Chloroquine is associated with an increased risk of QT prolongation and torsade de pointes (TdP); the risk of QT prolongation is increased with higher chloroquine doses. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Chlorpheniramine; Codeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Dihydrocodeine; Phenylephrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Dihydrocodeine; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpheniramine; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Chlorpromazine: (Major) Concurrent use of chlorpromazine with aripiprazole should be approached with caution and careful monitoring due to a possible risk o f QT prolongation. In addition, chlorpromazine is a CYP2D6 inhibitor. A dosage reduction of aripiprazole may be clinically warranted in patients receiving chlorpromazine and caution is advisable when aripiprazole is given in combination with other antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.

Cimetidine: (Moderate) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as cimetidine. Alternate H2-antagonist therapy that may not interact should be considered. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor.

Cinacalcet: (Major) Because aripiprazole is partially metabolized by CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving potent inhibitors of CYP2D6 such as cinacalcet. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if a potent CYP2D6 inhibitor is used for more than 14 days. Adults receiving 662 mg or 882 mg of Aristada every 4 weeks should have their Aristada dose reduced to the next lower strength if a potent CYP2D6 inhibitor is used for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified.

Ciprofloxacin: (Moderate) Caution is advised when administering aripiprazole with ciprofloxacin, as use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, rare cases of QT prolongation and TdP have been reported with ciprofloxacin during post-marketing surveillance.

Cisapride: (Contraindicated) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. QT prolongation and ventricular arrhythmias, including torsade de pointes (TdP) and death, have been reported with cisapride. Because of the potential for QT prolongation or torsade de pointes (TdP), concurrent use is contraindicated.

Citalopram: (Major) Because both citalopram and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), this combination should be used cautiously and with close monitoring. In addition, citalopram is a weak inhibitor of CYP2D6, and increased plasma concentrations of CYP2D6 substrates, such as aripiprazole, may occur. Decreased metabolism of aripiprazole may lead to clinically important adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.

Clarithromycin: (Major) Because both clarithromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as clarithromycin. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Clemastine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Clobazam: (Moderate) Benzodiazepines such as clobazam should be combined cautiously with antipsychotics because of the potential for additive CNS depressant effects, and reduced effectiveness of clobazam as an anticonvulsant due to the possible lowering of the seizure threshold by antipsychotics.

Clofazimine: (Major) Monitor ECGs for QT prolongation when clofazimine is administered with aripiprazole. QT prolongation and torsade de pointes have been reported in patients receiving clofazimine in combination with QT prolonging medications. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Clomipramine: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Clonazepam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Clorazepate: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Clozapine: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Clozapine is an atypical antipsychotic with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.

Cobicistat: (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Codeine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Codeine; Guaifenesin: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Codeine; Phenylephrine; Promethazine: (Moderate) Both promethazine and aripiprazole are associated with a possible risk for QT prolongation; therefore, caution is advisable during coadministration. In addition, because aripiprazole is partially metabolized by CYP2D6, patients should be monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as promethazine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Coadministration of phenothiazines such as promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Codeine; Promethazine: (Moderate) Both promethazine and aripiprazole are associated with a possible risk for QT prolongation; therefore, caution is advisable during coadministration. In addition, because aripiprazole is partially metabolized by CYP2D6, patients should be monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as promethazine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Coadministration of phenothiazines such as promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

COMT inhibitors: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Conivaptan: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as conivaptan. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Crizotinib: (Major) Avoid coadministration of crizotinib with aripiprazole due to the risk of QT prolongation. Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may also occur if the drug is coadministered with moderate inhibitors of CYP3A such as crizotinib. If concomitant use is unavoidable, monitor ECGs for QT prolongation and monitor electrolytes. An interruption of therapy, dose reduction, or discontinuation of therapy may be necessary for crizotinib patients if QT prolongation occurs. The patient should also be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. Crizotinib has been associated with concentration-dependent QT prolongation. Prolongation of the QT interval has occurred during therapeutic use of aripiprazole as well as following overdose.

Cyclizine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Cyproheptadine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Dacomitinib: (Major) Dacomitinib, a strong inhibitor of CYP2D6, may decrease the metabolism of CYP2D6 substrates such as aripiprazole. Decreased metabolism of aripiprazole may lead to adverse effects such as extrapyramidal symptoms, QT prolongation, and torsade de pointes (TdP). The manufacturer of aripiprazole recommends that the oral aripiprazole dose be reduced to one-half of the usual dose when coadministered with strong CYP2D6 inhibitors. Adults receiving 300 mg or 400 mg of Abilify Maintena should have a dose reduction to 200 mg or 300 mg, respectively, during coadministration of a strong CYP2D6 inhibitor if used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP2D6 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP2D6 inhibitors because the dose of Aristada Initio cannot be modified. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.

Danazol: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as danazol. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Dapagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Dapagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Dapagliflozin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Darifenacin: (Moderate) Carefully monitor for aripiprazole-related adverse reactions if coadministered with darifenacin. Darifenacin is a moderate CYP2D6 inhibitor and may increase exposure to aripiprazole, a CYP2D6 substrate. In addition, because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Darunavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Darunavir; Cobicistat: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified. (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Darunavir; Cobicistat; Emtricitabine; Tenofovir alafenamide: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as darunavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified. (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Dasabuvir; Ombitasvir; Paritaprevir; Ritonavir: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ritonavir. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor, such as ritonavir, should have a dose reduction to 200 mg/month IM. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Dasatinib: (Moderate) Monitor for evidence of QT prolongation if aripiprazole and dasatinib are coadministered. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In vitro studies have shown that dasatinib has the potential to prolong the QT interval.

Degarelix: (Moderate) Consider whether the benefits of androgen deprivation therapy outweigh the potential risks in patients receiving aripiprazole as concurrent use may increase the risk of QT prolongation. Androgen deprivation therapy (i.e., degarelix) may prolong the QT/QTc interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Delavirdine: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as delavirdine. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as delavirdine, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Desipramine: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Deutetrabenazine: (Moderate) The risk of QT prolongation may be increased with coadministration of deutetrabenazine and aripiprazole. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Deutetrabenazine may prolong the QT interval, but the degree of QT prolongation is not clinically significant when deutetrabenazine is administered within the recommended dosage range. Monitor for signs and symptoms of neuroleptic malignant syndrome (NMS), restlessness, and agitation. If NMS is diagnosed, immediately discontinue deutetrabenazine, and provide intensive symptomatic treatment and medical monitoring. Recurrence of NMS has been reported with resumption of drug therapy. If akathisia or parkinsonism develops during treatment, the deutetrabenazine dose should be reduced; discontinuation may be required. Deutetrabenazine is a reversible, dopamine depleting drug and aripiprazole is a partial dopamine agonist. The risk for parkinsonism, NMS, or akathisia may be increased with concomitant administration. Monitor for excessive sedation and somnolence during coadministration of aripiprazole and deutetrabenazine. Concurrent use may result in additive CNS depression.

Dexamethasone: (Moderate) Because aripiprazole is metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as dexamethasone may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during concurrent use of a mild or moderate CYP3A4 inducer.

Dexchlorpheniramine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Dexmethylphenidate: (Moderate) Atypical antipsychotics and dexmethylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Dexmethylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of dexmethylphenidate.

Dextromethorphan; Promethazine: (Moderate) Both promethazine and aripiprazole are associated with a possible risk for QT prolongation; therefore, caution is advisable during coadministration. In addition, because aripiprazole is partially metabolized by CYP2D6, patients should be monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as promethazine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Coadministration of phenothiazines such as promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures.

Dextromethorphan; Quinidine: (Contraindicated) Avoid use of aripiprazole with quinidine unless the benefit outweighs the risk. Quinidine is generally contraindicated with other drugs that prolong the QT interval and are metabolized by CYP2D6, such as aripiprazole, as the effects on the QT interval may be increased. Manufacturer recommendations for this combination have varied. Do not use the combination product of dextromethorphan; quinidine with aripiprazole. The manufacturers of aripiprazole products do not contraindicate use of quinidine, but recommend dosage adjustments of aripiprazole when used with potent CYP2D6 inhibitors, such as quinidine. For example, the oral aripiprazole dose should be reduced by 50%. Injectable forms of aripiprazole require dose adjustment when the potent CYP2D6 inhibitor will be used for more than 14 days. See the manufacturer prescribing information for detailed recommendations. Both aripiprazole and quinidine are associated with QT prolongation. Increased aripiprazole exposure is likely when a potent CYP2D6 inhibitor like quinidine is used concurrently. In one evaluation, concurrent use of quinidine and oral aripiprazole resulted in an increase in the AUC of aripiprazole of 112% and a decrease in the AUC of its active metabolite by 35%.

