CLASSES

Anti-Rheumtic Monoclonal Antibodies

Interleukin-6 (IL-6) Inhibitors

BOXED WARNING

Diabetes mellitus, fungal infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, influenza, sepsis, surgery, tuberculosis

Patients who receive tocilizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Infections include active tuberculosis and invasive fungal infections including candidiasis, aspergillosis, and pneumocystis. Bacterial, viral, and other infections due to opportunistic pathogens have been reported. Most patients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. Patients who have surgery while taking tocilizumab may be at greater risk for postoperative infections. Patients with an invasive fungal infection may present with disseminated disease, and tuberculosis may present as pulmonary or extrapulmonary disease. Evaluate patients for tuberculosis risk factors before starting tocilizumab. Also, test patients for latent tuberculosis before and during tocilizumab receipt. Initiate treatment for latent infection before tocilizumab use. Consider anti-tuberculosis therapy prior to tocilizumab initiation for 2 patient groups: patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and patients with a negative test for latent tuberculosis but with risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Carefully consider the risks and benefits of tocilizumab before initiating therapy in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or opportunistic infection, with underlying conditions that may predispose them to infection (e.g., patients with advanced or uncontrolled diabetes mellitus, human immunodeficiency virus (HIV) infection, or immunosuppression), or who have resided or traveled in areas of endemic tuberculosis or endemic mycoses. Tocilizumab initiation is not recommended for patients with an absolute neutrophil count (ANC) less than 2,000/mm3, tocilizumab discontinuation is advised for an ANC less than 500/mm3, and tocilizumab interruption is advised for an ANC between 500/mm3 and 1000/mm3. Closely monitor patients for the development of signs and symptoms of infection during and after tocilizumab treatment; signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. Consider the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to taking tocilizumab. Do not administer tocilizumab to a patient with an active infection including localized infections. If a serious infection such as sepsis or influenza or an opportunistic infection develops, interrupt tocilizumab receipt until the infection is controlled. If a new infection develops during tocilizumab receipt, complete a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

DEA CLASS

Rx

DESCRIPTION

Humanized IL-6 receptor-inhibiting monoclonal antibody

In adults, used for moderate to severe rheumatoid arthritis (RA) with inadequate response to DMARDs, for giant cell arteritis (temporal arteritis), and for cytokine release syndrome

Used in pediatric patients at least 2 years of age for active systemic or polyarticular juvenile idiopathic arthritis (JIA) and for cytokine release syndrome

Boxed warning regarding risk for serious infections

COMMON BRAND NAMES

Actemra

HOW SUPPLIED

Actemra Intravenous Inj Sol: 1mL, 20mg

Actemra Subcutaneous Sol: 0.9mL, 162mg

DOSAGE & INDICATIONS

For the treatment of moderately- to severely-active rheumatoid arthritis in patients who have had an inadequate response to one or more disease-modifying antirheumatic drugs.

Intravenous dosage

Adults

4 mg/kg IV given over 1 hour every 4 weeks. If needed, increase dose to 8 mg/kg IV every 4 weeks; doses greater than 800 mg per infusion are not recommended. Tocilizumab may be used alone or in combination with methotrexate or another disease modifying antirheumatic drugs (DMARDs). However, avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept. Guidelines suggest switching to a non-TNF biologic such as tocilizumab for patients with established disease who have a serious adverse event with a TNF blocker. Further, a switch to a non-TNF biologic is an option for patients with moderate or high disease activity after 3 or more months of a TNF blocker or with a non-serious adverse event. Also, a switch to another non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of rituximab or abatacept or with a non-serious adverse event to either drug. Lastly, a switch to another type or category of non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of the new drug. The goal is low disease activity or remission.

Subcutaneous dosage

Adults weighing less than 100 kg

162 mg subcutaneously every other week as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs. Increase to 162 mg subcutaneously once weekly based on clinical response. If transitioning from IV tocilizumab, give first subcutaneous dose instead of the next scheduled IV dose. Guidelines suggest switching to a non-TNF biologic such as tocilizumab for patients with established disease who have a serious adverse event with a TNF blocker. Further, a switch to a non-TNF biologic is an option for patients with moderate or high disease activity after 3 or more months of a TNF blocker or with a non-serious adverse event. Also, a switch to another non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of rituximab or abatacept or with a non-serious adverse event to either drug. Lastly, a switch to another type or category of non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of the new drug. The goal is low disease activity or remission.

Adults weighing 100 kg or more

162 mg subcutaneously once weekly as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs. If transitioning from IV tocilizumab, give first subcutaneous dose instead of the next scheduled IV dose. Guidelines suggest switching to a non-TNF biologic such as tocilizumab for patients with established disease who have a serious adverse event with a TNF blocker. Further, a switch to a non-TNF biologic is an option for patients with moderate or high disease activity after 3 or more months of a TNF blocker or with a non-serious adverse event. Also, a switch to another non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of rituximab or abatacept or with a non-serious adverse event to either drug. Lastly, a switch to another type or category of non-TNF biologic is an option for patients with moderate or high disease activity after 6 or more months of the new drug. The goal is low disease activity or remission.

For the treatment of active polyarticular juvenile idiopathic arthritis .

NOTE: Tocilizumab has been designated an orphan drug by the FDA for this indication.

Intravenous dosage

Children and Adolescents 2 to 17 years weighing 30 kg or more

8 mg/kg/dose IV every 4 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

Children and Adolescents 2 to 17 weighing less than 30 kg

10 mg/kg/dose IV every 4 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

Subcutaneous dosage

Children and Adolescents 2 to 17 years weighing 30 kg or more

162 mg/dose subcutaneously every 2 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

Children and Adolescents 2 to 17 years weighing less than 30 kg

162 mg/dose subcutaneously every 3 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

For the treatment of active systemic juvenile idiopathic arthritis.

Intravenous dosage

Children and Adolescents 2 to 17 years weighing 30 kg or more

8 mg/kg/dose IV every 2 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

Children and Adolescents 2 to 17 years weighing less than 30 kg

12 mg/kg/dose IV every 2 weeks; administer over 1 hour. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.[38283]

Subcutaneous dosage

Children and Adolescents 2 to 17 years weighing 30 kg or more

162 mg/dose subcutaneously every week. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.

