CLASSES

Oral Anti-Acne Retinoids

DEA CLASS

Rx

DESCRIPTION

Oral retinoid; synthetic 13-cis isomer of naturally occurring tretinoin

Used primarily for severe, recalcitrant nodular acne

Due to teratogenicity potential, only available through isotretinoin iPLEDGE REMs program

COMMON BRAND NAMES

Absorica, Accutane, Amnesteem, Claravis, MYORISAN, Sotret, ZENATANE

HOW SUPPLIED

Absorica/Accutane/Amnesteem/Claravis/Isotretinoin/MYORISAN/Sotret/ZENATANE Oral Cap: 10mg, 20mg, 25mg, 30mg, 35mg, 40mg

DOSAGE & INDICATIONS

For the treatment of severe recalcitrant cystic acne vulgaris (nodular acne) in patients with multiple inflammatory nodules with a diameter of at least 5 mm.

Oral dosage (All formulations EXCEPT Absorica LD)

Adults

0.5 to 1 mg/kg/day PO, given in 2 divided doses, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Absorica may be taken with or without food; however, all other formulations should be taken with food. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosages up to 2 mg/kg/day PO given in 2 divided doses. Prior to upward dosage adjustments, patients should be questioned regarding their compliance with food and administration instructions. Adult Max: 2 mg/kg/day PO. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics.

Children and Adolescents 12 years and older

0.5 to 1 mg/kg/day PO, given in 2 divided doses, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Absorica may be taken with or without food; however, all other formulations should be taken with food. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics. Given careful consideration prior to use in this population, especially for those patients where a known metabolic or structural bone disease exists.

Oral dosage (Absorica LD only)

NOTE: Due to different bioavailability and recommended dosage, Absorica LD is not substitutable with other formulations of isotretinoin.

Adults

0.4 to 0.8 mg/kg/day PO, given in 2 divided doses with or without food, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. Adult patients whose disease is very severe with scarring or is primarily manifested on the trunk may require dosages up to 1.6 mg/kg/day PO given in 2 divided doses. Prior to upward dosage adjustments, patients should be questioned regarding their compliance. Adult Max: 1.6 mg/kg/day PO. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics.

Children and Adolescents 12 years and older

0.4 to 0.8 mg/kg/day PO, given in 2 divided doses with or without food, for 15 to 20 weeks or until the total cyst count decreases by 70%, whichever occurs first. Once daily dosing is not recommended. Long term use of isotretinoin has not been studied; do not exceed the recommended dosing duration. If further treatment with isotretinoin is necessary, do not reinitiate therapy for at least 2 months following completion of the previous course. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Due to significant adverse effects associated with its use, isotretinoin should be reserved for the treatment of patients with severe nodular acne that is unresponsive to conventional therapy, including antibiotics. Given careful consideration prior to use in this population, especially for those patients where a known metabolic or structural bone disease exists.

For the treatment of keratinization disorders including keratosis follicularis†, lamellar ichthyosis†, and pityriasis rubra pilaris†.

Oral dosage

Adults and Adolescents

Dosages up to 4 mg/kg/day PO have been used. The specific disease and its severity will determine the appropriate dosage.

For the treatment of juvenile chronic myelogenous leukemia (CML)†.

Oral dosage

Infants and Children

100 mg/m2/day orally resulted in 2 complete (CR) and 3 partial (PR) responses in 10 patients with juvenile chronic myelogenous leukemia in a multicenter, pilot study. The isotretinoin dosage could be increased by 25% each week after 1 month of therapy and some patients received up to 200 mg/m2/day. CR was defined as white blood cell (WBC) normalization and resolution of organomegaly and PR was defined as a greater than 50% decrease in WBC count and organomegaly. Additionally, one patient had a minimal response (defined as a 26% to 50% decrease in WBC count and organomegaly). The duration of response was 6 to 83 months in responding patients; 3 patients received a bone marrow transplant.

For the treatment of newly diagnosed, high-risk neuroblastoma† following autologous bone marrow transplantation.

Oral dosage

Children and Adolescents

160 mg/m2/day PO divided in 2 divided doses for 14 days repeated every 28 days for 6 cycles was studied in 258 pediatric patients aged 1 to 18 years with no evidence of progressive disease following 5 cycles of induction chemotherapy and either high-dose chemotherapy followed by autologous bone marrow transplantation or 3 additional cycles of chemotherapy in a randomized, phase III trial. At median follow-up of 36 months, the 3-year event-free survival (EFS) rate (46% vs. 29%; p = 0.027) but not the 3-year overall survival (OS) rate (56% vs. 50%; p = 0.45) was significantly improved in patients who received isotretinoin compared with patients who did not receive isotretinoin. At a median follow-up of 8 years, the 5-year EFS (42% vs. 31%; p = 0.1219) and OS (50% vs. 39%; p = 0.1946) rates were not significantly improved in patients who received isotretinoin compared with no isotretinoin when evaluated using a log-rank comparison, although the 5-year OS rate was statistically superior with isotretinoin therapy when a log (-log(.)) transformation evaluation was used (p = 0.0006). Additionally, the 5-year EFS rate was significantly improved in patients who received ABMT and isotretinoin compared with patients who continued receiving chemotherapy with no isotretinoin (p = 0.0038). Grade 3 or 4 infection occurred in 12% of patients who received isotretinoin.