Diazepam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Diazoxide: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Dihydrocodeine; Guaifenesin; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Diltiazem: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as diltiazem. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. Due to aripiprazole's antagonism at alpha 1-adrenergic receptors, the drug may enhance the hypotensive effects of alpha-blockers and other antihypertensive agents.

Dimenhydrinate: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Dipeptidyl Peptidase-4 Inhibitors: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Diphenhydramine; Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Disopyramide: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Disopyramide administration is associated with QT prolongation and torsades de pointes (TdP). Aripiprazole should be used cautiously and with close monitoring with disopyramide.

Dofetilide: (Major) Coadministration of dofetilide and aripiprazole is not recommended as concurrent use may increase the risk of QT prolongation. Dofetilide, a Class III antiarrhythmic agent, is associated with a well-established risk of QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Dolasetron: (Moderate) Administer dolasetron with caution in combination with aripiprazole as concurrent use may increase the risk of QT prolongation. Dolasetron has been associated with a dose-dependent prolongation in the QT, PR, and QRS intervals on an electrocardiogram. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Dolutegravir; Rilpivirine: (Moderate) Caution is advised when administering rilpivirine with aripiprazole as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Donepezil: (Moderate) Use donepezil with caution in combination with aripiprazole. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Donepezil; Memantine: (Moderate) Use donepezil with caution in combination with aripiprazole. Case reports indicate that QT prolongation and torsade de pointes (TdP) can occur during donepezil therapy. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Dorzolamide; Timolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Doxazosin: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Doxepin: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Doxylamine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.

Doxylamine; Pyridoxine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics.

Dronabinol: (Moderate) Drugs that can cause CNS depression such as dronabinol, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.

Dronedarone: (Contraindicated) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Dronedarone administration is associated with a dose-related increase in the QTc interval. The increase in QTc is approximately 10 milliseconds at doses of 400 mg twice daily (the FDA-approved dose) and up to 25 milliseconds at doses of 1600 mg twice daily. Although there are no studies examining the effects of dronedarone in patients receiving other QT prolonging drugs, coadministration of such drugs may result in additive QT prolongation. The concomitant use of dronedarone with other drugs that prolong the QTc may induce Torsade de Pointes (TdP) and is contraindicated.

Droperidol: (Major) According to the manufacturer of droperidol, any drug known to have the potential to prolong the QT interval should not be used together with droperidol. The product labeling contains a boxed warning regarding the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. If concurrent use is unavoidable, extreme caution is recommended.

Dulaglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Duloxetine: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, increased aripiprazole plasma concentrations may occur during concurrent use of moderate inhibitors of CYP2D6, such as duloxetine. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.

Efavirenz: (Moderate) Consider alternatives to efavirenz when coadministering with aripiprazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, decreased aripiprazole blood levels are expected when aripiprazole is coadministered with inducers of CYP3A4, such as efavirenz. Monitor the patient carefully for toxicity and efficacy if these agents are used in combination. Dosage adjustments of aripiprazole may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Efavirenz; Emtricitabine; Tenofovir: (Moderate) Consider alternatives to efavirenz when coadministering with aripiprazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, decreased aripiprazole blood levels are expected when aripiprazole is coadministered with inducers of CYP3A4, such as efavirenz. Monitor the patient carefully for toxicity and efficacy if these agents are used in combination. Dosage adjustments of aripiprazole may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Efavirenz; Lamivudine; Tenofovir Disoproxil Fumarate: (Moderate) Consider alternatives to efavirenz when coadministering with aripiprazole as concurrent use may increase the risk of QT prolongation. QTc prolongation has been observed with the use of efavirenz. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In addition, decreased aripiprazole blood levels are expected when aripiprazole is coadministered with inducers of CYP3A4, such as efavirenz. Monitor the patient carefully for toxicity and efficacy if these agents are used in combination. Dosage adjustments of aripiprazole may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Elagolix: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration of a CYP3A4 inducer, such as elagolix. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Elagolix; Estradiol; Norethindrone acetate: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration of a CYP3A4 inducer, such as elagolix. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Elbasvir; Grazoprevir: (Moderate) Administering aripiprazole with grazoprevir may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and grazoprevir is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.

Eliglustat: (Major) Coadminister aripiprazole and eliglustat cautiously and with close monitoring. Eliglustat is predicted to cause PR, QRS, and/or QT prolongation at significantly elevated plasma concentrations and aripiprazole has the potential for QT prolongation with both therapeutic use and overdose. In addition, because aripiprazole is partially metabolized by CYP2D6, increased aripiprazole plasma concentrations may occur during concurrent use of CYP2D6 inhibitors such as eliglustat. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Alafenamide: (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Elvitegravir; Cobicistat; Emtricitabine; Tenofovir Disoproxil Fumarate: (Major) The plasma concentrations of aripiprazole, a CYP3A4 and CYP2D6 substrate, may be elevated when administered concurrently with cobicistat, a CYP2D6 inhibitor and strong CYP3A4 inhibitor. The manufacturer of aripiprazole recommends that patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor, such as cobicistat, for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Empagliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Empagliflozin; Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Empagliflozin; Linagliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Empagliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Emtricitabine; Rilpivirine; Tenofovir alafenamide: (Moderate) Caution is advised when administering rilpivirine with aripiprazole as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Emtricitabine; Rilpivirine; Tenofovir disoproxil fumarate: (Moderate) Caution is advised when administering rilpivirine with aripiprazole as concurrent use may increase the risk of QT prolongation. Supratherapeutic doses of rilpivirine (75 to 300 mg/day) have caused QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Enalapril; Felodipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Encorafenib: (Major) Avoid coadministration of encorafenib and aripiprazole due to QT prolongation. If concurrent use cannot be avoided, monitor ECGs for QT prolongation and monitor electrolytes; correct hypokalemia and hypomagnesemia prior to treatment. Encorafenib is associated with dose-dependent prolongation of the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Entacapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Entrectinib: (Major) Avoid coadministration of entrectinib with aripiprazole due to the risk of QT prolongation. Entrectinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Enzalutamide: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as enzalutamide, is added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is discontinued, the aripiprazole dose should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a strong CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer for more than 14 days, no dose adjustment is necessary for the 662 mg or the 882 mg dose; increase the 441 mg dose to 662 mg. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Eplerenone: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Epoprostenol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Eribulin: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Eribulin has been associated with QT prolongation. If eribulin and another drug that prolongs the QT interval must be coadministered, ECG monitoring is recommended; closely monitor the patient for QT interval prolongation.

Ertugliflozin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Ertugliflozin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Ertugliflozin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Erythromycin: (Major) Because both erythromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as erythromycin. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Erythromycin; Sulfisoxazole: (Major) Because both erythromycin and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, because aripiprazole is partially metabolized by CYP3A4, increased aripiprazole blood levels may occur when the drug is coadministered with inhibitors of CYP3A4 such as erythromycin. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Escitalopram: (Moderate) Monitor for aripiprazole-related adverse reactions and QT prolongation if aripiprazole is administered with escitalopram. Increased aripiprazole plasma concentrations may occur during concurrent use of inhibitors of CYP2D6, such as escitalopram. In patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed. Escitalopram is a CYP2D6 inhibitor that has been associated with a risk of QT prolongation and torsade de pointes (TdP). Aripiprazole is a CYP2D6 and CYP3A4 substrate; QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Esketamine: (Moderate) Closely monitor patients receiving esketamine and aripiprazole for sedation and other CNS depressant effects. Instruct patients who receive a dose of esketamine not to drive or engage in other activities requiring alertness until the next day after a restful sleep.

