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  • CLASSES

    Anti-Rheumtic Monoclonal Antibody Preparations
    Interleukin 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
    Used for moderate to severe rheumatoid arthritis in adults who have had an inadequate response to 1 or more disease-modifying antirheumatic drugs; for active systemic or polyarticular juvenile idiopathic arthritis in children at least 2 years old; for cytokine release syndrome in adults and children at least 2 years old; and for giant cell arteritis (temporal arteritis) in adults
    May cause serious infections; interrupt drug receipt for a serious infection

    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 years and older, and weighing 30 kg or more

    8 mg/kg IV infusion administered over 1 hour, given every 4 weeks. 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 or other non-biologic disease modifying antirheumatic drugs (DMARDs). However, avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept.

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

    10 mg/kg IV infusion administered over 1 hour, given every 4 weeks. 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 or other non-biologic disease modifying antirheumatic drugs (DMARDs). However, avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept.

    For the treatment of active systemic juvenile idiopathic arthritis.
    Intravenous dosage
    Children and Adolescents 2 years and older, and weighing 30 kg or more

    8 mg/kg IV infusion administered over 1 hour, given every 2 weeks. 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 or other non-biologic disease modifying antirheumatic drugs (DMARDs). However, avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept.

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

    12 mg/kg IV infusion administered over 1 hour, given every 2 weeks. 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 or other non-biologic disease modifying antirheumatic drugs (DMARDs). However, avoid concurrent use with biological DMARDs such as tumor necrosis factor (TNF) modifiers, anakinra, rituximab, ofatumumab, and abatacept.

    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.  
    Subcutaneous dosage
    Adults

    The dose used in phase 2 clinical trials has been 162 mg subcutaneously once weekly. There is no FDA-approved treatment for systemic sclerosis at this time. More study is needed with tocilizumab, but treatment appears to have potential. Tocilizumab decreased the modified Rodnan skin score (primary endpoint) but not statistically significantly so vs placebo in the phase 2 study. However, more patients in the tocilzumab group (37%) achieved clinically important decrease in skin score (more than 4.7 units) compared to patients receiving placebo (25%). Also, at 48 weeks, less patients in the tocilizumab group had more than 10% (absolute) decrease in the percent predicted forced vital capacity values vs. placebo, and tocilizumab resulted in gene downregulation in skin biopsy samples. Serious infections were more common in the tocilzumab group (16%) than in the placebo group (5%), and 1 patient in the tocilzumab group died. A 2-year Phase 3 randomized controlled trial (NCT02453256) is in progress.

    †Indicates off-label use

    MAXIMUM DOSAGE

    Adults

    Rheumatoid arthritis, weight more than 100 kg: 800 mg/dose IV and 162 mg/dose SC.
    Rheumatoid arthritis and giant cell arteritis, weight 100 kg or less: 8 mg/kg/dose IV and 162 mg/dose SC.
    Cytokine Release Syndrome (CRS), weight 30 kg or more: 800 mg/dose IV.
    CRS, weight less than 30 kg: 12 mg/kg IV.

    Geriatric

    Rheumatoid arthritis, weight more than 100 kg: 800 mg/dose IV and 162 mg/dose SC.
    Rheumatoid arthritis and giant cell arteritis, weight 100 kg or less: 8 mg/kg/dose IV and 162 mg/dose SC.
    Cytokine Release Syndrome (CRS), 30 kg or more: 800 mg/dose IV.
    CRS, less than 30 kg: 12 mg/kg IV.

    Adolescents

    Weight 30 kg or more: 8 mg/kg/dose IV.
    Weight less than 30 kg: 12 mg/kg/dose IV for systemic juvenile idiopathic arthritis and cytokine release syndrome (CRS); 10 mg/kg/dose IV for polyarticular juvenile idiopathic arthritis.

    Children

    2 years and older and weight 30 kg or more: 8 mg/kg/dose IV.
    2 years and older and weight less than 30 kg: 12 mg/kg/dose IV for systemic juvenile idiopathic arthritis and cytokine release syndrome (CRS); 10 mg/kg/dose IV for polyarticular juvenile idiopathic arthritis.
    Less than 2 years: Safe and effective use have not been established.

    Infants

    Safe and effective use 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 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.
    Hepatic enzyme elevations occurring during treatment:
    AST and/or ALT from 1 to 3 times the ULN: Dose modify concomitant DMARDs, if appropriate. For persistent increases of transaminases in this range, reduce IV tocilizumab dose to 4 mg/kg or reduce subcutaneous dosing interval to every other week, or interrupt tocilizumab dosing until AST/ALT have normalized. For subcutaneous dosing, once ALT/AST have normalized, resume at every other week dosing and increase to once weekly as clinically appropriate.
    AST and/or ALT greater than 3 times and up to 5 times the ULN, confirmed by repeat testing: Interrupt tocilizumab dosing until AST/ALT is less than 3 times the ULN. Then, if appropriate, dose modify concomitant DMARDs. For persistent increases of transaminases 3 times the ULN or less, reduce IV tocilizumab dose to 4 mg/kg, or reduce subcutaneous dosing interval to every other week, or interrupt tocilizumab until AST/ALT have normalized. For subcutaneous dosing, once ALT/AST have normalized, resume at every other week dosing and increase to once weekly as clinically appropriate. 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
    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. If appropriate, concomitant methotrexate and/or other medications should be dose modified or stopped and tocilizumab dosing interrupted 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.