Children and Adolescents 2 to 17 years weighing less than 30 kg

162 mg/dose subcutaneously every 2 weeks. When transitioning from IV to subcutaneous administration, administer the first subcutaneous dose instead of the next scheduled IV dose. Do not change dose based solely on a single visit body weight measurement, as weight may fluctuate. May use as monotherapy or in combination with methotrexate.[38283]

For the treatment of temporal arteritis, also known as giant cell arteritis (GCA).

Subcutaneous dosage

Adults

162 mg subcutaneously once every week, in combination with a tapering course of glucocorticoids, is the recommended dose. A dose of 162 mg subcutaneously once every other week, in combination with a tapering course of glucocorticoids, may be prescribed based on clinical considerations. Tocilizumab may be used alone following discontinuation of glucocorticoids.

For the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS).

Intravenous dosage

Adults, Adolescents, and Children 2 years old and older, weighing 30 kg or more

8 mg/kg IV over 60 minutes for one dose, alone or in combination with corticosteroids. If no clinical improvement in the signs and symptoms of CRS occur after the first dose, up to 3 additional doses of tocilizumab may be administered at least 8 hours apart; doses exceeding 800 mg are not recommended. Only the intravenous route should be used for the treatment of CRS; subcutaneous administration is not approved for this use. In a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematologic malignancies, 69% of patients with a first episode of CRS who were treated with tocilizumab achieved a response, defined as resolution (lack of fever and off vasopressors for at least 24 hours) within 14 days of the first dose of tocilizumab, less than 2 doses of tocilizumab administered, and no additional treatment beyond tocilizumab and corticosteroids. This was confirmed in a second study using an independent cohort that included 14 patients with CAR T cell-induced CRS.

Adults, Adolescents, and Children 2 years old and older, weighing less than 30 kg

12 mg/kg IV over 60 minutes for one dose, alone or in combination with corticosteroids. If no clinical improvement in the signs and symptoms of CRS occur after the first dose, up to 3 additional doses of tocilizumab may be administered at least 8 hours apart; doses exceeding 800 mg are not recommended. Only the intravenous route should be used for the treatment of CRS; subcutaneous administration is not approved for this use. In a retrospective analysis of pooled outcome data from clinical trials of CAR T-cell therapies for hematologic malignancies, 69% of patients with a first episode of CRS who were treated with tocilizumab achieved a response, defined as resolution (lack of fever and off vasopressors for at least 24 hours) within 14 days of the first dose of tocilizumab, less than 2 doses of tocilizumab administered, and no additional treatment beyond tocilizumab and corticosteroids. This was confirmed in a second study using an independent cohort that included 14 patients with CAR T cell-induced CRS.

For the treatment of systemic scleroderma (systemic sclerosis)†.

NOTE: Tocilizumab has been designated an orphan drug by the FDA for this indication.

Intravenous dosage

Adults

8 mg/kg IV once monthly.

Subcutaneous dosage

Adults

162 mg subcutaneously once weekly.

†Indicates off-label use

MAXIMUM DOSAGE

Adults

Rheumatoid arthritis, weighing more than 100 kg: 800 mg/dose IV and 162 mg/dose subcutaneously.

Rheumatoid arthritis and giant cell arteritis, weighing 100 kg or less: 8 mg/kg/dose IV and 162 mg/dose subcutaneously.

Cytokine Release Syndrome (CRS), weighing 30 kg or more: 800 mg/dose IV.

CRS, weighing less than 30 kg: 12 mg/kg IV.

Geriatric

Rheumatoid arthritis, weighing more than 100 kg: 800 mg/dose IV and 162 mg/dose subcutaneously.

Rheumatoid arthritis and giant cell arteritis, weighing 100 kg or less: 8 mg/kg/dose IV and 162 mg/dose subcutaneously.

Cytokine Release Syndrome (CRS), weighing 30 kg or more: 800 mg/dose IV.

CRS, weighing less than 30 kg: 12 mg/kg IV.

Adolescents

Weighing 30 kg or more: 8 mg/kg/dose IV and 162 mg/dose subcutaneously.

Weighing less than 30 kg: 12 mg/kg/dose IV for systemic juvenile idiopathic arthritis (SJIA) and cytokine release syndrome (CRS); 10 mg/kg/dose IV for polyarticular juvenile idiopathic arthritis (PJIA); 162 mg/dose subcutaneously for SJIA and PJIA.

Children

2 to 12 years weighing 30 kg or more: 8 mg/kg/dose IV and 162 mg/dose subcutaneously.

2 to 12 years weighing less than 30 kg: 12 mg/kg/dose IV for systemic juvenile idiopathic arthritis (SJIA) and cytokine release syndrome (CRS); 10 mg/kg/dose IV for polyarticular juvenile idiopathic arthritis (PJIA); 162 mg/dose subcutaneously for SJIA and PJIA.

Younger than 2 years: Safety and efficacy have not been established.

Infants

Safety and efficacy have not been established.

DOSING CONSIDERATIONS

Hepatic Impairment

Adult Patients with rheumatoid arthritis or giant cell arteritis with hepatic impairment

Prior to treatment initiation: Do not initiate treatment with tocilizumab if active liver disease or hepatic impairment is present, or if baseline AST/ALT is more than 1.5 times the upper limit of normal (ULN). However, patients with severe or life-threatening cytokine release syndrome (CRS) frequently have elevated ALT or AST; the decision to administer tocilizumab should take into account the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab.[38283]

Hepatic enzyme elevations occurring during treatment:[38283]

AST and/or ALT from 1 to 3 times the ULN: Dose modify concomitant DMARDs, if appropriate.

- Intravenous dosing: For persistent increases of 3 times the ULN or less, reduce IV tocilizumab dose to 4 mg/kg or interrupt tocilizumab dosing until AST/ALT have normalized.

- Subcutaneous dosing: Reduce subcutaneous dosing interval to every other week or hold tocilizumab dosing until AST/ALT have normalized. Once ALT/AST have normalized, resume subcutaneous injection at every other week dosing and increase to once weekly as clinically appropriate.