Eslicarbazepine: (Moderate) In vivo studies suggest eslicarbazepine is an inducer of CYP3A4. Coadministration of CYP3A4 substrates, such as aripiprazole, may result in decreased serum concentrations of the substrate. Monitor for decreased efficacy of aripiprazole if coadministered with eslicarbazepine. Dosage adjustments of aripirazole may be necessary. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Esmolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Estazolam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Eszopiclone: (Moderate) A reduction in the dose of eszopiclone should be considered during co-administration of other CNS depressants, such as antipsychotics, to minimize additive sedative effects. In addition, the risk of next-day psychomotor impairment is increased during co-administration of eszopiclone and other CNS depressants, which may decrease the ability to perform tasks requiring full mental alertness such as driving. Antipsychotics with a higher incidence of sedation, such as olanzapine, clozapine, quetiapine, lurasidone, chlorpromazine, and thioridazine, are more likely to interact with eszopiclone. In one evaluation, concurrent use of eszopiclone and olanzapine reduced psychomotor function as measured by the Digit Symbol Substitution Test (DSST).

Ethanol: (Moderate) Alcohol may potentiate the CNS effects of the atypical antipsychotics, which have the potential to cause increased sedation, or to impair judgment, thinking, or motor skills. Patients should be appropriately cautioned.

Ethotoin: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when potent CYP3A4 inducers, such as phenytoin or other hydantoins, are added to aripiprazole therapy. Carefully monitor the patient for evidence of a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the oral aripiprazole dose in adults should be reduced to the previous dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Etravirine: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during use of a CYP3A4 inducer, such as etravirine. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Everolimus: (Major) Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response if coadministration with everolimus is necessary; monitor for aripiprazole-related adverse reactions. Adults receiving everolimus for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Aripiprazole is a substrate for CYP2D6 and CYP3A4; everolimus is a weak CYP3A4 inhibitor as well as a competitive inhibitor of CYP2D6.

Exenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Ezogabine: (Moderate) Aripiprazole should be used cautiously with ezogabine as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Ezogabine has been associated with QT prolongation.

Famotidine: (Minor) Coadministration of aripiprazole with famotidine decreases aripiprazole's solubility and rate of absorption. The Cmax of aripiprazole and the metabolite dehydroaripiprazole are decreased by 37% and 21%, respectively, and the AUC of aripiprazole and the dehydroaripiprazole metabolite are decreased by 13% and 15%, respectively. This interaction does not appear to cause clinically relevant effects and therefore no dosage adjustments are required.

Famotidine; Ibuprofen: (Minor) Coadministration of aripiprazole with famotidine decreases aripiprazole's solubility and rate of absorption. The Cmax of aripiprazole and the metabolite dehydroaripiprazole are decreased by 37% and 21%, respectively, and the AUC of aripiprazole and the dehydroaripiprazole metabolite are decreased by 13% and 15%, respectively. This interaction does not appear to cause clinically relevant effects and therefore no dosage adjustments are required.

Fedratinib: (Major) Reduce the oral aripiprazole dose to one-quarter (25%) of the usual dose in patients receiving fedratinib as aripiprazole exposure and adverse effects may be increased. Adults receiving this combination for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during concurrent use. Aripiprazole is a CYP3A4 and CYP2D6 substrate; fedratinib is a moderate inhibitor of both CYP3A4 and CYP2D6.

Felodipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Fenfluramine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of fenfluramine and aripiprazole. Concurrent use may result in additive CNS depression.

Fenoldopam: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Fentanyl: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Fingolimod: (Moderate) Exercise caution when administering fingolimod concomitantly with aripiprazole as concurrent use may increase the risk of QT prolongation. Fingolimod initiation results in decreased heart rate and may prolong the QT interval. Fingolimod has not been studied in patients treated with drugs that prolong the QT interval, but drugs that prolong the QT interval have been associated with cases of TdP in patients with bradycardia. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Flecainide: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Flecainide is a Class IC antiarrhythmic associated with a possible risk for QT prolongation and/or torsades de pointes (TdP); flecainide increases the QT interval, but largely due to prolongation of the QRS interval. Although causality for TdP has not been established for flecainide, patients receiving concurrent drugs which have the potential for QT prolongation may have an increased risk of developing proarrhythmias. Aripiprazole should be used cautiously and with close monitoring with flecainide.

Fluconazole: (Contraindicated) Avoid use of aripiprazole with fluconazole unless the benefit outweighs the risk of QT prolongation or other side effects. Conflicting recommendations are available from the manufacturers of the drugs. According to the manufacturer of fluconazole, coadministration of drugs known to prolong the QT interval and which are CYP3A4 substrates, such as aripiprazole, is contraindicated in patients receiving fluconazole. Metabolism of aripiprazole occurs mainly through CYP3A4 and CYP2D6. Both fluconazole and aripiprazole have been associated with QT prolongation. The manufacturers of aripiprazole products do not contraindicate use of fluconazole, but do recommend dosage adjustments of oral aripiprazole when used with CYP3A4 inhibitors such as fluconazole. Manufacturers of aripiprazole injections recommend adjustments when a potent CYP3A4 inhibitor will be used for more than 14 days. See the manufacturer prescribing information for detailed recommendations.

Fluoxetine: (Major) Reduce the oral aripiprazole dosage by one-half of the usual dose in patients receiving strong CYP2D6 inhibitors such as fluoxetine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A4 inhibitor, as aripiprazole is also metabolized by CYP3A4. Addtionally, aripiprazole and fluoxetine are both associated with prolongation of the QT interval; caution and close monitoring are recommended. Avoid concurrent use of Aristada Initio and fluoxetine because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with strong CYP2D6 inhibitors and combined strong CYP2D6/CYP3A4 inhibitors; the recommendations are dependent on the aripiprazole IM depot dosage, the product given, and the duration of the concomitant inhibitors as specified in the product labels.

Fluoxetine; Olanzapine: (Major) Reduce the oral aripiprazole dosage by one-half of the usual dose in patients receiving strong CYP2D6 inhibitors such as fluoxetine. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP3A4 inhibitor, as aripiprazole is also metabolized by CYP3A4. Addtionally, aripiprazole and fluoxetine are both associated with prolongation of the QT interval; caution and close monitoring are recommended. Avoid concurrent use of Aristada Initio and fluoxetine because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with strong CYP2D6 inhibitors and combined strong CYP2D6/CYP3A4 inhibitors; the recommendations are dependent on the aripiprazole IM depot dosage, the product given, and the duration of the concomitant inhibitors as specified in the product labels. (Moderate) Coadministration may result in additive effects on the QT interval. Both aripiprazole and olanzapine have been associated with QT prolongation. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.

Fluphenazine: (Major) Fluphenazine,a phenothiazine, is associated with a possible risk for QT prolongation. Theoretically, prochlorperazine may increase the risk of QT prolongation if coadministered with drugs with a possible risk for QT prolongation, such as aripiprazole. Co-administration of fluphenazine with atypical agents (e.g., lurasidone and others) may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.

Flurazepam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Fluticasone; Salmeterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Fluticasone; Umeclidinium; Vilanterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Fluticasone; Vilanterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Fluvoxamine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of fluvoxamine and aripiprazole. Coadminister with caution. QT prolongation and TdP have been reported during postmarketing use of fluvoxamine. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Fluvoxamine is an inhibitor of CYP3A4 and CYP2D6, which may result in decreased clearance of substrates of these isoenzymes including aripiprazole. Decreased metabolism of aripiprazole may lead to clinically important adverse reactions that are associated with antipsychotic use, such as extrapyramidal symptoms. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 or CYP3A4 inhibitor. Aripiprazole dosage adjustments are not required when aripiprazole is added as adjunctive treatment to antidepressants for major depressive disorder provided that the manufacturer's dosing guidelines for this indication are followed.

Food: (Major) It is recommended that patients avoid the use of marijuana, by any route, if they are treated for a psychiatric history, including psychosis and bipolar disorder, as the cannabinoids (the psychoactive ingredients, such as THC) in marijuana can produce psychotoxic effects and may exacerbate psychiatric disorders. A high frequency of use and use of products with high-potency of THC are potential risk factors for psychiatric effects. Additionally, additive CNS effects, such as sedation or CNS depression are possible. Clinical studies suggest that cannabis use may reduce the efficacy of some antipsychotic drugs. In addition, several cannabinoids in marijuana appear to influence the activity of CYP enzymes and P-glycoprotein, which may alter the concentrations of antipsychotics and influence either safety or efficacy, For example, the smoking of marijuana influences the metabolism of some medications in a manner similar to tobacco by inducing CYP1A2.

Formoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Formoterol; Mometasone: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Fosamprenavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as fosamprenavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Foscarnet: (Major) When possible, avoid concurrent use of foscarnet with other drugs known to prolong the QT interval, such as aripiprazole. Foscarnet has been associated with postmarketing reports of both QT prolongation and torsade de pointes (TdP). QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose. If these drugs are administered together, obtain an electrocardiogram and electrolyte concentrations before and periodically during treatment.