For the treatment of recurrent cervical cancer, in combination with interferon alfa†.

Oral dosage

Adults

The dosage has not been established, although 1 mg/kg/day PO (rounded to the nearest 10 mg) divided into 2 doses has been studied in a phase II trial. Isotretinoin (n = 42) or tretinoin (n = 21) plus interferon alfa 3 million units/m2/day subcutaneously was studied in 63 patients; patient accrual was stopped in the tretinoin arm due to a low response in the first 20 patients. Of 39 evaluable patients who received isotretinoin plus interferon alfa, 3 patients (8%) experienced a partial response lasting 17, 22, and 24 weeks. Additionally, the median progression-free survival time was 3 months and the median overall survival time was 8 months in patients who received isotretinoin plus interferon alfa. Grade 3 and 4 toxicities reported in the isotretinoin plus interferon alfa arm included malaise and fatigue (26%), anemia (21%), and granulocytopenia (10%).

For the adjuvant treatment of advanced squamous cell head and neck cancer†, in combination with interferon alfa and vitamin E.

Oral dosage

Adults

50 mg/m2/day PO with interferon alfa 3 million international units/m2 SC 3 times weekly and alfa-tocopherol 1200 international units/day POfor 12 months following surgery, radiotherapy, or both was studied in 45 patients with locally advanced stage III or IV squamous-cell carcinoma of the head and neck in a nonrandomized, phase II study. Therapy was well tolerated with 86% of patients able to complete the full 12 months of therapy. At a median follow-up of 49.4 months, the 3- and 5-year progression-free survival rates were 82.2% and 80%, respectively, and the 3- and 5-years overall survival rates were 88.9% and 81.3%, respectively. Additionally, only 1 secondary primary tumor (acute promyelocytic leukemia) was reported. Serious toxicities reported in this study include grade 3 arthralgia/myalgia (9%), fatigue (7%), and weight loss (7%) and grade 3 and 4 infection (4%). One patient developed optic neuritis which resolved after withdrawing therapy.

For the adjuvant treatment of aggressive squamous cell skin carcinoma†, in combination with interferon alfa.

Oral dosage

Adults

Use has not been established, although 1 mg/kg/day PO plus interferon alfa 3 million units subcutaneously 3 times weekly for 6 months (median duration, 4.9 months) has been studied. Isotretinoin/interferon alfa was administered as adjuvant therapy following surgery or radiation therapy (RT) in 31 patients and compared to 34 patients who received no adjuvant therapy following surgery or RT in a randomized, phase III study. All patients had aggressive squamous-cell skin cancer defined as tumor size 2 cm or larger, perineural invasion, evidence of deep invasion, or proven metastases. At a median follow-up of 21.5 months, the primary endpoint of recurrence- and second primary tumor (SPT)-free survival rate was not significantly different in patients who received adjuvant therapy compared with patients who did not receive adjuvant therapy (hazard ratio = 1.13; 95% CI, 0.53 to 2.41). Additionally, the 2-year cumulative recurrence - and SPT-free survival rates were 51.5% and 62.4% for patients who received adjuvant therapy and no adjuvant therapy, respectively. Grade 3 and 4 toxicities reported in the adjuvant treatment arm included fatigue (26%), dry eye or conjunctivitis (19%), dry skin and skin rash (16%), and cheilitis (13%).

†Indicates off-label use

MAXIMUM DOSAGE

Adults

2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.

Geriatric

2 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 1.6 mg/kg/day PO (Absorica LD) for cystic acne.

Adolescents

1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.

Children

12 years: 1 mg/kg/day PO (all formulations EXCEPT Absorica LD) for cystic acne; 0.8 mg/kg/day PO (Absorica LD) for cystic acne.

younger than 12 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

Neonates

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Hepatic Impairment

Specific guidelines for dosage adjustments in hepatic impairment are not available; it appears that no dosage adjustments are needed.

Renal Impairment

Specific guidelines for dosage adjustments in renal impairment are not available; it appears that no dosage adjustments are needed.

ADMINISTRATION

Oral Administration

Absorica and Absorica LD may be administered without regard to meals. Administer all other isotretinoin formulations with food to maximize GI absorption. Failure to take certain isotretinoin formulations with food will significantly decrease absorption. Do not crush or open capsules. To minimize the risk of esophageal irritation, all isotretinoin formulations should be swallowed whole with a full glass of liquid.