AST and/or ALT more than 3 times and up to 5 times the ULN: Interrupt tocilizumab dosing until AST/ALT is less than 3 times the ULN and then follow dosing recommendations for AST and/or ALT more than 1 to 3 times ULN. For persistent increases more than 3 times the ULN, discontinue tocilizumab.

AST and/or ALT greater than 5 times the ULN: Discontinue tocilizumab.

Pediatric Patients with hepatic impairment

Tocilizumab dose reduction has not been studied in the systemic juvenile idiopathic arthritis (SJIA) or polyarticular juvenile idiopathic arthritis (PJIA) population. Tocilizumab dose interruptions are recommended for liver enzyme abnormalities in patients with SJIA or PJIA at levels similar to what is outlined for adult patients with rheumatoid arthritis and giant cell arteritis. If appropriate, dose modify or stop concomitant DMARDs and hold tocilizumab dosing until the clinical situation has been evaluated. In SJIA and PJIA, base the decision to discontinue tocilizumab upon the medical assessment of the individual patient and the laboratory abnormality involved.[38283]

Renal Impairment

CrCl 30 mL/minute or more: No dose adjustment is needed.

CrCl less than 30 mL/minute: Tocilizumab has not been studied in patients with severe renal impairment.

ADMINISTRATION

Injectable Administration

Visually inspect parenteral products for particulate matter and discoloration prior to administration whenever solution and container permit. Tocilizumab is a clear and colorless to pale yellow liquid.

The prefilled syringe and the autoinjector are ONLY for subcutaneous injection use.

The vial is ONLY for use in preparing an intravenous infusion.

Intravenous Administration

Administer intravenous infusions under the supervision of a qualified health professional. Have appropriate medical treatment available for immediate use in the event of a serious hypersensitivity reaction.

The drug must be diluted as an infusion prior to use. Do not administer as an intravenous push or bolus.

Infusion Preparation

Compatible infusion solutions for preparation: 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection.

Utilize a 50 mL infusion bag or bottle for patients who weigh less than 30 kg. Utilize a 100 mL infusion bag or bottle for patients who weigh at least 30 kg.

From a 50 mL or 100 mL infusion bag or bottle, withdraw a volume of the 0.9% Sodium Chloride Injection or 0.45% Sodium Chloride Injection equal to the volume of the tocilizumab solution required for the patient's dose.

Each tocilizumab vial contains a 20 mg/mL solution.

For a 4 mg/kg dose, 0.2 mL/kg of tocilizumab is needed.

For a 8 mg/kg dose, 0.4 mL/kg is needed.

For a 10 mg/kg dose, 0.5 mL/kg is needed.

For a 12 mg/kg dose, 0.6 mL/kg is needed.

Withdraw the amount of tocilizumab for intravenous infusion from the vial(s) and slowly add to the infusion bag or bottle.

Gently invert the bag to mix and to avoid foaming.

Fully diluted tocilizumab solutions are compatible with polypropylene, polyethylene, and polyvinyl chloride infusion bags and polypropylene, polyethylene, and glass infusion bottles.

Storage: The fully diluted tocilizumab solutions for infusion using 0.9% Sodium Chloride Injection may be stored at 2 to 8 degrees C (36 to 46 degrees F) or room temperature for up to 24 hours and should be protected from light. The fully diluted tocilizumab solutions for infusion using 0.45% Sodium Chloride Injection may be stored at 2 to 8 degrees C (36 to 46 degrees F) for up to 24 hours or at room temperature for up to 4 hours and should be protected from light. Do not freeze.

Do not use any unused product remaining in vials; tocilizumab does not contain preservatives.

Intravenous Infusion Administration

Prior to infusion, allow the fully diluted tocilizumab infusion to reach room temperature.

Administer as an intravenous infusion over 60 minutes with an infusion set.

Do not infuse tocilizumab concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the coadministration of tocilizumab with other drugs.

Subcutaneous Administration

General information

Administer the first injection of tocilizumab under the supervision of a qualified health professional. Have appropriate medical treatment available for immediate use in the event of a serious hypersensitivity reaction.

Assess the suitability of the patient for home use after the first dose. Patients should inform their provider before administering the next dose if they experience any symptoms of an allergic reaction. Patients should seek immediate medical attention if they develop symptoms of serious allergic reactions.

After the first dose, the subcutaneous injection may subsequently be given by the patient or patient's caregiver after proper training in injection technique, and a healthcare practitioner determines that it is appropriate.

Pediatric patients may self-inject with the prefilled syringe if both the healthcare practitioner and the parent/legal guardian determines it is appropriate. The ability of pediatric patients to self-inject using the autoinjector has not been tested.[38283]

Prefilled Syringe:

Remove the prefilled syringe from the refrigerator and allow it to sit at room temperature outside of the carton for 30 minutes. Do not warm tocilizumab in any other way.

Pick an injection site such as the front of a thigh, the outer area of an upper arm, or the abdomen except for the 2-inch area around the navel. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Rotate injection sites with each injection. Inject at least 1 inch from the last area injected.

Remove the needle cap immediately before injection, and gently pinch a cleaned area of skin. Using a dart-like motion, insert the needle at a 45-degree or 90-degree angle. Release the pinched skin, and gently push the plunger all the way down to inject the full amount in the prefilled syringe (0.9 mL), which provides 162 mg of tocilizumab.

The prefilled syringe is for single-use only, as it does not have a preservative.

Remove the needle from the skin while continuing the depress the plunger. After the needle is completely removed, release the plunger, which will allow the needle-shield to protect the needle. Do not rub the injection site.

Dispose of needles and syringes in an FDA-cleared sharps disposal container right away after use.[38283]

Autoinjector:

Remove the autoinjector from the refrigerator and allow it to sit at room temperature outside of the carton for 45 minutes. Do not warm tocilizumab in any other way.

Pick an injection site such as the front of a thigh, the outer area of an upper arm, or the abdomen except for the 2-inch area around the navel. Do not inject into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.

Do not auto inject through clothing.

Rotate injection sites with each injection. Inject at least 1 inch from the last area injected.

Remove the needle cap immediately before injection, and gently pinch a cleaned area of skin. Place the needle-shield at a 90-degree angle against the pinched skin.