Fosphenytoin: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when potent CYP3A4 inducers, such as phenytoin or other hydantoins, are added to aripiprazole therapy. Carefully monitor the patient for evidence of a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the oral aripiprazole dose in adults should be reduced to the previous dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Fostemsavir: (Moderate) Use aripiprazole and fostemsavir together with caution due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Supratherapeutic doses of fostemsavir (2,400 mg twice daily, four times the recommended daily dose) have been shown to cause QT prolongation. Fostemsavir causes dose-dependent QT prolongation.

Gabapentin: (Moderate) Monitor for excessive sedation and somnolence during coadministration of aripiprazole and gabapentin. Concurrent use may result in additive CNS depression.

Ganirelix: (Moderate) Antipsychotic-induced hyperprolactinemia results in down-regulation of the number of pituitary GnRH receptors and may interfere with the response to ganirelix, a gonadotropin-releasing hormone (GnRH) analog.

Gefitinib: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as gefitinib. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Gemifloxacin: (Moderate) Gemifloxacin should be used cautiously with aripiprazole as concurrent use may increase the risk of QT prolongation. Gemifloxacin may prolong the QT interval in some patients. The maximal change in QTc interval occurs approximately 5 to 10 hours following oral administration of gemifloxacin. The likelihood of QTc prolongation may increase with increasing dose of the drug; therefore, the recommended dose should not be exceeded especially in patients with renal or hepatic impairment where the Cmax and AUC are slightly higher. QT prolongation has occurred during the therapeutic use of aripiprazole and following overdose.

Gemtuzumab Ozogamicin: (Moderate) Use gemtuzumab ozogamicin and aripiprazole together with caution due to the potential for additive QT interval prolongation and risk of torsade de pointes (TdP). If these agents are used together, obtain an ECG and serum electrolytes prior to the start of gemtuzumab and as needed during treatment. Although QT interval prolongation has not been reported with gemtuzumab, it has been reported with other drugs that contain calicheamicin. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Gilteritinib: (Moderate) Use caution and monitor for additive QT prolongation if concurrent use of gilteritinib and aripiprazole is necessary. Gilteritinib has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Glasdegib: (Major) Avoid coadministration of glasdegib with aripiprazole due to the potential for additive QT prolongation. If coadministration cannot be avoided, monitor patients for increased risk of QT prolongation with increased frequency of ECG monitoring. Glasdegib therapy may result in QT prolongation and ventricular arrhythmias including ventricular fibrillation and ventricular tachycardia. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Glimepiride; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Glimepiride; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Glipizide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Glyburide; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Glycopyrrolate; Formoterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Goserelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., goserelin) outweigh the potential risks in patients receiving aripiprazole. Both drugs may cause QT prolongation.

Granisetron: (Moderate) Use granisetron with caution in combination with apriprazole due to the risk of QT prolongation. Granisetron has been associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Grapefruit juice: (Moderate) Grapefruit and grapefruit juice inhibit CYP3A4 metabolism in gut enterocytes, and therefore may decrease aripiprazole metabolism, resulting in increased blood concentrations of aripiprazole. Patients should not significantly adjust their intake of grapefruit or grapefruit juice while taking aripiprazole. As with drugs that significantly inhibit the CYP3A4 pathway, consideration should be given to altering the aripiprazole dose.

Guaifenesin; Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Guaifenesin; Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Halofantrine: (Moderate) Because aripiprazole is partially metabolized by CYP2D6, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as halofantrine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Halogenated Anesthetics: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Halogenated anesthetics can prolong the QT interval and should be used cautiously and with close monitoring with aripirazole.

Haloperidol: (Moderate) Caution is advisable when combining haloperidol concurrently with aripiprazole as concurrent use may increase the risk of QT prolongation and antipsychotic-related adverse effects. It may be advisable to initiate treatment with lower dosages if combination therapy is necessary as the risk of adverse effects(e.g., drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, cardiac conduction abnormalities, seizures) may be increased. A dosage reduction of aripiprazole may be necessary in patients receiving concomitant haloperidol and a CYP3A4 inhibitor. Haloperidol is a CYP2D6 inhibitor that has been associated with QT prolongation and torsade de pointes (TdP). Excessive doses (particularly in the overdose setting) or IV administration of haloperidol may be associated with a higher risk of QT prolongation. Aripiprazole is partially metabolized through CYP2D6; QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. In patients receiving aripiprazole with haloperidol and a CYP3A4 inhibitor, the oral aripiprazole dose should be reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 haloperidol for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Histrelin: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., histrelin) outweigh the potential risks of QT prolongation in patients receiving aripiprazole. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose.

Homatropine; Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydantoins: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when potent CYP3A4 inducers, such as phenytoin or other hydantoins, are added to aripiprazole therapy. Carefully monitor the patient for evidence of a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the oral aripiprazole dose in adults should be reduced to the previous dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Hydralazine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Hydralazine; Hydrochlorothiazide, HCTZ: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Hydralazine; Isosorbide Dinitrate, ISDN: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Hydrochlorothiazide, HCTZ; Metoprolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Hydrochlorothiazide, HCTZ; Propranolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Hydrocodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydrocodone; Ibuprofen: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydrocodone; Phenylephrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydrocodone; Potassium Guaiacolsulfonate: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydrocodone; Potassium Guaiacolsulfonate; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydrocodone; Pseudoephedrine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Avoid prescribing opioid cough medications in patients taking aripiprazole Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydromorphone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Hydroxychloroquine: (Major) Avoid coadministration of aripiprazole and hydroxychloroquine due to the risk of increased QT prolongation. If use together is necessary, obtain an ECG at baseline to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Hydroxychloroquine prolongs the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Hydroxyzine: (Moderate) Caution is recommended if hydroxyzine is administered with aripiprazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). In addition, because hydroxyzine causes pronounced sedation, an enhanced CNS depressant effect may occur when it is combined with other CNS depressants including aripiprazole. Postmarketing data indicate that hydroxyzine causes QT prolongation and TdP. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Ibuprofen; Oxycodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Ibutilide: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Ibutilide administration can cause QT prolongation and torsades de pointes (TdP); proarrhythmic events should be anticipated. The potential for proarrhythmic events with ibutilide increases with the coadministration of other drugs that prolong the QT interval. Ibutilide should be used cautiously and with close monitoring with aripiprazole.

Idelalisib: (Major) If possible, avoid concomitant use of idelalisib, a strong CYP3A inhibitor, with aripiprazole, a CYP3A substrate, as aripiprazole toxicities may be significantly increased. If these drugs must be used together, the manufacturer of aripiprazole recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Iloperidone: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Iloperidone is an atypical antipsychotics with a possible risk for QT prolongation and TdP that should be used cautiously and with close monitoring with aripiprazole. In addition, caution is advisable when aripiprazole is given in combination with other CNS depressants such as other atypical antipsychotics. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. The likelihood of these pharmacodynamic interactions varies based upon the individual properties of the co-administered antipsychotic agent.

Iloprost: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Imatinib: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as imatinib, STI-571. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor.

Imipramine: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Incretin Mimetics: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Indacaterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Indacaterol; Glycopyrrolate: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Indinavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as indinavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Inotuzumab Ozogamicin: (Major) Avoid coadministration of inotuzumab ozogamicin with aripiprazole due to the potential for additive QT prolongation and risk of torsade de pointes (TdP). If coadministration is unavoidable, obtain an ECG and serum electrolytes prior to the start of treatment, after treatment initiation, and periodically during treatment. Inotuzumab has been associated with QT interval prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Insulin Degludec; Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Insulin Glargine; Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Insulins: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Isavuconazonium: (Moderate) Concomitant use of isavuconazonium with aripiprazole may result in increased serum concentrations of aripiprazole. Aripiprazole is a substrate of CYP3A4 and isavuconazole, the active moiety of isavuconazonium, is a moderate inhibitor of this enzyme. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor.

Isocarboxazid: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.

Isoniazid, INH: (Moderate) Administering aripiprazole with isoniazid may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and isoniazid is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.

Isoniazid, INH; Pyrazinamide, PZA; Rifampin: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as rifampin, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is discontinued, the aripiprazole dose in adults should be reduced to the original dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. (Moderate) Administering aripiprazole with isoniazid may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and isoniazid is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.