All prescribers, patients, and pharmacists MUST comply with the conditions of the iPLEDGE REMS program when prescribing, dispensing, or receiving isotretinoin.

PRESCRIBERS must register and be activated in the iPLEDGE REMS program and must agree to comply with the following requirements:

determine reproductive status of all patients prior to initiating treatment

provide contraception counseling to patients who can get pregnant prior to and during treatment, or refer patients who can get pregnant to an expert for such counseling

provide scheduled pregnancy testing, and verify and document the negative pregnancy test results prior to writing each prescription, for no more than a 30-day supply

follow requirements described in the following booklets:

Guide to Best Practices for the iPLEDGE Program

Prescriber Contraception Counseling Guide

Recognizing Psychiatric Disorders in Adolescents and Young Adults: A Guide for Prescribers of Isotretinoin

MALE PATIENTS AND FEMALES OF NON-REPRODUCTIVE POTENTIAL must:

understand the risks and benefits of the drug

comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Cannot Get Pregnant

sign a Patient Information/Informed Consent form

obtain the prescription within 30 days of the office visit

FEMALES OF REPRODUCTIVE POTENTIAL WHO ARE NOT PREGNANT must:

understand the risks and benefits of the drug

comply with the REMS requirements described in the booklet entitled Guide to Isotretinoin for Patients Who Can Get Pregnant and Birth Control Workbook (including the pregnancy testing and contraception requirements)

sign a Patient Information/Informed Consent form and Patient Information/Informed Consent About Birth Defects form

demonstrate comprehension of the safe-use conditions of the program every month

obtain the prescription within 7 days of the pregnancy test collection

PHARMACIES must register and be activated with iPLEDGE, only dispense isotretinoin to patients who are authorized to receive the drug, and agree to comply with REMS requirements described in the booklet entitled Pharmacist Guide; specifically, the "Key Information for Pharmacists" section which includes the following dispensing information:

prescriptions must be obtained no later than the "Do Not Dispense To After" date, if not obtained, then the RMA must be reversed in the iPLEDGE Program system and the product returned to the inventory

no more than a 30-day supply, with Medication Guide, may be dispensed

refills require a new prescription and a new authorization from the iPLEDGE system

WHOLESALERS AND DISTRIBUTORS must register with iPLEDGE and agree to comply with the REMS requirements.[49581] [50393] [50394] [50395]

STORAGE

Absorica:

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

Accutane:

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

Amnesteem :

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

Claravis :

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

MYORISAN:

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

Sotret:

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

ZENATANE:

- Protect from light

- Store at controlled room temperature (between 68 and 77 degrees F)

CONTRAINDICATIONS / PRECAUTIONS

Paraben hypersensitivity, retinoid hypersensitivity

Isotretinoin is contraindicated in patients with retinoid hypersensitivity, including hypersensitivity to vitamin A, tretinoin, and etretinate, due to the possibility of cross-sensitivity. Similarly, isotretinoin is contraindicated in patients with paraben hypersensitivity because the drug is prepared with paraben as a preservative.

Pregnancy

Isotretinoin is contraindicated for use during pregnancy. Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. Documented birth defects associated with isotretinoin include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Spontaneous abortion and premature births have also been reported. To prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Patients must sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form, all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, use of the drug must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the iPLEDGE pregnancy registry at 866-495-0654.[49581] [50395]

Blood donation

Blood donation must be avoided while patients are receiving isotretinoin and for 1 month following completion of therapy because the donated blood might be given to a pregnant woman and expose the fetus.

Breast-feeding

According to the manufacturer, breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. Lactating women who are exposed to isotretinoin should avoid breast-feeding during treatment and for at least 8 days after the last dose. It is unknown whether isotretinoin is distributed into breast milk, effects the breast-fed infant, or effects milk production. Vitamin A, which is structurally related to isotretinoin, is present in breast milk. A topical agent may be preferred (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin, tretinoin) for the treatment of acne in a nursing mother, especially while nursing a neonate or preterm infant. 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.

Anorexia nervosa, children, corticosteroid therapy, hyperostosis, infants, neonates, osteomalacia, osteoporosis

Although an effect of isotretinoin on bone loss is not established, prescribers should use caution when treating patients with a genetic predisposition for age-related osteoporosis, a history of childhood osteoporosis conditions, osteomalacia, or other disorders of bone metabolism. This would include patients diagnosed with anorexia nervosa and those who are receiving chronic drug therapy that induces osteoporosis or osteomalacia or that affects vitamin D metabolism (e.g., corticosteroid therapy or anticonvulsant therapy). Effects of multiple courses of isotretinoin on the developing musculoskeletal system are unknown. It is important that isotretinoin be given at the recommended dosage for not longer than the recommended duration. There is some evidence that long-term, high-dose, or multiple courses of therapy with isotretinoin have more of an effect on the musculoskeletal system than a single course of therapy. The use of isotretinoin has not been studied in neonates, infants and children younger than 12 years of age. Use of isotretinoin in pediatric patients 12 to 17 years of age should be given careful consideration. Limited data suggest that isotretinoin may cause premature epiphyseal closure. The optimal interval before retreatment has not been defined for patients who have not completed skeletal growth. Patients may be at increased risk for adverse effects on the musculoskeletal system when participating in sports with repetitive impact where the risks of spondylolisthesis with and without pars fractures and hip growth plate injuries in early and late adolescence are known. There are spontaneous reports of fractures and delayed healing in patients involved in these activities while receiving isotretinoin treatment or following cessation of treatment. A high prevalence of skeletal hyperostosis has been noted in clinical trials for keratinization disorders using a mean isotretinoin dose of 2.24 mg/kg/day. Minimal skeletal hyperostosis and calcification of ligaments and tendons have also been observed by X-ray in prospective studies of nodular acne patients treated with a single course of isotretinoin at recommended doses.

Alcoholism, diabetes mellitus, hepatic disease, hepatitis, hypercholesterolemia, hyperlipidemia, hypertriglyceridemia, obesity, pancreatitis

Caution should be exercised when administering isotretinoin to patients with hyperlipidemia or those with conditions that may predispose them to high serum triglyceride levels (i.e., hypertriglyceridemia) such as alcoholism, other hepatic disease, diabetes mellitus, hypercholesterolemia, or obesity. If isotretinoin therapy is started, more frequent monitoring of serum lipids and/or blood sugar is recommended. Pancreatitis, and in rare instances fatal hemorrhagic pancreatitis, has occurred in patients receiving isotretinoin with elevated or normal levels of triglycerides. Pretreatment serum triglyceride levels should be obtained in all patients, followed by periodic lipid determinations throughout treatment (biweekly until lipid response is determined, followed by monthly monitoring). Isotretinoin should be discontinued if hypertriglyceridemia cannot be controlled at an acceptable level or if symptoms of pancreatitis occur. Clinical hepatitis considered possible or probably related to isotretinoin therapy has been reported. If normalization of liver enzyme levels does not readily occur with dose reduction or continuation of the drug or if hepatitis is suspected during isotretinoin treatment, the drug should be discontinued.

Inflammatory bowel disease

Isotretinoin has been temporally associated with inflammatory bowel disease (including regional ileitis). Isotretinoin may exacerbate symptoms and should be used with caution in patients with inflammatory bowel disease.

Depression, psychosis, suicidal ideation

Isotretinoin should be used cautiously in patients with psychotic disorders. Postmarketing reports show that isotretinoin may cause major depression, psychosis, and rarely, suicidal ideation, suicide attempts, suicide, and aggressive or violent behaviors. Discontinuation of isotretinoin therapy may be insufficient; further evaluation by a mental health professional may be necessary. Prescribers should read the brochure, Recognizing Psychiatric Disorders in Adolescents and Young Adults.

Contact lenses, driving or operating machinery, papilledema, visual disturbance

Patients should be warned against driving or operating machinery at night while taking isotretinoin. Decreased night vision and other visual disturbance have been reported during isotretinoin therapy; onset of visual changes may be sudden. Patients may experience decreased tolerance to contact lenses during and after isotretinoin therapy. All visual problems reported during isotretinoin treatment should be carefully monitored. All patients experiencing visual difficulties should discontinue isotretinoin therapy and have an ophthalmologic examination. Isotretinoin therapy has been associated with cases of pseudotumor cerebri (benign intracranial hypertension), some of which involved the concomitant use of systemic tetracyclines. Concurrent use of isotretinoin with systemic tetracyclines should be avoided. Early signs and symptoms of pseudotumor cerebri include papilledema, headache, nausea, vomiting, and visual disturbances. Patients with these symptoms should be screened for papilledema and, if present, they should be told to discontinue isotretinoin therapy immediately and be referred to a neurologist for follow-up and treatment.

Hearing impairment

Hearing impairment, which continued after discontinuing the drug, has been reported in patients taking isotretinoin. Patients who experience tinnitus or hearing impairment should discontinue isotretinoin treatment and be referred to for further follow-up.

Sunlight (UV) exposure

Retinoids may cause photosensitivity. Patients should avoid prolong sunlight (UV) exposure while receiving isotretinoin. Appropriate protective clothing (e.g., hat) and sunscreen should be used if patients are in the sunlight for an extended period of time. Wax epilation and skin resurfacing procedures (e.g., dermabrasion or laser treatments) should be avoided during isotretinoin therapy and for at least 6 months thereafter due to the possibility of scarring.

Agranulocytosis, leukopenia, neutropenia

Neutropenia and rare cases of agranulocytosis have been reported during isotretinoin therapy. Isotretinoin should be discontinued in patients show develop clinically significant leukopenia or neutropenia.