Unlock the green activation button by firmly pressing the autoinjector against the pinched skin, then press the green button to start the injection. Continue to hold the autoinjector firmly against the skin until the purple indicator stops moving and the full dose administered; the complete injection may take up to 10 seconds.

Release the green button and lift autoinjector off the skin at a 90-degree angle.

The autoinjector is for single-use only, as it does not have a preservative. Dispose of needles and syringes in an FDA-cleared sharps disposal container right away after use.[38283]

STORAGE

Actemra:

- Discard product if it contains particulate matter, is cloudy, or discolored

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

- Do not freeze

- Protect from light

- Refrigerate (between 36 and 46 degrees F)

- Store in a dry place

- Store in original package until time of use

CONTRAINDICATIONS / PRECAUTIONS

General Information

Tocilizumab is contraindicated for use by patients with known hypersensitivity to tocilizumab. Serious hypersensitivity reactions, including anaphylaxis, have been reported in association with infusion of tocilizumab. Appropriate medical treatment should be available for immediate use in the event of an anaphylactic reaction during drug administration.

Diabetes mellitus, fungal infection, human immunodeficiency virus (HIV) infection, immunosuppression, infection, influenza, sepsis, surgery, tuberculosis

Patients who receive tocilizumab are at increased risk for developing serious infections that may lead to hospitalization or death. Infections include active tuberculosis and invasive fungal infections including candidiasis, aspergillosis, and pneumocystis. Bacterial, viral, and other infections due to opportunistic pathogens have been reported. Most patients who developed serious infections were taking concomitant immunosuppressives such as methotrexate or corticosteroids. Patients who have surgery while taking tocilizumab may be at greater risk for postoperative infections. Patients with an invasive fungal infection may present with disseminated disease, and tuberculosis may present as pulmonary or extrapulmonary disease. Evaluate patients for tuberculosis risk factors before starting tocilizumab. Also, test patients for latent tuberculosis before and during tocilizumab receipt. Initiate treatment for latent infection before tocilizumab use. Consider anti-tuberculosis therapy prior to tocilizumab initiation for 2 patient groups: patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed and patients with a negative test for latent tuberculosis but with risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient. Carefully consider the risks and benefits of tocilizumab before initiating therapy in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of a serious or opportunistic infection, with underlying conditions that may predispose them to infection (e.g., patients with advanced or uncontrolled diabetes mellitus, human immunodeficiency virus (HIV) infection, or immunosuppression), or who have resided or traveled in areas of endemic tuberculosis or endemic mycoses. Tocilizumab initiation is not recommended for patients with an absolute neutrophil count (ANC) less than 2,000/mm3, tocilizumab discontinuation is advised for an ANC less than 500/mm3, and tocilizumab interruption is advised for an ANC between 500/mm3 and 1000/mm3. Closely monitor patients for the development of signs and symptoms of infection during and after tocilizumab treatment; signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants. Consider the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to taking tocilizumab. Do not administer tocilizumab to a patient with an active infection including localized infections. If a serious infection such as sepsis or influenza or an opportunistic infection develops, interrupt tocilizumab receipt until the infection is controlled. If a new infection develops during tocilizumab receipt, complete a prompt and complete diagnostic workup appropriate for an immunocompromised patient, initiate appropriate antimicrobial therapy, and closely monitor the patient.

Neutropenia, thrombocytopenia

Initiation of tocilizumab is not recommended for thrombocytopenia defined as a platelet count below 100,000 cells/mm3 or for neutropenia defined as an absolute neutrophil count (ANC) below 2,000 cells/mm3. Thrombocytopenia and neutropenia have been noted with tocilizumab, and drug interruption or discontinuation may be needed. Check platelet count and ANC before tocilizumab receipt, 4 to 8 weeks after tocilizumab initiation, and every 3 months thereafter for adult patients. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (JIA), monitor neutrophils and platelets at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. In patients with severe or life-threatening cytokine release syndrome (CRS) who also have cytopenias due to lymphodepleting chemotherapy or the CRS, consider the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab.

Hepatic disease, hepatitis, hepatitis B exacerbation, hepatotoxicity, jaundice

Use tocilizumab with caution in patients with active hepatic disease or hepatic impairment. Initiation of tocilizumab is not recommended in patients who have ALT or AST above 1.5 times the upper limit of normal (ULN). Hepatotoxicity, including hepatic injury, hepatic failure, liver transplant, and death have been reported with tocilizumab therapy. Following tocilizumab initiation, the time to onset of hepatic injury ranged from months to years, and a majority of the patients presented with transaminases levels greater than 5 times the upper limit of normal (ULN). However, some patients had mild transaminase elevations along with signs and symptoms of liver impairment. Persistent hepatic enzyme elevations during therapy may require dose interruption or consideration of drug discontinuation, depending on the clinical abnormality and severity. Check liver function tests before tocilizumab receipt, 4 to 8 weeks after the start of therapy for the first 6 months, and then every 3 months after that in adult patients. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (JIA), monitor liver function tests at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Liver function tests (LFTs) should also be measured in any patient displaying signs and symptoms of liver dysfunction, such as fatigue, anorexia, dark urine, jaundice, or right upper abdominal pain. If elevated LFTs are detected, then tocilizumab should be stopped and only restarted once liver enzymes have normalized and an alternative cause identified. In patients with severe or life-threatening cytokine release syndrome (CRS) who also have elevated hepatic enzymes due to lymphodepleting chemotherapy or the CRS, consider the potential benefit of treating the CRS versus the risks of short-term treatment with tocilizumab. The safety and efficacy of tocilizumab have not been studied in patients with positive hepatitis B virus (HBV) or hepatitis C virus (HCV) serology. Tocilizumab may cause HBV or HCV reactivation in patients who are HBV or HCV carriers, which may lead to hepatitis C or hepatitis B exacerbation. Consider evaluating patients at risk for HBV and HCV infection for prior evidence of infection before tocilizumab initiation. If tocilizumab is initiated in an HBV or HCV carrier, carefully monitor the patient for clinical and laboratory signs of active HBV or HCV infection.[38283]

Multiple sclerosis, neurological disease

Cautious use of tocilizumab may be warranted by patients with neurological disease such as preexisting or recent onset demyelinating disorders. The impact of tocilizumab on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Closely monitor patients for signs and symptoms potentially indicative of demyelinating disorders.

Corticosteroid therapy, diverticulitis, GI perforation

Gastrointestinal (GI) perforations and other GI adverse reactions have been reported in clinical studies of tocilizumab. GI perforation risk may be increased with concurrent diverticulitis or concomitant use of NSAIDs or corticosteroid therapy. Promptly evaluate patients presenting with new onset abdominal symptoms. Cautious tocilizumab use is warranted by patients with diverticulitis.

Neoplastic disease, new primary malignancy

Tocilizumab is an immunosuppressant and treatment with immunosuppressants may result in an increased risk of cancer. The impact of tocilizumab on the development of a new primary malignancy is unknown, but malignancies were observed in clinical studies. Consider the risks and benefits of tocilizumab before treatment initiation in patients with a history of neoplastic disease. Also, consider the risks and benefits of tocilizumab continuation in patients who develop a malignancy.[38283]

Hypercholesterolemia, hyperlipidemia, hypertriglyceridemia

Cautious use of tocilizumab may be warranted for patients with hyperlipidemia, hypercholesterolemia, or hypertriglyceridemia. Increased total cholesterol, increased HDL-C, increased LDL-C, and increased triglycerides may occur with tocilizumab. Assess lipid parameters approximately 4 to 8 weeks after tocilizumab initiation. Subsequently, it is recommended to manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.[38283]

Vaccination

Avoid use of live vaccines concurrently with tocilizumab as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. No data are available on the effectiveness of vaccination in patients receiving tocilizumab. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all treated patients, particularly pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Geriatric

In clinical trials for rheumatoid arthritis, the frequency of serious infections among geriatric patients was higher as compared with the frequency among younger adult patients. As there is a higher incidence of infections in the geriatric population in general, caution should be used when treating the elderly. Clinical studies that for cytokine release syndrome did not include sufficient numbers of patients aged 65 years and older to determine whether they respond differently from younger patients.

Infants, labor, neonates, obstetric delivery, pregnancy

Limited available data are not sufficient to determine whether the use of tocilizumab during human pregnancy is associated with risk for major birth defects or miscarriage. Based on animal data, there may be a potential risk to the fetus. In animal reproduction studies, intravenous administration of tocilizumab to Cynomolgus monkeys during organogenesis resulted in abortion/embryo-fetal death at doses 1.25 times or more of the maximum recommended human dose (MRHD). Monoclonal antibodies, like tocilizumab, are increasingly transported across the placenta as pregnancy progresses, with the largest amount transferred during the third trimester. This may affect the immune response in the in utero exposed infant; consider risks and benefits before administering live or live-attenuated vaccines to neonates or infants exposed to tocilizumab in utero. A pregnancy registry has been established to monitor maternal and fetal outcomes; health care providers are encouraged to register pregnant women exposed to tocilizumab by calling 1-877-311-8972.[38283] Due to limited data during pregnancy, guidelines state that tocilizumab should be replaced before conception by other medication, if possible. The drug should be used during pregnancy only when no other pregnancy-compatible drug can effectively control the maternal disease.[62180] Tocilizumab may affect labor and obstetric delivery. Inhibition of IL-6 signaling may interfere with cervical ripening and dilatation and myometrial contractile activity, leading to potential delays in parturition.[38283]

Breast-feeding

The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab to the breast-feeding infant; therefore the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for tocilizumab and the potential adverse effects on the breastfed child from exposure to the drug or the underlying maternal condition. There is no information available on the presence of tocilizumab in human milk or its effects on the breast-fed infant or milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal (GI) tract and potential limited systemic exposure in the infant to tocilizumab are unknown.[38283] Until more data are available, guidelines state that tocilizumab should generally be avoided during breast-feeding if another therapy is available to control the maternal disease. The drug has a large molecular weight, and experts suggest the oral bioavailability of any drug exposure to the infant through the GI tract is likely low. Breast-feeding should not be discouraged, however, when using the drug if no other options are available.[62180]

Children

Tocilizumab is indicated in pediatric patients 2 years of age and older for the treatment of active systemic or polyarticular juvenile idiopathic arthritis (JIA) or cytokine release syndrome (CRS). The safety and efficacy of tocilizumab in infants and young children less than 2 years of age have not been established. It is recommended that all pediatric patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating tocilizumab therapy. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

ADVERSE REACTIONS

Severe

anaphylactic shock / Rapid / 0.1-0.9

anaphylactoid reactions / Rapid / 0.1-0.9

GI perforation / Delayed / Incidence not known

hepatotoxicity / Delayed / Incidence not known

hepatic failure / Delayed / Incidence not known

new primary malignancy / Delayed / Incidence not known

angioedema / Rapid / Incidence not known

Stevens-Johnson syndrome / Delayed / Incidence not known

macrophage activation syndrome / Delayed / Incidence not known

pancreatitis / Delayed / Incidence not known

visual impairment / Early / Incidence not known

optic neuritis / Delayed / Incidence not known

Moderate

elevated hepatic enzymes / Delayed / 2.2-48.0

neutropenia / Delayed / 0-25.9

infusion-related reactions / Rapid / 4.0-20.2

hyperlipidemia / Delayed / 0-19.6

hypertension / Early / 4.0-6.0

thrombocytopenia / Delayed / 1.0-4.0

oral ulceration / Delayed / 1.0-2.0

gastritis / Delayed / 1.0-2.0

dyspnea / Early / 0-2.0

antibody formation / Delayed / 0.9-1.6

candidiasis / Delayed / Incidence not known

jaundice / Delayed / Incidence not known

hepatitis / Delayed / Incidence not known

hypercholesterolemia / Delayed / Incidence not known

hypertriglyceridemia / Delayed / Incidence not known

hypotension / Rapid / Incidence not known

peripheral neuropathy / Delayed / Incidence not known

Mild

injection site reaction / Rapid / 7.1-41.2

infection / Delayed / 3.0-8.0

pharyngitis / Delayed / 4.0-7.0

headache / Early / 5.0-7.0

rash / Early / 2.0-4.0

abdominal pain / Early / 2.0-3.0

dizziness / Early / 2.0-3.0

cough / Delayed / 0-2.0

urticaria / Rapid / Incidence not known

pruritus / Rapid / Incidence not known

arthralgia / Delayed / Incidence not known

diarrhea / Early / Incidence not known

weakness / Early / Incidence not known

fatigue / Early / Incidence not known

DRUG INTERACTIONS

Abatacept: (Major) Tocilizumab use should be avoided in combination with biologic DMARDs, including interleukin-1 receptor (IL-1Ra) modulators such as abatacept because of the possibility of increased immunosuppression and increased infection risk. The use of tocilizumab concurrently with biologic DMARDs such as anakinra has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Chlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Dextromethorphan: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Dextromethorphan; Doxylamine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Dextromethorphan; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Acetaminophen; Dextromethorphan; Pseudoephedrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Amlodipine; Atorvastatin: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as atorvastatin.

Amoxicillin; Clarithromycin; Omeprazole: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. In clinical trials of patients taking both omeprazole and tocilizumab, a decrease in omeprazole exposure (AUC) was noted. One week after a single tocilizumab dose, a 12 to 28% decrease in omeprazole exposure occurred. Use caution when using tocilizumab in combination with CYP-metabolized drugs where a decrease in effectiveness is undesirable.

Anakinra: (Major) Tocilizumab should be avoided in combination with other biologic DMARDs, including interleukin-1 receptor antagonists (IL-1Ra) such as anakinra because of the possibility of increased immunosuppression and increased infection risk. The use of tocilizumab with biologic DMARDs such as anakinra has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Antithymocyte Globulin: (Moderate) Closely observe patients for signs of infection if biologic agents are used concomitantly. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressive agents.

Aspirin, ASA; Omeprazole: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. In clinical trials of patients taking both omeprazole and tocilizumab, a decrease in omeprazole exposure (AUC) was noted. One week after a single tocilizumab dose, a 12 to 28% decrease in omeprazole exposure occurred. Use caution when using tocilizumab in combination with CYP-metabolized drugs where a decrease in effectiveness is undesirable.

Atorvastatin: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as atorvastatin.

Atorvastatin; Ezetimibe: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as atorvastatin.

Azathioprine: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Patients receiving immunosuppressants, including azathioprine, are at increased risk for bacterial, viral, fungal, protozoal, and opportunistic infections, including reactivation of latent infections.

Bacillus Calmette-Guerin Vaccine, BCG: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Baricitinib: (Major) Concomitant use of baricitinib with biologic DMARDs, such as tocilizumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Baricitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

Basiliximab: (Major) Avoid using tocilizumab with immunosuppressive biological agents such as basilixumab because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with other biological agents has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Brompheniramine; Dextromethorphan; Guaifenesin: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Carbinoxamine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Chlorpheniramine; Dextromethorphan: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Chlorpheniramine; Dextromethorphan; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Cyclophosphamide: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Cyclophosphamide can cause myelosuppression (leukopenia, neutropenia, thrombocytopenia and anemia), bone marrow failure, and severe immunosuppression which may lead to serious and sometimes fatal infections, including sepsis and septic shock. Latent infections can be reactivated.

Cyclosporine: (Moderate) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as cyclosporine. If tocilizumab is initiated or discontinued in a patient taking cyclosporine, check the drug concentration; cyclosporine dose adjustment may be needed.

Daclizumab: (Major) Avoid using tocilizumab with biological immunosuppressive agents because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as daclizumab has not been studied. Daclizumab is a biologic monoclonal antibody binds specifically to the alpha subunit of the human high-affinity interleukin (IL)-2 receptor, producing immunosuppression.

Dexamethasone: (Moderate) Closely observe patients for signs of infection if biologic agents are used concomitantly. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.

Dexchlorpheniramine; Dextromethorphan; Pseudoephedrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Diphenhydramine; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Guaifenesin: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Guaifenesin; Phenylephrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Guaifenesin; Potassium Guaiacolsulfonate: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Guaifenesin; Pseudoephedrine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Promethazine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Dextromethorphan; Quinidine: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. For example, before tocilizumab receipt by patients with rheumatoid arthritis, the exposure of dextromethorphan, a CYP2D6 and CYP3A4 substrate, was comparable to exposure data from healthy subjects, but exposure to its metabolite dextrorphan, a CYP3A4 substrate was a fraction of that observed in healthy subjects. One week after a single tocilizumab dose, a 5% decrease in dextromethorphan exposure and a 29% decrease in dextrorphan levels were noted. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Efalizumab: (Major) Avoid using tocilizumab with other biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as efalizumab has not been studied.

Everolimus: (Moderate) Monitor for clinical response in patients taking everolimus concurrently with tocilizumab. For indications where therapeutic drug monitoring is appropriate, monitor everolimus trough concentrations and adjust the dose of everolimus accordingly. Everolimus is a substrate of P-glycoprotein (P-gp). Tocilizumab is a P-gp inhibitor, and may interact with P-gp substrates.

Ezetimibe; Simvastatin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Hydrocortisone: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.

Intranasal Influenza Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Live Vaccines: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Lovastatin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as lovastatin.

Lovastatin; Niacin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as lovastatin.

Measles Virus; Mumps Virus; Rubella Virus; Varicella Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Measles/Mumps/Rubella Vaccines, MMR: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Methotrexate: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as methotrexate.

Methylprednisolone: (Moderate) Closely observe patients for signs of infection. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.

Muromonab-CD3: (Major) Closely observe patients for signs of infection if immunosuppressive biologic agents such as Muromonab-CD3 are used concomitantly with tocilizumab. The use of tocilizumab with other biologic immunosuppressive agents has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Niacin; Simvastatin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Ofatumumab: (Major) Avoid using tocilizumab with other biological agents because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological agens such as anti-CD20 monoclonal antibodies like ofatumumab has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Omeprazole: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. In clinical trials of patients taking both omeprazole and tocilizumab, a decrease in omeprazole exposure (AUC) was noted. One week after a single tocilizumab dose, a 12 to 28% decrease in omeprazole exposure occurred. Use caution when using tocilizumab in combination with CYP-metabolized drugs where a decrease in effectiveness is undesirable.

Omeprazole; Sodium Bicarbonate: (Minor) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. It is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. In clinical trials of patients taking both omeprazole and tocilizumab, a decrease in omeprazole exposure (AUC) was noted. One week after a single tocilizumab dose, a 12 to 28% decrease in omeprazole exposure occurred. Use caution when using tocilizumab in combination with CYP-metabolized drugs where a decrease in effectiveness is undesirable.

Oral Contraceptives: (Moderate) Exercise caution when coadministering tocilizumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, such as with combined hormonal oral contraceptives. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in exposure of a CYP3A4 substrate was noted 1 week after a single tocilizumab dose.

Prednisolone: (Moderate) Closely observe patients for signs of infection if biologic agents are used concomitantly. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.

Prednisone: (Moderate) Closely observe patients for signs of infection if biologic agents are used concomitantly. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives such as systemic corticosteroids.

Rituximab: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.

Rituximab; Hyaluronidase: (Major) Avoid the concomitant use of rituximab and tocilizumab; coadministration has not been studied and may result in additive immunosuppression and an increased risk of infection.

Rotavirus Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Rubella Virus Vaccine Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Secukinumab: (Major) Concomitant use of biologic DMARDs, such as secukinumab, is not recommended with tocilizumab because of the lack of data and the possibility of increased immunosuppression and increased infection risk. Tocilizumab may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

Simvastatin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Simvastatin; Sitagliptin: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable.

Sirolimus: (Moderate) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as sirolimus. If tocilizumab is initiated or discontinued in a patient taking sirolimus, check the drug concentration; sirolimus dose adjustment may be needed.

Smallpox and Monkeypox Vaccine, Live, Nonreplicating: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Smallpox Vaccine, Vaccinia Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Tacrolimus: (Moderate) Closely observe patients for signs of infection, altered clinical response, or drug toxicity. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives. Tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as tacrolimus. If tocilizumab is initiated or discontinued in a patient taking tacrolimus, check the drug concentration; tacrolimus dose adjustment may be needed.

Theophylline, Aminophylline: (Moderate) In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes, including CYP3A4. A 57% decrease in simvastatin exposure was noted 1 week after a single tocilizumab dose; simvastatin is a CYP3A4 substrate. Utilize caution when using tocilizumab in combination with CYP3A4 substrate drugs where a decrease in effectiveness is undesirable such as theophylline.

Tofacitinib: (Major) Concomitant use of tofacitinib with biologic DMARDs, such as tocilizumab, is not recommended due to the lack of data and because of the possibility of increased immunosuppression and increased infection risk. Tocilizumab may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

Tumor Necrosis Factor modifiers: (Major) Tocilizumab has not been studied and its use should be avoided in combination with biologic DMARDs because of the possibility of increased immunosuppression and increased infection risk. Tocilizumab has not been studied in combination with biologi DMARDs such as tumor necrosis factor (TNF) antagonists. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.

Typhoid Vaccine: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Upadacitinib: (Major) Concomitant use of upadacitinib with biologic DMARDs, such as tocilizumab, is not recommended because of the possibility of increased immunosuppression and increased infection risk. Upadacitinib may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

Ustekinumab: (Major) Concomitant use of biologic DMARDs, such as ustekinumab, is not recommended with tocilizumab because of the lack of data and the possibility of increased immunosuppression and increased infection risk. Tocilizumab may be used as monotherapy or concomitantly with methotrexate or other nonbiologic DMARDs.

Varicella-Zoster Virus Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Warfarin: (Moderate) The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab. In vitro, tocilizumab has the potential to affect expression of multiple CYP enzymes including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. Clinically relevant drug interactions may occur with CYP450 substrates that have a narrow therapeutic index such as warfarin. If tocilizumab is initiated or discontinued in a patient taking warfarin, check the INR; warfarin dose adjustment may be needed.

Yellow Fever Vaccine, Live: (Major) Avoid concurrent use of live vaccines during treatment with tocilizumab due to potentially increased risk of infections; clinical safety of live vaccines during tocilizumab treatment has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving tocilizumab. The interval between live vaccinations and initiation of tocilizumab therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

PREGNANCY AND LACTATION

Pregnancy

The lack of clinical data during lactation precludes clear determination of the risk of tocilizumab to the breast-feeding infant; therefore the developmental and health benefits of breast-feeding should be considered along with the mother's clinical need for tocilizumab and the potential adverse effects on the breastfed child from exposure to the drug or the underlying maternal condition. There is no information available on the presence of tocilizumab in human milk or its effects on the breast-fed infant or milk production. Maternal immunoglobulin G (IgG) is present in human milk. If tocilizumab is transferred into human milk, the effects of local exposure in the gastrointestinal (GI) tract and potential limited systemic exposure in the infant to tocilizumab are unknown.[38283] Until more data are available, guidelines state that tocilizumab should generally be avoided during breast-feeding if another therapy is available to control the maternal disease. The drug has a large molecular weight, and experts suggest the oral bioavailability of any drug exposure to the infant through the GI tract is likely low. Breast-feeding should not be discouraged, however, when using the drug if no other options are available.[62180]

MECHANISM OF ACTION

Tocilizumab competes with IL-6 for binding to the IL-6 receptor. Two types of IL-6 receptors exist: membrane-bound and soluble; soluble IL-6 receptor is present in serum and synovial fluids. Tocilizumab binds to both soluble and membrane-bound IL-6 receptors and inhibits IL-6 mediated signaling through these receptors. Normally, the IL-6 receptor binds to IL-6 and to a cell-surface glycoprotein called gp130, which is necessary for signal transduction. The gp130-mediated IL-6 signaling pathway works even for cells that do not express the IL-6 receptor on their surface. For example, the soluble IL-6 receptor can bind to IL-6 and can associate with gp130 to transduce the IL-6 signal into cells.

IL-6 is a proinflammatory cytokine that can cause malaise, fatigue, and anemia. IL-6 is involved in diverse physiological processes such as T-cell activation, immunoglobulin secretion induction, hepatic acute phase protein synthesis initiation, and hematopoietic precursor cell proliferation and differentiation stimulation. In vitro, IL-6 induces osteoclast differentiation and activation. IL-6 is produced by synovial and endothelial cells leading to local production of IL-6 in joints affected by inflammatory processes such as rheumatoid arthritis. Thus, inhibition of IL-6 signal transduction by tocilizumab may attenuate rheumatoid arthritis associated symptoms and joint damage.