Isoniazid, INH; Rifampin: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a potent CYP3A4 inducer, such as rifampin, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is discontinued, the aripiprazole dose in adults should be reduced to the original dose over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dosage adjustment is necessary for the 662 mg, 882 mg, or 1,064 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. (Moderate) Administering aripiprazole with isoniazid may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and isoniazid is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.

Isradipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Istradefylline: (Moderate) Administering aripiprazole with istradefylline 40 mg daily may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and istradefylline administered as 40 mg daily is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor. There was no effect on drug exposure when istradefylline 20 mg daily was coadministered with a sensitive CYP3A4 substrate.

Itraconazole: (Major) Caution is advised when administering itraconazole with drugs that are known to prolong that QT interval and are metabolized by CYP3A4, such as aripiprazole. Both aripiprazole and itraconazole are associated with QT prolongation; coadministration may increase this risk. In addition, coadministration of itraconazole, a potent CYP3A4 inhibitor, with aripiprazole, a partial CYP3A4 substrate, may result in an elevated aripiprazole plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs must be used together, the manufacturer recommends the oral dose of aripiprazole dose be reduced to one-half of the usual dose. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Ivosidenib: (Major) Avoid coadministration of ivosidenib with aripiprazole due to an increased risk of QT prolongation. If concomitant use is unavoidable, monitor ECGs for QTc prolongation and monitor electrolytes; correct any electrolyte abnormalities as clinically appropriate. An interruption of therapy and dose reduction of ivosidenib may be necessary if QT prolongation occurs. Prolongation of the QTc interval and ventricular arrhythmias have been reported in patients treated with ivosidenib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Ketoconazole: (Major) Aripiprazole and ketoconazole are both associated with prolongation of the QT interval; caution and close monitoring is recommended. In addition, because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as ketoconazole. Concurrent use of aripiprazole (15 mg single dose) and ketoconazole (200 mg/day for 14 days) resulted in an increase in the AUC of aripiprazole and its active metabolite by 63% and 77%, respectively. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Labetalol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Lamotrigine: (Minor) Coadministration of aripiprazole and lamotrigine may slightly decrease lamotrigine plasma concentrations; however, this interaction is not expected to be clinically meaningful. During clinical trials, lamotrigine exposure was reduced approximately 10% in patients (n = 18) on a stable regimen of lamotrigine 100 mg/day to 400 mg/day who received ariprazole 10 mg/day to 30 mg/day for 7 days, followed by 30 mg/day for an additional 7 days.

Lapatinib: (Moderate) Monitor for evidence of QT prolongation if lapatinib is administered with aripiprazole. Lapatinib has been associated with concentration-dependent QT prolongation; ventricular arrhythmias and torsade de pointes (TdP) have been reported in postmarketing experience with lapatinib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Larotrectinib: (Moderate) Administering aripiprazole with larotrectinib may result in elevated aripiprazole plasma concentrations. Aripiprazole is a substrate of CYP3A4 and larotrectinib is a weak CYP3A inhibitor. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada during use of a mild to moderate CYP3A4 inhibitor.

Lasmiditan: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lasmiditan and aripiprazole. Concurrent use may result in additive CNS depression.

Lefamulin: (Major) Avoid coadministration of lefamulin with aripiprazole as concurrent use may increase the risk of QT prolongation. If coadministration cannot be avoided, monitor ECG during treatment. Lefamulin has a concentration dependent QTc prolongation effect. The pharmacodynamic interaction potential to prolong the QT interval of the electrocardiogram between lefamulin and other drugs that effect cardiac conduction is unknown. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Lemborexant: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lemborexant and atypical antipsyhotics. Dosage adjustments of lemborexant and the atypical antipsychotic may be necessary when administered together because of potentially additive CNS effects. The risk of next-day impairment, including impaired driving, is increased if lemborexant is taken with other CNS depressants.

Lenvatinib: (Major) Avoid coadministration of lenvatinib with aripiprazole due to the risk of QT prolongation. Prolongation of the QT interval has been reported with lenvatinib therapy. QT prolongation has also occurred during therapeutic use of aripiprazole and following overdose.

Letermovir: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, patients should be carefully monitored for aripiprazole-related adverse reactions during concurrent use of a moderate CYP3A4 inhibitor such as letermovir. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP2D6, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inhibitor. During coadministration of letermovir and cyclosporine, letermovir may exhibit more potent CYP3A4 inhibitory properties. When letermovir and cyclosporine are used concurrently with aripiprazole, consult the aripiprazole product information for dosage adjustments of aripiprazole necessary during use of a potent CYP3A4 inhibitor.

Leuprolide: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving aripiprazole. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose.

Leuprolide; Norethindrone: (Moderate) Consider whether the benefits of androgen deprivation therapy (i.e., leuprolide) outweigh the potential risks of QT prolongation in patients receiving aripiprazole. Androgen deprivation therapy may prolong the QT/QTc interval. Prolongation of the QT interval has also occurred during therapeutic use of aripiprazole and following overdose.

Levalbuterol: (Minor) Use caution if administering aripiprazole with other drugs that may cause QT prolongation, including the short-acting beta-agonists (SABAs). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. SABAs may rarely cause adverse cardiovascular effects such as QT prolongation, usually at higher doses and/or when associated with hypokalemia.

Levamlodipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Levobetaxolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Levobunolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Levocetirizine: (Moderate) Concurrent use of cetirizine/levocetirizine with atypical antipsychotics should generally be avoided. Coadministration may increase the risk of CNS depressant-related side effects. If concurrent use is necessary, monitor for excessive sedation and somnolence.

Levodopa: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or levodopa during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and levodopa may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with levodopa and other antiparkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Levofloxacin: (Moderate) Levofloxacin should be used cautiously with other agents that may prolong the QT interval or increase the risk of torsade de pointes (TdP). Levofloxacin has been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of levofloxacin. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Levorphanol: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Linagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Linagliptin; Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Liraglutide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Lithium: (Moderate) Aripiprazole and lithium are associated with QT prolongation. Coadministration may increase the risk of QT prolongation; therefore, aripiprazole and lithium should be coadministered with caution and close monitoring. Some atypical antipsychotics, including aripiprazole, are indicated as adjunctive therapy to mood stabilizers such as lithium. However, it is advisable to monitor patients for neurotoxicity during co-administration. Neuroleptic malignant syndrome (NMS) has been observed occasionally during concurrent use of lithium and either atypical or conventional antipsychotics. Additive extrapyramidal effects have also been noted. Early case reports described an encephalopathic syndrome consisting of delirium, tremulousness, dyskinesia, seizures, leukocytosis, weakness, hyperpyrexia, confusion, extrapyramidal symptoms, elevations in laboratory values (e.g., liver function tests, blood urea nitrogen, fasting blood sugar) and, in some cases, irreversible brain damage, during use of lithium and conventional antipsychotics, particularly haloperidol. Subsequent rare reports of NMS or NMS-like reactions have been described during coadministration of lithium and atypical antipsychotics (e.g., risperidone, olanzapine, clozapine). Following resolution of NMS, there are isolated instances of re-emergence of symptoms following re-initiation of lithium as monotherapy. Lithium may be a risk factor for antipsychotic-induced NMS; however, this hypothesis has not been confirmed. In many reported cases, confounding factors have been present (e.g., previous history of NMS, high dose therapy). The ability of antipsychotics alone to precipitate NMS and the rarity of the condition further complicate assessment of lithium as a risk factor. Aripiprazole does not change the pharmacokinetic parameters of lithium.

Lixisenatide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Lofexidine: (Moderate) Monitor ECG and for hypotension if lofexidine is coadministered with aripiprazole due to the potential for additive QT prolongation and effects on blood pressure. Due to its alpha adrenergic antagonism, aripiprazole has the potential to enhance the effect of lofexidine on blood pressure. Lofexidine may also cause additive sedation with CNS depressants, such as the atypical antipsychotics. Lofexidine prolongs the QT interval, and torsade de pointes (TdP) has been reported during postmarketing use. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Patients being given lofexidine in an outpatient setting should be capable of and instructed on self-monitoring for hypotension, orthostasis, bradycardia, and associated symptoms. If clinically significant or symptomatic hypotension and/or bradycardia occur, the next dose of lofexidine should be reduced in amount, delayed, or skipped.