Contraception requirements, pregnancy testing, reproductive risk

Isotretinoin has been associated with an extremely high risk of birth defects if taken during pregnancy in any amount even for a short period of time. Discuss reproductive risk with the patient prior to initiation of therapy. Isotretinoin must not be initiated in females of childbearing potential, regardless of whether they are sexually active, until negative results from 2 urine or serum pregnancy tests are confirmed and the patient or her guardian completes the consent form; the interval between the 2 tests should be at least 19 days. Monthly pregnancy testing during isotretinoin therapy is also required. Discuss contraception requirements with the patient before beginning treatment and monthly during treatment. Women who are, or might become, sexually active with a male partner must select and use 2 forms of effective contraception simultaneously for at least 1 month before beginning, during, and for 1 month following discontinuation of therapy, even when there has been a history of infertility, unless due to hysterectomy. Low-dose progestins may be an inadequate method of contraception during isotretinoin therapy. In addition, females who are using hormonal contraception as a primary form of birth control should not take St. John's Wort, as it may decrease the effectiveness of hormonal contraceptives.[49581] [50395]

ADVERSE REACTIONS

Severe

erythema multiforme / Delayed / Incidence not known

Stevens-Johnson syndrome / Delayed / Incidence not known

toxic epidermal necrolysis / Delayed / Incidence not known

fetal death / Delayed / Incidence not known

spontaneous fetal abortion / Delayed / Incidence not known

teratogenesis / Delayed / Incidence not known

anaphylactoid reactions / Rapid / Incidence not known

vasculitis / Delayed / Incidence not known

glomerulonephritis / Delayed / Incidence not known

pancreatitis / Delayed / Incidence not known

rhabdomyolysis / Delayed / Incidence not known

epiphyseal closure / Delayed / Incidence not known

bone fractures / Delayed / Incidence not known

agranulocytosis / Delayed / Incidence not known

ileus / Delayed / Incidence not known

esophageal ulceration / Delayed / Incidence not known

stroke / Early / Incidence not known

retinal hemorrhage / Delayed / Incidence not known

seizures / Delayed / Incidence not known

increased intracranial pressure / Early / Incidence not known

suicidal ideation / Delayed / Incidence not known

night blindness / Delayed / Incidence not known

keratitis / Delayed / Incidence not known

optic neuritis / Delayed / Incidence not known

visual impairment / Early / Incidence not known

corneal opacification / Delayed / Incidence not known

hearing loss / Delayed / Incidence not known

proteinuria / Delayed / Incidence not known

bronchospasm / Rapid / Incidence not known

Moderate

hypertriglyceridemia / Delayed / 25.0-25.0

elevated hepatic enzymes / Delayed / 15.0-15.0

hypercholesterolemia / Delayed / 7.0-7.0

impaired wound healing / Delayed / Incidence not known

hematoma / Early / Incidence not known

contact dermatitis / Delayed / Incidence not known

erythema / Early / Incidence not known

diabetes mellitus / Delayed / Incidence not known

hyperglycemia / Delayed / Incidence not known

chest pain (unspecified) / Early / Incidence not known

osteopenia / Delayed / Incidence not known

hyperostosis / Delayed / Incidence not known

osteoporosis / Delayed / Incidence not known

neutropenia / Delayed / Incidence not known

thrombocytosis / Delayed / Incidence not known

thrombocytopenia / Delayed / Incidence not known

anemia / Delayed / Incidence not known

inflammatory bowel disease / Delayed / Incidence not known

esophagitis / Delayed / Incidence not known

colitis / Delayed / Incidence not known

constipation / Delayed / Incidence not known

hepatitis / Delayed / Incidence not known

pseudotumor cerebri / Delayed / Incidence not known

depression / Delayed / Incidence not known

hallucinations / Early / Incidence not known

euphoria / Early / Incidence not known

psychosis / Early / Incidence not known

conjunctivitis / Delayed / Incidence not known

blurred vision / Early / Incidence not known

photophobia / Early / Incidence not known

conjunctival hyperemia / Early / Incidence not known

cataracts / Delayed / Incidence not known

hematuria / Delayed / Incidence not known

pyuria / Delayed / Incidence not known

impotence (erectile dysfunction) / Delayed / Incidence not known

palpitations / Early / Incidence not known

sinus tachycardia / Rapid / Incidence not known

hyperuricemia / Delayed / Incidence not known

edema / Delayed / Incidence not known

lymphadenopathy / Delayed / Incidence not known

Mild

back pain / Delayed / 29.0-29.0

arthralgia / Delayed / 22.0-22.0

musculoskeletal pain / Early / 16.0-16.0

cheilitis / Delayed / Incidence not known

hirsutism / Delayed / Incidence not known

skin hyperpigmentation / Delayed / Incidence not known

rash / Early / Incidence not known

photosensitivity / Delayed / Incidence not known

pruritus / Rapid / Incidence not known

xerosis / Delayed / Incidence not known

alopecia / Delayed / Incidence not known

hyperhidrosis / Delayed / Incidence not known

acneiform rash / Delayed / Incidence not known

urticaria / Rapid / Incidence not known

flushing / Rapid / Incidence not known

skin hypopigmentation / Delayed / Incidence not known

seborrhea / Delayed / Incidence not known

xerostomia / Early / Incidence not known

purpura / Delayed / Incidence not known

myalgia / Early / Incidence not known

diarrhea / Early / Incidence not known

vomiting / Early / Incidence not known

gingivitis / Delayed / Incidence not known

weight loss / Delayed / Incidence not known

abdominal pain / Early / Incidence not known

nausea / Early / Incidence not known

weakness / Early / Incidence not known

insomnia / Early / Incidence not known

headache / Early / Incidence not known

paresthesias / Delayed / Incidence not known

malaise / Early / Incidence not known

lethargy / Early / Incidence not known

dizziness / Early / Incidence not known