PHARMACOKINETICS

Tocilizumab is administered subcutaneously or intravenously as an infusion. Among patients with rheumatoid arthritis, the tocilizumab volume of distribution (Vd) at steady-state was 6.4 L: the central Vd was 3.5 L, and the peripheral Vd was 2.9 L. The total clearance is concentration-dependent and is the sum of the linear and nonlinear clearance. At higher concentrations, clearance is mainly determined by the linear clearance, which was estimated to be 12.5 mL/hour. Linear clearance increases with body size. The concentration-dependent nonlinear clearance plays a major role at low concentrations. The half-life of tocilizumab is dependent on the concentration. A population pharmacokinetic model, based on data in rheumatoid arthritis patients who received either intravenous or subcutaneous tocilizumab, found a terminal half-life of approximately 21.5 days at high serum concentrations and linear clearance of tocilizumab. For patients with rheumatoid arthritis, the concentration-dependent apparent half-life at steady-state is up to 11 days for 4 mg/kg/dose IV, up to 13 days for 8 mg/kg/dose IV every 4 weeks, up to 13 days for 162 mg subcutaneously every week, and 5 days for 162 mg subcutaneously every other week. For patients with giant cell arteritis at steady-state, the effective half-life for 162 mg subcutaneously every week and every other week was 18.3 to 18.9 days and 4.2 to 7.9 days, respectively.[38283]

Decreases in C-reactive protein to within normal ranges were seen as early as week 2 after tocilizumab 4 mg/kg/dose or 8 mg/kg/dose initiation. Decreases in rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A, fibrinogen, and increases in hemoglobin were noted with both tocilizumab doses, but the greatest improvements were noted with the 8 mg/kg dose.[38283]

Affected cytochrome P450 (CYP450) isoenzymes and drug transporters:

In vitro, tocilizumab has the potential to affect the expression of multiple CYP enzymes, including CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, and CYP3A4. The formation of CYP450 enzymes may be suppressed by increased concentrations of cytokines, such as IL-6 during chronic inflammation. Thus, it is expected that the formation of CYP450 enzymes could be normalized during tocilizumab receipt leading to increased metabolism of drugs that are CYP450 substrates. The effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping tocilizumab.[38283]

Intravenous Route

After receipt of either 4 mg/kg/dose IV or 8 mg/kg/dose IV every 4 weeks, a more than dose-proportional increase in systemic exposure and in the trough concentration was noted. At steady-state, the mean concentration with 8 mg/kg dosing was 3-fold higher than the systemic exposure after 4 mg/kg dosing. The trough concentration at steady-state with 8 mg/kg dosing was 134-fold higher than the trough concentration after 4 mg/kg dosing. In contrast, the maximum tocilizumab concentration increased dose-proportionally. After 4 mg/kg/dose IV every 4 weeks, the median Cmean at steady-state was 86.1 mcg/mL (44.8 to 202 mcg/mL), the median steady-state Cmin was 0.1 mcg/mL (0.0 to 14.6 mcg/mL), and the median steady-state Cmax was 86.1 mcg/mL (44.8 to 202 mcg/mL). Ninety percent of steady-state was reached after the first dose for Cmax and AUC and after the fourth dose for Cmin. After 8 mg/kg/dose IV every 4 weeks, the median Cmean at steady-state was 54 mcg/mL (17 to 260 mcg/mL), the median Cmin at steady-state 13.4 mcg/mL (0.1 to 154 mcg/mL), and median Cmax at steady-state was 176 mcg/mL (75.4 to 557 mcg/mL). Approximately 90% of steady-state was reached after the first dose for Cmax, after the third dose for AUC, and after the fourth dose for Cmin. Tocilizumab AUC, Cmin, and Cmax increased with increased body weight. Among patients with a body weight of 100 kg or greater, the mean steady-state exposure values were higher than those from the patient population. A tocilizumab dose greater than 800 mg per infusion is not recommended.[38283]

Subcutaneous Route

After weekly or every other week of 162 mg subcutaneous tocilizumab receipt to patients with rheumatoid arthritis, steady-state was achieved after 10 weeks and 12 weeks, respectively. At steady state, the estimated median Cmean was 47.3 mcg/mL (2.4 to 147 mcg/mL), Cmin was 42.9 mcg/mL (1.3 to 144 mcg/mL), and Cmax was 49.8 mcg/mL (3 to 150 mcg/mL) with once weekly subcutaneous dosing. After every other week subcutaneous dosing, the estimated median Cmean AUC was 9.2 mcg/mL (0.2 to 43.6 mcg/mL), Cmin was 4.1 mcg/mL (0.0 to 34.2 mcg/mL), and Cmax was 12.1 mcg/mL (0.4 to 49.3 mcg/mL) at steady-state. Systemic exposures with once-weekly dosing were 5.1-fold higher for Cmean and 10.5-fold higher for Cmin compared to every other week dosing. Accumulation for Cmin was greater following subcutaneous, both once weekly and every other week regimens, compared to intravenous administration and is expected based on the non-linear clearance at lower concentrations. Greater than 90% of the steady-state value for Cmax was achieved after the fifth dose with the once weekly regimen and 12th dose with every other week regimen. Ninety percent of the steady-state values for the Cmean and Cmin were achieved after the 6th and 12th injections, for the every other week and once weekly regimens, respectively. In patients, at steady-state, with giant cell arteritis who received 162 mg tocilizumab subcutaneously every week, the estimated median Cmax was 72.1 mcg/mL (12.2 to 151 mcg/mL), Cmin was 67.2 mcg/mL (10.7 to 145 mcg/mL), and Cmean was 70.6 mcg/mL (11.7 to 149 mcg/mL). For patients at steady-state who received 162 mg every other week, the estimated median Cmax, Cmin, and Cmean were 17.2 mcg/mL (1.1 to 56.2 mcg/mL), 7.7 mcg/mL (0.1 to 37.3 mcg/mL), and 13.7 mcg/mL (0.5 to 49 mcg/mL), respectively. Steady-state was reached at 17 weeks and 14 weeks following once weekly and every other week dosing regimens, respectively.[38283]