Lonafarnib: (Major) Reduce the oral aripiprazole dosage by one-half of the usual dose during coadministration of lonafarnib. Reduce the oral aripiprazole dosage to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response in patients also receiving a CYP2D6 inhibitor or who are CYP2D6 poor metabolizers. Avoid concurrent use of Aristada Initio and lonafarnib because the dose of Aristada Initio cannot be modified. For other long-active aripiprazole injectables (e.g., Ability Maintena, Aristada), dose adjustments are recommended with combined strong CYP2D6/CYP3A4 inhibitors; the recommendations are dependent on the aripiprazole IM depot dosage, the product given, and the duration of the concomitant inhibitors as specified in the product labels. Aripiprazole is a substrate for CYP2D6 and CYP3A4; lonafarnib is a strong CYP3A4 inhibitor. Based on simulation studies, a 3-fold increase in aripiprazole exposure is expected when CYP2D6 poor metabolizers are administered a strong CYP3A4 inhibitor. A 4.5-fold increase in aripiprazole exposure is expected when CYP2D6 extensive metabolizers are administered both a strong CYP3A4 and CYP2D6 inhibitor.

Long-acting beta-agonists: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Loop diuretics: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Loperamide: (Moderate) Loperamide should be used cautiously and with close monitoring with aripiprazole. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Coadministration my further increase the risk of QT prolongation and TdP.

Loperamide; Simethicone: (Moderate) Loperamide should be used cautiously and with close monitoring with aripiprazole. At high doses, loperamide has been associated with serious cardiac toxicities, including syncope, ventricular tachycardia, QT prolongation, torsade de pointes (TdP), and cardiac arrest. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Coadministration my further increase the risk of QT prolongation and TdP.

Lopinavir; Ritonavir: (Major) Avoid coadministration of lopinavir with aripiprazole due to the potential for additive QT prolongation. If use together is necessary, obtain a baseline ECG to assess initial QT interval and determine frequency of subsequent ECG monitoring, avoid any non-essential QT prolonging drugs, and correct electrolyte imbalances. Lopinavir is associated with QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ritonavir. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor, such as ritonavir, should have a dose reduction to 200 mg/month IM. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Lorazepam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Loxapine: (Major) Caution is advisable during concurrent use of aripiprazole with other CNS depressants such as loxapine. The risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary. Although the incidence of tardive dyskinesia from combination antipsychotic therapy has not been established and data are very limited, the risk appears to be increased during use of a conventional and atypical antipsychotic versus use of a conventional antipsychotic alone.

Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of aripiprazole. Lumacaftor is a strong CYP3A inducer and aripiprazole is a partial CYP3A4 substrate. Coadministration of aripiprazole (30 mg daily) with carbamazepine (200 mg twice daily), another strong CYP3A inducer, resulted in a 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite. If used together, the oral aripiprazole dose should be doubled over 1 to 2 weeks. Monitor the patient closely for antipsychotic efficacy; additional dosage increases should be based on clinical evaluation. If lumacaftor; ivacaftor therapy is later withdrawn, the oral ariprazole dosage should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dose adjustment is necessary for the 662 mg or the 882 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Lumacaftor; Ivacaftor: (Major) Lumacaftor; ivacaftor may decrease the systemic exposure and therapeutic efficacy of aripiprazole. Lumacaftor is a strong CYP3A inducer and aripiprazole is a partial CYP3A4 substrate. Coadministration of aripiprazole (30 mg daily) with carbamazepine (200 mg twice daily), another strong CYP3A inducer, resulted in a 70% decrease in Cmax and AUC values of both aripiprazole and its active metabolite. If used together, the oral aripiprazole dose should be doubled over 1 to 2 weeks. Monitor the patient closely for antipsychotic efficacy; additional dosage increases should be based on clinical evaluation. If lumacaftor; ivacaftor therapy is later withdrawn, the oral ariprazole dosage should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving Aristada with a strong CYP3A4 inducer, no dose adjustment is necessary for the 662 mg or the 882 mg dose; increase the 441 mg dose to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Lumateperone: (Moderate) Coadministration of antipsychotics, such as lumateperone and aripiprazole, may increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. Although the incidence of tardive dyskinesia from antipsychotic combinations has not been established and data are very limited, the risk may be increased during combined use versus use of an antipsychotic alone.

Lurasidone: (Moderate) Monitor for adverse effects including excessive sedation, somnolence, dizziness, orthostatic hypotension, extrapyramidal symptoms, neuroleptic malignant syndrome, and seizures during coadministration of lurasidone and aripiprazole. The risk of these adverse effects may be increased during concurrent use. Lower dosages may be necessary if combination therapy is deemed necessary.

Macimorelin: (Major) Avoid concurrent administration of macimorelin with drugs that prolong the QT interval, such as aripiprazole. Use of these drugs together may increase the risk of developing torsade de pointes-type ventricular tachycardia. Sufficient washout time of drugs that are known to prolong the QT interval prior to administration of macimorelin is recommended. Treatment with macimorelin has been associated with an increase in the corrected QT (QTc) interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Maprotiline: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Maprotiline has been reported to prolong the QT interval, particularly in overdose or with higher-dose prescription therapy (elevated serum concentrations). Cases of long QT syndrome and torsade de pointes (TdP) tachycardia have been described with maprotiline use, but rarely occur when the drug is used alone in normal prescribed doses and in the absence of other known risk factors for QT prolongation. Limited data are available regarding the safety of maprotiline in combination with other QT-prolonging drugs. Aripiprazole should be used cautiously with maprotiline.

Mecamylamine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Meclizine: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including sedating H1-blockers. Additive drowsiness or other CNS effects may occur.

Mefloquine: (Moderate) Mefloquine should be used with caution in patients receiving aripiprazole as concurrent use may increase the risk of QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. There is evidence that the use of halofantrine after mefloquine causes a significant lengthening of the QTc interval. Mefloquine alone has not been reported to cause QT prolongation.

Meglitinides: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Meperidine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Meperidine; Promethazine: (Moderate) Both promethazine and aripiprazole are associated with a possible risk for QT prolongation; therefore, caution is advisable during coadministration. In addition, because aripiprazole is partially metabolized by CYP2D6, patients should be monitored for aripiprazole-related adverse reactions during concurrent use of a CYP2D6 inhibitor such as promethazine. Because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor. Coadministration of phenothiazines such as promethazine and antipsychotics may also increase the risk of adverse effects such as drowsiness, dizziness, orthostatic hypotension, anticholinergic effects, extrapyramidal symptoms, neuroleptic malignant syndrome, or seizures. (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Mephobarbital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Meprobamate: (Moderate) The CNS-depressant effects of meprobamate can be potentiated with concomitant administration of other drugs known to cause CNS depression including antipsychotics.

Mesoridazine: (Major) Due to the CNS effects of aripiprazole, caution is advisable when aripiprazole is given in combination with centrally-acting medications including other antipsychotics. The risk of drowsiness, dizziness, hypotension, or extrapyramidal symptoms may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.

Metaproterenol: (Minor) Use caution if administering aripiprazole with other drugs that may cause QT prolongation, including the short-acting beta-agonists (SABAs). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. SABAs may rarely cause adverse cardiovascular effects such as QT prolongation, usually at higher doses and/or when associated with hypokalemia.

Metformin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Metformin; Pioglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Metformin; Repaglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Metformin; Rosiglitazone: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. Atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition. (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Metformin; Saxagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Metformin; Sitagliptin: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Methadone: (Major) Aripiprazole should be used cautiously and with close monitoring with methadone due to the potential for increased risk of QT prolongation, torsade de pointes (TdP), and additive CNS depressant effects. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression and QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Methadone is considered to be associated with an increased risk for QT prolongation and torsade de pointes (TdP), especially at higher doses (> 200 mg/day but averaging approximately 400 mg/day in adult patients). Laboratory studies, both in vivo and in vitro, have demonstrated that methadone inhibits cardiac potassium channels and prolongs the QT interval. Most cases involve patients being treated for pain with large, multiple daily doses of methadone, although cases have been reported in patients receiving doses commonly used for maintenance treatment of opioid addiction.

Methohexital: (Major) Because aripiprazole is metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when strong CYP3A4 inducers, such as barbiturates, are added to aripiprazole therapy. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When the CYP3A4 inducer is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced over 1 to 2 weeks to the original level. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers. Additive CNS effects are possible, including drowsiness or dizziness. Patients should report any unusual changes in moods or behaviors while taking this combination.