drowsiness / Early / Incidence not known

fatigue / Early / Incidence not known

syncope / Early / Incidence not known

anxiety / Delayed / Incidence not known

emotional lability / Early / Incidence not known

ocular pruritus / Rapid / Incidence not known

xerophthalmia / Early / Incidence not known

ocular irritation / Rapid / Incidence not known

lacrimation / Early / Incidence not known

diplopia / Early / Incidence not known

tinnitus / Delayed / Incidence not known

libido decrease / Delayed / Incidence not known

menstrual irregularity / Delayed / Incidence not known

epistaxis / Delayed / Incidence not known

nasal dryness / Early / Incidence not known

pharyngitis / Delayed / Incidence not known

infection / Delayed / Incidence not known

DRUG INTERACTIONS

Adapalene; Benzoyl Peroxide: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.

Azelastine; Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Beclomethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Benzoyl Peroxide: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.

Benzoyl Peroxide; Clindamycin: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.

Benzoyl Peroxide; Erythromycin: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.

Benzoyl Peroxide; Sulfur: (Moderate) Benzoyl peroxide will cause additive irritant and drying effects with concomitant oral isotretinoin use. Reduction in the dose or temporary discontinuation of the benzoyl peroxide product may be needed until skin irritation resolves.

Betamethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Budesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Budesonide; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Budesonide; Glycopyrrolate; Formoterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Cholestyramine: (Moderate) Cholestyramine can bind with and possibly decrease the oral absorption of isotretinoin. To minimize drug interactions, administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of cholestyramine.

Ciclesonide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Colestipol: (Moderate) Colestipol can bind with and possibly decrease the oral absorption of isotretinoin. Administer other drugs at least 1 hour before or at least 4 to 6 hours after the administration of colestipol.

Conjugated Estrogens; Medroxyprogesterone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Corticosteroids: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Cortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Deflazacort: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Dexamethasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Drospirenone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Drospirenone; Estradiol: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Drospirenone; Ethinyl Estradiol: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Drospirenone; Ethinyl Estradiol; Levomefolate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.

Elagolix; Estradiol; Norethindrone acetate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Eravacycline: (Major) Avoid the concomitant use of isotretinoin and eravacycline due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.

Estradiol Cypionate; Medroxyprogesterone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Estradiol; Levonorgestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Estradiol; Norethindrone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethanol: (Minor) Ethanol can potentiate the hypertriglyceridemic effects of isotretinoin; patients experiencing hyperlipidemia while on isotretinoin should be advised to limit their intake of ethanol.

Ethinyl Estradiol: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Desogestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Ethynodiol Diacetate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Etonogestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Levonorgestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Levonorgestrel; Ferrous bisglycinate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Levonorgestrel; Folic Acid; Levomefolate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.

Ethinyl Estradiol; Norelgestromin: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norethindrone Acetate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norethindrone Acetate; Ferrous fumarate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norethindrone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norethindrone; Ferrous fumarate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norgestimate: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Ethinyl Estradiol; Norgestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy. (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Fludrocortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Flunisolide: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Fluticasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Fluticasone; Salmeterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Fluticasone; Umeclidinium; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Fluticasone; Vilanterol: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Formoterol; Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Fosphenytoin: (Minor) Long-term use of fosphenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between fosphenytoin and isotretinoin therapy. Patients receiving fosphenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.

Hydrocortisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Leuprolide; Norethindrone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Levomefolate: (Minor) L-methylfolate and isotretinoin should be used together cautiously. Plasma concentrations of L-methylfolate may be reduced when used concomitantly with isotretinoin. Monitor patients for decreased efficacy of L-methylfolate if these agents are used together.

Levonorgestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Lomitapide: (Moderate) Caution should be exercised when lomitapide is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of lomitapide with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.

Medroxyprogesterone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Mestranol; Norethindrone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Methotrexate: (Major) Concomitant use of systemic retinoids, such as isotretinoin, and methotrexate could increase risk of liver-related side effects of methotrexate and such patients should be monitored closely during methotrexate therapy.

Methoxsalen: (Moderate) Use methoxsalen and retinoids together with caution; the risk of severe burns/phototoxicity may be additive. If concurrent use is necessary, closely monitor patients for signs or symptoms of skin toxicity.

Methylprednisolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Mipomersen: (Moderate) Caution should be exercised when mipomersen is used with other medications known to have potential for hepatotoxicity, such as isotretinoin. The effect of concomitant administration of mipomersen with other hepatotoxic medications is unknown. More frequent monitoring of liver-related tests may be warranted.

Mometasone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Norethindrone: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Norgestrel: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Orlistat: (Moderate) The bioavailability of orally administered retinoids may be decreased during coadministration with isotretinoin. In patients receiving orally-administered retinoids along with orlistat, close monitoring is recommended. In addition, the manufacturer recommends that fat-soluble vitamin analogues be administered at least 2 hours before or after the administration of orlistat to limit effects on oral absorption.

Phenytoin: (Minor) Long-term use of phenytoin has been associated with osteomalacia. No formal clinical studies have been conducted to assess if there is an additive or interactive effect on bone loss between phenytoin and isotretinoin therapy. Patients receiving phenytoin or other anticonvulsants that may affect the bone should receive isotretinoin therapy with caution.

Porfimer: (Major) Avoid coadministration of porfimer with retinoids due to the risk of increased photosensitivity. Porfimer is a light-activated drug used in photodynamic therapy; all patients treated with porfimer will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.

Prednisolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Prednisone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.

Segesterone Acetate; Ethinyl Estradiol: (Major) Although other hormonal contraceptives are highly effective during isotretinoin therapy, there have been reports of pregnancy in women who have used combination oral contraceptives or injectable/implantable contraceptive products. These reports are more frequent for women who use only a single method of contraception. Therefore, it is critically important for women of childbearing potential to select and commit to use 2 forms of contraception simultaneously, at least 1 of which must be a primary form, unless absolute abstinence is the chosen method or the patient has undergone a hysterectomy.

Sodium Thiosulfate; Salicylic Acid: (Moderate) Dryness of the skin and mucus membranes are common side effects of retinoid therapy. Simultaneous use of retinoids and topical drying agents, such as salicylic acid, can potentiate the drying effects of retinoids on the skin. Be alert for signs of skin irritation, the offending topical agents may need to be used less often or discontinued during retinoid therapy.

St. John's Wort, Hypericum perforatum: (Major) Because of the teratogenic potential of isotretinoin, the coadministration of St. John's wort, Hypericum perforatum and isotretinoin is not recommended in females who are using hormonal contraceptives as their primary form of birth control. St. John's wort, Hypericum perforatum appears to interact with estrogens and oral contraceptives. Breakthrough bleeding and pregnancies have been reported following coadministration of St. John's Wort and hormonal contraception. It is thought that St. John's wort induces hormone metabolism via induction of the hepatic CYP3A4 isoenzyme. It is possible that, as with other CYP3A4 inducers, St. John's wort could also reduce the therapeutic efficacy of non-oral combination contraceptives or progestin-only contraceptives (i.e., norgestrel, levonorgestrel, and medroxyprogesterone).

Tetracyclines: (Major) Avoid the concomitant use of isotretinoin and systemic tetracyclines due to the potential for increased cranial pressure and an increased risk of pseudotumor cerebri (benign intracranial hypertension). Pseudotumor cerebri has been reported with both systemic retinoid and tetracycline use alone. Early signs and symptoms include papilledema, headache, nausea, vomiting, and visual disturbances.

Triamcinolone: (Minor) Both isotretinoin and corticosteroids can cause osteoporosis during chronic use. Patients receiving systemic corticosteroids should receive isotretinoin therapy with caution.

Verteporfin: (Moderate) Use caution if coadministration of verteporfin with retinoids is necessary due to the risk of increased photosensitivity. Verteporfin is a light-activated drug used in photodynamic therapy; all patients treated with verteporfin will be photosensitive. Concomitant use of other photosensitizing agents like retinoids may increase the risk of a photosensitivity reaction.

Warfarin: (Moderate) Isotretinoin can decrease the anticoagulation effects of warfarin. If these drugs are coadministered, monitor INR and adjust warfarin doses as needed.

PREGNANCY AND LACTATION

Pregnancy

Isotretinoin is contraindicated for use during pregnancy. Although not every exposure to isotretinoin has resulted in a birth defect, there is an extremely high risk that birth defects can occur if pregnancy occurs while taking isotretinoin in any amount even for a short period of time. Documented birth defects associated with isotretinoin include abnormalities of the face, eyes, ears, skull, central nervous system, cardiovascular system, thymus, and parathyroid glands. Spontaneous abortion and premature births have also been reported. To prevent isotretinoin exposure during pregnancy, the iPLEDGE program has been developed. This program requires prescribers, pharmacists and patients to comply with certain conditions prior to prescribing, dispensing or receiving isotretinoin. Patients must sign a Patient Information/Consent form about isotretinoin and birth defects, in addition to the consent form, all patients should receive information about other potentially serious risks. If pregnancy does occur during treatment, use of the drug must be discontinued immediately. The patient should be referred to an Obstetrician-Gynecologist experienced in reproductive toxicity for further evaluation and counseling. Prescribers should report all cases of pregnancy to the FDA MedWatch program at 800-FDA-1088 and the iPLEDGE pregnancy registry at 866-495-0654.[49581] [50395]

According to the manufacturer, breast-feeding women should not receive isotretinoin due to the potential adverse effects to the nursing infant. Lactating women who are exposed to isotretinoin should avoid breast-feeding during treatment and for at least 8 days after the last dose. It is unknown whether isotretinoin is distributed into breast milk, effects the breast-fed infant, or effects milk production. Vitamin A, which is structurally related to isotretinoin, is present in breast milk. A topical agent may be preferred (e.g., azelaic acid, benzoyl peroxide, clindamycin, erythromycin, tretinoin) for the treatment of acne in a nursing mother, especially while nursing a neonate or preterm infant. 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.

MECHANISM OF ACTION

Retinoids are intracrine and paracrine mediators of cell differentiation and proliferation, apoptosis (programmed cell death), and reproduction. Cells regulate the formation of specific retinoid isomers depending upon the cellular action required. The numerous effects of retinoids reflect the complex biology of the nuclear receptors that mediate retinoid activity. Retinoids exert their effects through binding to specific nuclear retinoid receptors, which are members of the steroid-thyroid superfamily of nuclear receptors. Retinoid receptors are divided into retinoid X receptors (RXRs) and retinoic acid receptors (RARs); both types can be further divided into 3 subtypes: Alpha, beta, and gamma. These receptor subtypes are further divided into many isoforms. Retinoid receptors are structurally similar but have different affinities for different types of retinoids and distribution varies throughout the body resulting in a wide range of actions. Isotretinoin acts primarily on the RAR family of receptors.

The primary action of isotretinoin in the treatment of acne is a reversible inhibition of sebum production through a reduction in the size of sebaceous glands and possible inhibition of follicular keratinization. The latter mechanism may be responsible for its beneficial effects in treating keratinization disorders. Sebum production can be reversibly reduced to 10% of pretreatment levels. Given in high dosages, isotretinoin can indirectly reduce the concentration of Propionibacterium acnes bacteria through decreased sebum production. Isotretinoin may inhibit prostaglandin E2 and collagenase, which would account for its antiinflammatory effect.

The role of retinoids in fetal development is to specify positional information for cells in developing limbs and possibly in the nervous system. In all age groups, retinoids are required for normal growth and proliferation of epithelial tissues. Dysregulation of retinoids may contribute to lung, gastric, uterine, bladder, testicular, breast, prostate, pancreatic, and skin cancers.

PHARMACOKINETICS

Isotretinoin is administered orally. Distribution has not been fully characterized; however, unlike vitamin A, isotretinoin does not accumulate in the liver. It is unknown whether isotretinoin crosses the placenta or is excreted into breast milk. The drug is 99.9% bound to plasma proteins, primarily albumin. Isotretinoin is metabolized in the liver by CYP2C8, CYP2C9, CYP3A4, and CYP2B6. At least 3 metabolites [4-oxo-isotretinoin, retinoic acid (tretinoin), 4-oxo-retinoic acid (4-oxo-tretinoin)] have been identified in human plasma. All of three metabolites have retinoid activity in vivo; however, the clinical significance of the metabolites' activity is unknown. The half-lives of isotretinoin and its active metabolite, 4-oxo-isotretinoin, are about 10 to 24 hours and 38 hours, respectively. The metabolites of isotretinoin are eliminated in the feces and urine in relatively equal amounts.

Affected cytochrome P450 isoenzymes: none

Oral Route

Isotretinoin is highly lipophilic and therefore, oral absorption is enhanced when given with a high-fat meal. With the exception of Absorica and Absorica LD, isotretinoin formulations should be administered with a meal to enhance bioavailability; however, in general, foods high in cholesterol or fat should be avoided to reduce the risk of developing hypertriglyceridemia. Compared to Accutane, Absorica is bioequivalent when taken with a high-fat meal. However, under fasting conditions, the Absorica AUC is approximately 83% higher and therefore, this formulation is not interchangeable with Accutane or its generic equivalents. Peak plasma concentrations are attained within approximately 3 hours under fasted conditions. Under fed conditions, the peak plasma concentrations are reached in approximately 5 to 6 hours.