    Renal Impairment

    CrCl 50 mL/minute or more: No dose adjustment is needed.
    CrCl less than 50 mL/minute: Tocilizumab has not been studied in patients with moderate to severe renal impairment, but it appears that no dosage adjustments are needed.

    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 is ONLY for subcutaneous injection.
    The vial is ONLY for intravenous infusion.
    Have appropriate medical treatment available for immediate use in the event of a serious hypersensitivity reaction.

    Intravenous Administration

    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, and 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 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 unused product remaining in vials; tocilizumab does not contain preservatives.
     
    Intravenous Infusion Administration
    Allow the fully diluted tocilizumab solution to reach room temperature before infusion if it has been refrigerated.
    Administer over 60 minutes with an infusion set. Do not administer as an intravenous push or bolus.
    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

    Subcutaneous injection of tocilizumab is only indicated for adults with rheumatoid arthritis or giant cell arteritis (GCA) and may be given by the patient or patient's caregiver after proper training in subcutaneous injection technique and a healthcare practitioner determines that it is appropriate.
    Subcutaneous injection:
    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, 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 or 90 degree angle to the skin. 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.

    STORAGE

    Actemra:
    - Discard product if it contains particulate matter, is cloudy, or discolored
    - Do not freeze
    - Protect from light
    - Refrigerate (between 36 and 46 degrees F)
    - 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

    Tocilizumab is not recommended 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). Elevated transaminases have been noted with tocilizumab, and drug interruption or discontinuation may be needed. Check hepatic transaminases before tocilizumab receipt, 4 to 8 weeks after start of therapy, and every 3 months thereafter for adult patients. Consider checking other liver function tests (LFTs) such as bilirubin when clinically indicated. For pediatric patients with either polyarticular or systemic juvenile idiopathic arthritis (JIA), monitor ALT and AST at the time of the second infusion and then every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Persistent hepatic enzyme elevations during therapy may require dose interruption or consideration of drug discontinuation, depending on the clinical abnormality and severity. 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 hepatic impairment including 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. 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, closely monitor the patient for clinical and laboratory signs of active HBV or HCV infection.

    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

    Tocilizumab is an immunosuppressant; therefore, tocilizumab may affect host defenses against neoplastic disease. The impact of tocilizumab on the development of malignancies is unknown, but malignancies were observed in clinical studies. Consider the risks and benefits of tocilizumab before treatment initiation in patients with a known malignancy. Also, consider the risks and benefits of tocilizumab continuation in patients who develop a malignancy.

    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 and subsequently at approximately 24 week intervals. Manage patients according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

    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, the frequency of serious infections among geriatric patients was higher as compared with the frequency among younger adult patients. Because there is a higher incidence of infections in the elderly in general, cautious tocilizumab use is advised.

    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. The safety and efficacy of tocilizumab in infants and 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.

    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 and higher 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 immune response in the in utero exposed infant; consider risks and benefits prior to 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. Tocilizumab may have an effect on 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.

    Breast-feeding

    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. While its large molecular weight decreases the likelihood of excretion into breast milk, the long elimination half-life (11 days) does increase the possibility. Additionally, toxicity risk may be limited as tocilizumab is a protein and would likely be digested in the infants gastrointestinal tract; however, the effects of local exposure on the gastrointestinal tract and potential limited systemic exposure to the infant are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tocilizumab and the potential adverse effects on the breast-fed infant from tocilizumab or the underlying maternal condition.

    ADVERSE REACTIONS

    Severe

    anaphylactoid reactions / Rapid / 0.1-0.9
    anaphylactic shock / Rapid / 0.1-0.9
    GI perforation / Delayed / Incidence not known
    Stevens-Johnson syndrome / Delayed / Incidence not known
    angioedema / Rapid / Incidence not known
    macrophage activation syndrome / Delayed / Incidence not known

    Moderate

    elevated hepatic enzymes / Delayed / 0-48.0
    infusion-related reactions / Rapid / 4.0-20.2
    hyperlipidemia / Delayed / 0-19.6
    neutropenia / Delayed / 0-17.0
    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
    hypercholesterolemia / Delayed / Incidence not known
    hypertriglyceridemia / Delayed / Incidence not known
    secondary malignancy / Delayed / Incidence not known
    hypotension / Rapid / Incidence not known

    Mild

    injection site reaction / Rapid / 7.1-10.0
    infection / Delayed / 3.0-8.0
    pharyngitis / Delayed / 4.0-7.0
    headache / Early / 5.0-7.0
    rash (unspecified) / Early / 2.0-4.0
    abdominal pain / Early / 2.0-3.0
    dizziness / Early / 2.0-3.0
    cough / Delayed / 0-2.0
    diarrhea / Early / Incidence not known
    urticaria / Rapid / Incidence not known
    pruritus / Rapid / Incidence not known
    arthralgia / Delayed / 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.
    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) 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 everolimus. If tocilizumab is initiated or discontinued in a patient taking everolimus, check the drug concentration; everolimus dose adjustment may be needed.
    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 systemiccorticosteroids.
    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.
    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 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) Avoid using tocilizumab with biological DMARDs because of the possibility of increased immunosuppression and increased risk of infection. The concurrent use of tocilizumab with biological DMARDs such as tofacitinib has not been studied. Most patients taking tocilizumab who developed serious infections were taking concomitant immunosuppressives.
    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.
    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

    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. While its large molecular weight decreases the likelihood of excretion into breast milk, the long elimination half-life (11 days) does increase the possibility. Additionally, toxicity risk may be limited as tocilizumab is a protein and would likely be digested in the infants gastrointestinal tract; however, the effects of local exposure on the gastrointestinal tract and potential limited systemic exposure to the infant are unknown. Consider the developmental and health benefits of breast-feeding along with the mother's clinical need for tocilizumab and the potential adverse effects on the breast-fed infant from tocilizumab or the underlying maternal condition.

    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. 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. For patients with rheumatoid arthritis, the concentration-dependent apparent half-life at steady-state is up to 11 days for 4 mg/kg IV, up to 13 days for 8 mg/kg IV every 4 weeks, up to 13 days for 162 mg SC every week, and 5 days for 162 mg SC every other week.
    Decreases in C-reactive protein to within normal ranges were seen as early as week 2 after tocilizumab 4 mg/kg or 8 mg/kg initiation. Decreases in rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A, and increases in hemoglobin were noted with both tocilizumab doses, but the greatest improvements were noted with the 8 mg/kg dose.
     
    Affected cytochrome P450 isoenzymes:
    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 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.

    Intravenous Route

    Among patients with rheumatoid arthritis, the tocilizumab volume of distribution at steady-state was 6.4 L: the central volume of distribution was 3.5 L, and the peripheral volume of distribution was 2.9 L. After receipt of either 4 mg/kg IV or 8 mg/kg IV every 4 weeks, a more than dose-proportional increase in systemic exposure and in the trough concentration was noted. At steady-state, the predicted systemic exposure with 8 mg/kg dosing was 2.7-fold higher than the systemic exposure after 4 mg/kg dosing. The predicted trough concentration with 8 mg/kg dosing was 6.5-fold higher than the trough concentration after 4 mg/kg dosing. In contrast, the maximum tocilizumab concentration increased dose-proportionally. After 4 mg/kg IV every 4 weeks, the predicted mean steady-state AUC was 13,000 +/- 5800 mcg•h/ml, the predicted mean C min was 1.49 +/- 2.13 mcg/ml, and the predicted mean steady-state Cmax was 88.3 +/- 41.4 mcg/ml. Steady-state was reached after the first dose for Cmax and AUC and after the fourth dose for Cmin. After 8 mg/kg IV every 4 weeks, the predicted mean steady-state AUC was 35,000 +/- 15,500 mcg•h/ml, the predicted mean C min was 9.74 +/- 10.5 mcg/ml, and the predicted mean steady-state Cmax was 183 +/- 85.6 mcg/ml. Steady-state was reached after the first dose for Cmax,after the second dose for AUC, and after the fifth dose for Cmin. Tocilizumab AUC, Cmin, and Cmax increased with increased body weight. Among patients with a body weight of at least 100 kg, the mean exposure values were higher than those from the patient population. Specifically, among patients with a body weight of at least 100 kg, the predicted mean steady-state AUC was 55,500 +/- 14,100 mcg•h/ml, the predicted mean C min was 19 +/- 12 mcg/ml, and the predicted mean steady-state Cmax was 269 +/- 57 mcg/ml. A tocilizumab dose greater than 800 mg per infusion is not recommended.

    Subcutaneous Route

    After weekly or every other week SC tocilizumab receipt to patients with rheumatoid arthritis, steady-state was achieved after 12 weeks. At steady state, the estimated mean AUC was 8200 +/- 3600 mcg•h/ml, Cmin was 44.6 +/- 20.6 mcg/ml, and Cmax was 50.9 +/- 21.8 mcg/ml with once weekly SC dosing. After every other week SC dosing, the estimated mean AUC was 3200 +/- 2700 mcg•h/ml, Cmin was 5.6 +/- 7 mcg/ml, and Cmax was 12.3 +/- 8.7 mcg/ml.