Methylphenidate: (Moderate) Atypical antipsychotics and methylphenidate may interact pharmacodynamically to diminish the therapeutic effects of either agent through opposing effects on dopamine. Methylphenidate blocks central dopamine reuptake, which has the potential to exacerbate psychosis, and antipsychotics, which are central dopamine antagonists, may diminish the effectiveness of methylphenidate.

Metoclopramide: (Contraindicated) Avoid metoclopramide in patients receiving atypical antipsychotics. There is a potential for additive effects, including increased frequency and severity of tardive dyskinesia (TD), other extrapyramidal symptoms (EPS), and neuroleptic malignant syndrome (NMS). Some manufacturer labels for metoclopramide contraindicate the use of these drugs together, while others state avoidance is necessary. If these agents must be used together, monitor closely for movement disorders and additive CNS effects. There also may be additive sedation. Discontinue these medications at the first signs of dyskinesia.

Metoprolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Metronidazole: (Moderate) Potential QT prolongation has been reported in limited case reports with metronidazole. Drugs with a possible risk for QT prolongation and TdP that should be used cautiously with metronidazole include aripiprazole.

Midazolam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Midostaurin: (Major) The concomitant use of midostaurin and aripiprazole may lead to additive QT interval prolongation. If these drugs are used together, consider obtaining electrocardiograms to monitor the QT interval. In clinical trials, QT prolongation was reported in patients who received midostaurin as single-agent therapy or in combination with cytarabine and daunorubicin. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Mifepristone: (Major) Because both mifepristone and aripiprazole are associated with a possible risk for QT prolongation and torsade de pointes (TdP), the combination should be used cautiously and with close monitoring. In addition, coadministration of mifepristone, a potent CYP3A4 inhibitor, with aripiprazole, a partial CYP3A4 substrate, may result in an elevated aripiprazole plasma concentrations and an increased risk for adverse events, including QT prolongation. If these drugs must be used together, the manufacturer recommends the oral dose of aripiprazole dose be reduced to one-half of the usual dose. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Miglitol: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Minoxidil: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Mirabegron: (Moderate) Mirabegron is a moderate CYP2D6 inhibitor. Exposure of drugs metabolized by CYP2D6 such as aripiprazole may be increased when administered with mirabegron. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. In addition, because aripiprazole is also metabolized by CYP3A4, patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP2D6 inhibitor.

Mirtazapine: (Moderate) There may be an increased risk for QT prolongation and torsade de pointes (TdP) during concurrent use of mirtazapine and aripiprazole. Coadminister with caution. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Cases of QT prolongation, TdP, ventricular tachycardia, and sudden death have been reported during postmarketing use of mirtazapine, primarily following overdose or in patients with other risk factors for QT prolongation, including concomitant use of other medications associated with QT prolongation.

Mitotane: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be doubled over 1 to 2 weeks when a strong CYP3A4 inducer, such as mitotane, is added to aripiprazole therapy with subsequent adjustments based upon clinical response. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. When mitotane is withdrawn from the combination therapy, the aripiprazole dose in adults should be reduced to the original level over 1 to 2 weeks. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. In adults receiving 662 mg, 882 mg, or 1,064 mg of Aristada and receiving a strong CYP3A4 inducer, no dosage adjustment is necessary; however, the 441 mg dose should be increased to 662 mg if the CYP inducer is added for more than 2 weeks. Avoid concurrent use of Aristada Initio and strong CYP3A4 inducers.

Modafinil: (Moderate) Because aripiprazole is metabolized by CYP3A4, concurrent use of CYP3A4 inducers such as modafinil may result in decreased plasma concentrations of aripiprazole. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Molindone: (Major) Close monitoring is advisable during concurrent use of molindone with other antipsychotics. Because molindone shares certain pharmacological properties with other antipsychotics, additive cardiac effects (e.g., hypotension), CNS effects (e.g., drowsiness), or anticholinergic effects (e.g., constipation, xerostomia) may occur. Clinicians should note that antimuscarinic effects might be seen not only on GI smooth muscle, but also on bladder function, the eye, and temperature regulation.

Monoamine oxidase inhibitors: (Moderate) Due to the potential for additive sedative and cardiovascular effects (e.g., hypotension), MAOIs and antipsychotics should be used together cautiously; some experts recommend initiating low doses of the antipsychotic and careful dosage titration.

Morphine: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Morphine; Naltrexone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Moxifloxacin: (Major) QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Prolongation of the QT interval has been reported with administration of moxifloxacin. Post-marketing surveillance has identified very rare cases of ventricular arrhythmias including torsade de pointes (TdP), usually in patients with severe underlying proarrhythmic conditions. The likelihood of QT prolongation may increase with increasing concentrations of moxifloxacin, therefore the recommended dose or infusion rate should not be exceeded. According to the manufacturer, moxifloxacin should be avoided in patients taking drugs that can result in prolongation of the QT interval.

Nabilone: (Moderate) Drugs that can cause CNS depression, if used concomitantly with atypical antipsychotics, can increase both the frequency and the intensity of adverse effects such as drowsiness, sedation, and dizziness.

Nadolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Nafarelin: (Moderate) Antipsychotics may cause hyperprolactinemia and should not be administered concomitantly with nafarelin since hyperprolactinemia down-regulates the number of pituitary GnRH receptors.

Nalbuphine: (Moderate) Monitor for excessive sedation and somnolence during coadministration of lumateperone and nalbuphine. Concurrent use may result in additive CNS depression.

Nateglinide: (Moderate) Atypical antipsychotic therapy may aggravate diabetes mellitus and cause metabolic changes such as hyperglycemia. Monitor patients on antidiabetic agents for worsening glycemic control. The atypical antipsychotics have been associated with metabolic changes, including hyperglycemia, diabetic ketoacidosis, hyperosmolar, hyperglycemic states, and diabetic coma. Aggravation of diabetes mellitus has been reported. Possible mechanisms include atypical antipsychotic-induced insulin resistance or direct beta-cell inhibition.

Nebivolol: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Nebivolol; Valsartan: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents. It may be advisable to monitor blood pressure when these medications are coadministered.

Nefazodone: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as nefazodone. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving Aristada 882 mg every 6 weeks or 1,064 mg every 2 months, reduce the dose to 441 mg every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs and receiving a strong CYP3A4 inhibitor for more than 14 days should have their Aristada dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg; no dosage adjustment is necessary in patients receiving 441 mg of Aristada, if tolerated. Avoid use of combination therapy with a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days in patients receiving 662 mg, 882 mg, or 1,064 mg of Aristada; no dosage adjustment is necessary in patients taking 441 mg of Aristada, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Nelfinavir: (Major) Because aripiprazole is partially metabolized by CYP3A4, the manufacturer recommends that the oral aripiprazole dose be reduced to one-half of the usual dose in patients receiving strong inhibitors of CYP3A4 such as nelfinavir. In adults receiving 300 mg or 400 mg of Abilify Maintena, dose reductions to 200 mg or 300 mg, respectively, are recommended if the CYP3A4 inhibitor is used for more than 14 days. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1,064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Because aripiprazole is also metabolized by CYP2D6, patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor or patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adult patients receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor should have a dose reduction to 200 mg/month IM. Patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1,064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1,064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Nevirapine: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration with a CYP3A4 inducer such as nevirapine. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. Adjust the aripiprazole dose if necessary. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Nicardipine: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as nicardipine. Adult patients receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. If these agents are used in combination, the patient should be carefully monitored for aripiprazole-related adverse reactions. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inhibitor. Lastly, aripiprazole may enhance the hypotensive effects of antihypertensive agents such as nicardipine.

Nifedipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Nilotinib: (Major) Avoid the concomitant use of nilotinib with aripiprazole as significant prolongation of the QT interval may occur. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Sudden deaths and QT prolongation have been reported with nilotinib therapy.

Nisoldipine: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Nitroprusside: (Minor) Aripiprazole may enhance the hypotensive effects of antihypertensive agents.

Non-Ionic Contrast Media: (Major) Aripiprazole lowers the seizure threshold and should be discontinued at least 48 hours before myelography and should not be resumed for at least 24 hours postprocedure.

Norfloxacin: (Moderate) Caution is advised when administering aripiprazole with norfloxacin, as use of these drugs together may increase the risk for QT prolongation and torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Quinolones have also been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during post-marketing surveillance of norfloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.

Nortriptyline: (Moderate) Combination therapy with aripiprazole and tricyclic antidepressants should be approached with caution and close monitoring. Aripiprazole has a risk for QT prolongation and torsade de pointes, and tricyclics at elevated serum concentrations may produce clinically significant prolongation of the QTc interval. In addition, there is potential for other interactions, such as augmentation of anticholinergic effects.

Octreotide: (Moderate) Use octreotide with caution in combination with aripiprazole as concurrent use may increase the risk of QT prolongation. Arrhythmias, sinus bradycardia, and conduction disturbances have occurred during octreotide therapy. Since bradycardia is a risk factor for development of torsade de pointes (TdP), the potential occurrence of bradycardia during octreotide administration could theoretically increase the risk of TdP in patients receiving drugs that prolong the QT interval. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Ofloxacin: (Moderate) Ofloxacin should be used cautiously with other agents, such as aripiprazole, that may prolong the QT interval or increase the risk of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. Quinolones have been associated with a risk of QT prolongation and TdP. Although extremely rare, TdP has been reported during postmarketing surveillance of ofloxacin. These reports generally involved patients with concurrent medical conditions or concomitant medications that may have been contributory.

Olanzapine: (Moderate) Coadministration may result in additive effects on the QT interval. Both aripiprazole and olanzapine have been associated with QT prolongation. In addition, the risk of drowsiness, dizziness, hypotension, extrapyramidal symptoms, anticholinergic effects, neuroleptic malignant syndrome, tardive dyskinesia, or seizures may be increased during combined use; therefore, it may be advisable to initiate treatment with lower dosages if combination therapy is deemed necessary.

Oliceridine: (Moderate) Concomitant use of oliceridine with aripiprazole may cause excessive sedation and somnolence. Limit the use of oliceridine with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect.

Olodaterol: (Moderate) Use caution when using aripiprazole with long-acting beta-agonists (LABAs) due to the potential for QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose. LABAs may be associated with cardiovascular effects including QT interval prolongation, usually at higher doses or if hypokalemia occurs.

Ombitasvir; Paritaprevir; Ritonavir: (Major) Because aripiprazole is metabolized by CYP3A4 and CYP2D6, the manufacturer recommends that the oral aripiprazole dose be reduced to one-quarter (25%) of the usual dose in patients receiving inhibitors of both CYP3A4 and CYP2D6 such as ritonavir. Patients classified as CYP2D6 poor metabolizers (PMs) who are receiving a strong CYP3A4 inhibitor should have their oral aripiprazole dose reduced to one-quarter (25%) of the usual dose with subsequent adjustments based upon clinical response. Adults receiving a combination of a CYP3A4 and CYP2D6 inhibitor for more than 14 days should have their Abilify Maintena dose reduced from 400 mg/month to 200 mg/month or from 300 mg/month to 160 mg/month, respectively. Adults receiving Abilify Maintena who are PMs and receiving a strong CYP3A4 inhibitor, such as ritonavir, should have a dose reduction to 200 mg/month IM. In adults receiving Aristada, the Aristada dose should be reduced to the next lower strength during use of a strong CYP3A4 inhibitor for more than 14 days. For patients receiving 882 mg of Aristada every 6 weeks or 1064 mg every 2 months, the next lower strength should be 441 mg administered every 4 weeks. No dosage adjustment is necessary in patients taking 441 mg IM of Aristada, if tolerated. Adults receiving Aristada who are PMs of CYP2D6 and receiving a strong CYP3A4 inhibitor for more than 14 days should have their dose reduced from 662 mg, 882 mg, or 1064 mg to 441 mg IM; no dose adjustment is needed in patients receiving 441 mg of Aristada, if tolerated. In adults receiving Aristada 662 mg, 882 mg, or 1064 mg, combined use of a strong CYP2D6 inhibitor and a strong CYP3A4 inhibitor for more than 14 days should be avoided; no dose adjustment is needed in patients taking 441 mg, if tolerated. Avoid concurrent use of Aristada Initio and strong CYP3A4 inhibitors because the dose of Aristada Initio cannot be modified.

Omeprazole; Amoxicillin; Rifabutin: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during coadministration of a CYP3A4 inducer, such as rifabutin. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Ondansetron: (Major) If ondansetron and aripiprazole must be coadministered, ECG monitoring is recommended. Ondansetron has been associated with a dose-related increase in the QT interval and postmarketing reports of torsade de pointes (TdP). QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Opicapone: (Moderate) Monitor for movement disorders, unusual changes in moods or behavior, and diminished effectiveness of the atypical antipsychotic or COMT inhibitor during coadministration. Due to mutually opposing effects on dopamine, atypical antipsychotics and COMT inhibitors may interfere with the effectiveness of each other. In general, atypical antipsychotics are less likely to interfere with COMT inhibitors and other Parkinson's treatments than traditional antipsychotics. The Beers Criteria recognize quetiapine and clozapine as exceptions to the general recommendation to avoid all antipsychotics in older adults with Parkinson's disease.

Oritavancin: (Moderate) Aripiprazole is metabolized by CYP3A4 and CYP2D6; oritavancin is a weak CYP3A4 and CYP2D6 inducer. Plasma concentrations and efficacy of aripiprazole may be reduced if these drugs are administered concurrently. An increase in aripiprazole dosage may be clinically warranted in some patients. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 and CYP2D6 inducer.

Osilodrostat: (Moderate) Monitor ECGs in patients receiving osilodrostat with aripiprazole. Osilodrostat is associated with dose-dependent QT prolongation. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Osimertinib: (Major) Avoid coadministration of aripiprazole with osimertinib if possible due to the risk of QT prolongation and Torsade de Pointes (TdP). If concomitant use is unavoidable, periodically monitor ECGs for QT prolongation and monitor electrolytes; an interruption of osimertinib therapy with dose reduction or discontinuation of therapy may be necessary if QT prolongation occurs. Concentration-dependent QTc prolongation occurred during clinical trials of osimertinib. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Oxaliplatin: (Major) Monitor ECGs and electrolytes in patients receiving oxaliplatin and aripiprazole concomitantly; correct electrolyte abnormalities prior to administration of oxaliplatin. QT prolongation and ventricular arrhythmias including fatal torsade de pointes have been reported with oxaliplatin use in postmarketing experience. QT prolongation has also occurred during therapeutic use of aripiprazole as well as following overdose.

Oxazepam: (Moderate) Due to the primary CNS effects of aripiprazole, caution should be used when aripiprazole is given in combination with other centrally-acting medications including benzodiazepines and other anxiolytics, sedatives, and hypnotics. The intensity of sedation and orthostatic hypotension is greater during concurrent use of lorazepam and oral aripiprazole and during use of a parenteral benzodiazepine and intramuscular (IM) aripiprazole compared to aripiprazole alone; therefore, patients receiving a benzodiazepine with oral or parenteral aripiprazole should be monitored for sedation and blood pressure and the dose should be adjusted accordingly. Data from the manufacturer indicate there are no clinically significant pharmacokinetic changes when aripiprazole is given with lorazepam.

Oxcarbazepine: (Moderate) Because aripiprazole is partially metabolized by CYP3A4, caution is advisable during use of a CYP3A4 inducer such as oxcarbazepine. If these agents are used in combination, the patient should be carefully monitored for a decrease in aripiprazole efficacy. A dose adjustment of aripiprazole may be needed. Avoid concurrent use of Abilify Maintena with a CYP3A4 inducer when the combined treatment period exceeds 14 days because aripiprazole blood concentrations decline and may become suboptimal. There are no dosing recommendations for Aristada or Aristada Initio during use of a mild to moderate CYP3A4 inducer.

Oxycodone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Oxymorphone: (Moderate) Concomitant use of opioid agonists with aripiprazole may cause excessive sedation and somnolence. Limit the use of opioid pain medications with aripiprazole to only patients for whom alternative treatment options are inadequate. If concurrent use is necessary, use the lowest effective doses and minimum treatment durations needed to achieve the desired clinical effect. Educate patients about the risks and symptoms of excessive CNS depression.

Ozanimod: (Major) In general, do not initiate ozanimod in patients taking aripiprazole due to the risk of additive bradycardia, QT prolongation, and torsade de pointes (TdP). If treatment initiation is considered, seek advice from a cardiologist. Ozanimod initiation may result in a transient decrease in heart rate and atrioventricular conduction delays. Ozanimod has not been studied in patients taking concurrent QT prolonging drugs; however, QT prolonging drugs have been associated with TdP in patients with bradycardia. QT prolongation has occurred during therapeutic use of aripiprazole and following overdose.

Paliperidone: