tocilizumab (Rx)

Brand and Other Names:Actemra
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injection, solution for IV infusion

  • 20mg/mL in 4-, 10-, and 20-mL vials

injection, single-use autoinjector (ACTPen) for SC

  • 162mg/0.9mL

injection, single-use prefilled syringe for SC

  • 162mg/0.9mL

Rheumatoid Arthritis

Indicated for adults with moderate-to-severe active rheumatoid arthritis with inadequate response to 1 or more disease modifying antirheumatic drugs (DMARDs) as an IV infusion or SC injection

May use alone or in combination with methotrexate or other DMARDs

IV infusion

  • 4 mg/kg IV over 60 min q4Weeks initially; may increase to 8 mg/kg q4Weeks based on clinical response  
  • Not to exceed 800 mg/dose q4weeks
  • Reduction of dose from 8 mg/kg to 4 mg/kg is recommended for management of certain dose-related laboratory changes; see Dosage Modifications

SC injection

  • Weight <100 kg: 162 mg SC every other week, followed by an increase to every week based on clinical response
  • Weight ≥100 kg: 162 mg SC every week
  • Transition IV to SC: Administer first SC dose instead of the next scheduled IV dose

Giant Cell Arteritis

Indicated for treatment of giant cell arteritis (GCA)

162 mg SC once weekly in combination with a tapering course of glucocorticoids

Based on clinical considerations, may consider administering 162 mg SC every other week in combination with a tapering course of glucocorticoids

May be used alone following discontinuation of glucocorticoids (eg, interruption of dosing may be needed for management of dose-related laboratory abnormalities, IV administration is not approved for GCA)

Cytokine Release Syndrome

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

SC is not approved for CRS

8 mg/kg IV over 60 min; may administer up to 3 additional doses of tocilizumab if no clinical improvement in signs/symptoms of CRS after first dose; not to exceed 800 mg/dose

Interval between consecutive doses should be >8 hr

May be administered as monotherapy or with corticosteroids

Dosage Modifications

Dose reductions have not been studied in PJIA and SJIA populations

The following dosage modifications apply to RA and GCA patients

Renal impairment

  • Mild: No dosage adjustment required
  • Moderate-to-severe: Not studied

Hepatic impairment

  • Not recommended with active hepatic disease or hepatic impairment

Transaminase elevations

  • >1-3x ULN
    • Modify dose of other DMARDs if possible
    • Persistent increases (IV infusion): Reduce dose to 4 mg/kg or discontinue therapy and restart when ALT/AST return to normal
    • Persistent increases (SC injection): Reduce injection frequency to every other week or hold dosing until ALT/AST return to normal, resume at every other week and increase frequency to every week as clinically appropriate
  • >3-5x ULN
    • Confirmed by repeat testing
    • Hold tocilizumab until <3x ULN and follow recommendations above for >1-3x ULN
    • Persistent increases >3x ULN, discontinue tocilizumab
  • >5 x ULN
    • Discontinue therapy

Neutropenia

  • ANC >1000 cells/mm³: Maintain dose
  • ANC <500 cells/mm³: Discontinue therapy
  • ANC 500-1000 cells/mm³
    • Hold treatment until ANC >1000 cells/mm³
    • IV: Resume at 4 mg/kg and increase to 8 mg/kg as clinically appropriate
    • SC: Resume 162 mg at every other week and increase frequency to every week as clinically appropriate

Thrombocytopenia

  • <50,000 cells/mm³: Discontinue therapy
  • 50,000-10,000 cells/mm³
    • Hold treatment until >100,000 cells/mm³
    • IV: Resume therapy at 4 mg/kg and increase to 8 mg/kg if clinically appropriate
    • SC: Resume at 162 mg every other week and increase frequency to every week as clinically appropriate

Dosing Considerations

Monitor neutrophils, platelets, and ALT/AST 4-8 weeks following of therapy and q3months thereafter

Monitor lipids 4-8 weeks following initiation of therapy and then at ~24 week intervals

Use not recommended if

  • ANC <2000/mm³
  • Platelets <100,000/mm³
  • ALT or AST >1.5x ULN
  • Patients with severe or life-threatening CRS frequently have cytopenias or elevated ALT or AST due to the lymphodepleting chemotherapy or CRS; evaluate potential benefit of treating CRS versus the risks of short-term treatment with tocilizumab

Systemic Sclerosis (Orphan)

Orphan designation for treatment of systemic sclerosis

Orphan sponsor

  • Genentech, Inc.; 1 DNA Way; South San Francisco, CA 94080-4990

Dosage Forms & Strengths

injection, solution for IV infusion

  • 20mg/mL in 4-, 10-, and 20-mL vials

injection, single-use prefilled syringe for SC

  • 162mg/0.9mL

Systemic Juvenile Idiopathic Arthritis

Indicated for the treatment of active systemic juvenile idiopathic arthritis (SJIA, Still's Disease) in in patients ≥2 years

IV or SC may be administered as monotherapy or with methotrexate

<2 years: Safety and efficacy not established

IV infusion

  • ≥2 years (<30 kg): 12 mg/kg IV q2weeks  
  • ≥2 years (≥30 kg): 8 mg/kg IV q2weeks
  • Infuse over 60 minutes

SC injection

  • ≥2 years (<30 kg): 162 mg SC once q2weeks
  • ≥2 years (≥30 kg): 162 mg SC once weekly
  • When transitioning from IV to SC administration, administer the first SC dose instead of the next scheduled IV dose

Polyarticular Juvenile Idiopathic Arthritis

Indicated for active polyarticular juvenile idiopathic arthritis (PJIA) in patients ≥2 years

IV or SC may be administered as monotherapy or with methotrexate

<2 years: Safety and efficacy not established

IV infusion

  • ≥2 years (<30 kg): 10 mg/kg IV q4weeks  
  • ≥2 years (≥30 kg): 8 mg/kg IV q4weeks
  • Infuse over 60 minutes

SC injection

  • ≥2 years (<30 kg): 162 mg SC once q3weeks
  • ≥2 years (≥30 kg): 162 mg SC once q2weeks
  • When transitioning from IV to SC administration, administer the first SC dose instead of the next scheduled IV dose

Cytokine Release Syndrome (CRS)

Indicated for the treatment of chimeric antigen receptor (CAR) T cell-induced severe or life-threatening cytokine release syndrome (CRS) in adults and pediatric patients aged ≥2 years

SC is not approved for CRS

<2 years: Safety and efficacy not established

≥2 years (<30 kg): 12 mg/kg IV once

≥2 years (≥30 kg): 8 mg/kg IV once

Infuse over 60 minutes

May be administered as monotherapy or with corticosteroids

May administer up to 3 additional doses of tocilizumab if no clinical improvement in signs/symptoms of CRS after first dose; not to exceed 800 mg/dose

Interval between consecutive doses should be >8 hr

Dosage Modifications

Dose reduction has not been studied in the PJIA and SJIA populations

Dose interruptions are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined for adults with RA

The following dosage modifications apply to RA and GCA patients

Renal impairment

  • Mild: No dosage adjustment required
  • Moderate-to-severe: Not studied

Hepatic impairment

  • Not recommended with active hepatic disease or hepatic impairment

Transaminase elevations

  • >1-3x ULN
    • Modify dose of other DMARDs if possible
    • Persistent increases (IV infusion): Reduce dose to 4 mg/kg or discontinue therapy and restart when ALT/AST return to normal
    • Persistent increases (SC injection): Reduce injection frequency to every other week or hold dosing until ALT/AST return to normal, resume at every other week and increase frequency to every week as clinically appropriate
  • >3-5x ULN
    • Confirmed by repeat testing
    • Hold tocilizumab until <3x ULN and follow recommendations above for >1-3x ULN
    • Persistent increases >3x ULN, discontinue tocilizumab
  • >5 x ULN
    • Discontinue therapy

Neutropenia

  • ANC >1000 cells/mm³: Maintain dose
  • ANC <500 cells/mm³: Discontinue therapy
  • ANC 500-1000 cells/mm³
    • Hold treatment until ANC >1000 cells/mm³
    • IV: Resume at 4 mg/kg and increase to 8 mg/kg as clinically appropriate
    • SC: Resume 162 mg at every other week and increase frequency to every week as clinically appropriate

Thrombocytopenia

  • <50,000 cells/mm³: Discontinue therapy
  • 50,000-10,000 cells/mm³
    • Hold treatment until >100,000 cells/mm³
    • IV: Resume therapy at 4 mg/kg and increase to 8 mg/kg if clinically appropriate
    • SC: Resume at 162 mg every other week and increase frequency to every week as clinically appropriate

Dosing Considerations

Monitor neutrophils, platelets, ALT and AST at the time of the second infusion and thereafter every 4-8 weeks for PJIA and every 2-4 weeks for SJIA

Monitor lipids 4-8 weeks following initiation of therapy and then at ~24 week intervals

Increased risk of serious infections in patient ≥65 years; use caution when treating the elderly

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Interactions

Interaction Checker

and tocilizumab

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    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

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            Adverse Effects

            >10%

            SC injection site reactions (7.1-10.1%)

            1-10%

            Upper respiratory tract infection (6-8%)

            Nasopharyngitis (4-7%)

            Headache (3-7%)

            Hypertension (3-6%)

            ALT increased (1-6%)

            Bronchitis (2-4%)

            Rash (1-4%)

            Dizziness (1-3%)

            Mouth ulceration (1-2%)

            Upper abdominal pain (2-3%)

            Gastritis (1-2%)

            Oral herpes simplex (<2%)

            Stomatitis (<2%)

            Gastric ulcer (<2%)

            Increased weight (<2%)

            Total bilirubin increased (<2%)

            Leukopenia (<2%)

            Peripheral edema (<2%)

            Dyspnea (<2%)

            Cough (<2%)

            Conjunctivitis (<2%)

            Postmarketing Reports

            Stevens-Johnson syndrome

            Pancreatitis

            Fatal anaphylaxis

            Drug-induced liver injury, hepatitis, hepatic failure, jaundice

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            Warnings

            Black Box Warnings

            Risk of serious infections

            • Increased risk for developing serious infections that may lead to hospitalization or death
            • Most patients who developed these infections were taking concomitant immunosuppressants (eg, methotrexate, corticosteroids)
            • If a serious infection develops, interrupt therapy until the infection is controlled
            • Reported infections include
              • Active tuberculosis, which may present with pulmonary or extrapulmonary disease
              • Test for latent tuberculosis before tocilizumab use and during therapy; initiate treatment for latent infection prior to use Invasive fungal infections (eg, candidiasis, aspergillosis, pneumocystis); patients with invasive fungal infections may present with disseminated, rather than localized, disease
              • Bacterial, viral and other infections due to opportunistic pathogens
            • Carefully consider risks and benefits of treatment prior to initiating therapy in patients with chronic or recurrent infection
            • Closely monitor signs and symptoms of infection during and after treatment, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy

            Contraindications

            Hypersensitivity

            Cautions

            Risk for serious infections (see Black Box Warnings)

            If a serious infection develops, interrupt therapy until infection controlled

            Tocilizumab has not been studied in combination with biological DMARDs (eg, TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies, selective costimulation modulators) and its use should be avoided in combination with these agents because of increased immunosuppression and risk of infection

            Nonmelanoma skin cancers reported; periodic skin examination recommended

            Caution if increased risk for GI perforation

            May cause neutropenia, decreased platelets, elevated liver transaminases, and increased lipid parameters; monitor neutrophils, platelets, lipids, and liver function tests every 4-8 weeks

            Anaphylaxis or serious hypersensitivity reactions have occurred, including fatalities, with or without concomitant arthritis therapies

            Impact of treatment with tocilizumab on demyelinating disorders is unknown, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies; monitor for signs and symptoms potentially indicative of demyelinating disorders

            Hepatic injury

            • Serious cases of hepatic injury with intravenous or subcutaneous therapy; some cases have resulted in liver transplant or death; time to onset for cases ranged from months to years after treatment initiation with tocilizumab
            • For rheumatoid arthritis (RA) and giant cell arteritis (GCA) patients, obtain a liver test panel (serum alanine aminotransferase [ALT], aspartate aminotransferase [AST], alkaline phosphatase, and total bilirubin) before initiating therapy, every 4 to 8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter
            • Not recommended to initiate treatment in RA or GCA patients with elevated transaminases ALT or AST greater than 1.5x ULN
            • In patients who develop elevated ALT or AST greater than 5x ULN, discontinue therapy; for recommended modifications based upon increase in transaminases
            • Measure liver tests promptly in patients who report symptoms that may indicate liver injury, such as fatigue, anorexia, right upper abdominal discomfort, dark urine or jaundice; if patient is found to have abnormal liver tests (e.g., ALT greater than three times the upper limit of the reference range, serum total bilirubin greater than two times the upper limit of the reference range)
            • Treatment should be interrupted and investigation done to establish probable cause; therapy should only be restarted in patients with another explanation for liver test abnormalities after normalization of liver tests

            Drug interactions overview

            • Do not coadminister with live vaccines (eg, MMR, intranasal influenza); IL-6 inhibition may interfere with the normal immune response to new antigens, all patients, particularly those with PJIA and SJIA, should be current with their immunizations before initiating therapy
            • Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates; exercise caution when coadministering tocilizumab with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, (eg, oral contraceptives, lovastatin, atorvastatin): effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy
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            Pregnancy & Lactation

            Pregnancy

            Pregnancy exposure registry that monitors pregnancy outcomes in women exposed to during pregnancy; patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972

            Limited available data in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage

            Monoclonal antibodies are increasingly transported across placenta as pregnancy progresses, with largest amount transferred during third trimester; risks and benefits should be considered prior to administering live or live-attenuated vaccines to infants exposed to therapy in utero

            Lactation

            No information is available on presence of tocilizumab in human milk, the effects of drug on breastfed infant, or effects of drug on milk production

            Maternal immunoglobulin G (IgG) is present in human milk; if tocilizumab is transferred into human milk, effects of local exposure in gastrointestinal tract and potential limited systemic exposure in infant to tocilizumab are unknown

            Developmental and health benefits of breastfeeding should be considered along with mother’s clinical need for therapy and potential adverse effects on breastfed child from tocilizumab or from underlying maternal condition

            Pregnancy Categories

            A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

            B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

            C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

            D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

            X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

            NA: Information not available.

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            Pharmacology

            Mechanism of Action

            Interleukin-6 receptor antagonist; changes in clinical trials observed include decreased C-reactive protein level to within normal range, decreased values in other pharmacodynamic parameters (eg, rheumatoid factor, erythrocyte sedimentation rate, amyloid A), and increased hemoglobin value

            Absorption

            Steady-state AUC: 13,000 mcg•hr/mL (4 mg/kg q4Weeks); 35000 mcg•hr per mL (8 mg/kg q4Weeks)

            Peak plasma concentration: 88.3 mcg/mL (4 mg/kg q4Weeks); 183 mcg/mL (8 mg/kg q4Weeks)

            Peak plasma time in RA patients: 2.8 days (after the tocilizumab every week dose); 4.7 days (after the tocilizumab every other week dose)

            Peak plasma time in GCA patients: 3 days (after the tocilizumab every week dose); 4.5 days (after the tocilizumab every other week dose)

            Distribution

            Vd: 6.4L (RA); 7.46 L (GCA); 4.08 L (PJIA); 2.54 L (SJIA)

            Elimination

            Half-life: up to 11 days (4 mg/kg); up to 13 days (8 mg/kg)

            Half-life in RA patients: 13 days (162 mg every week); 5 days (162 mg every other week)

            Half-life in GCA patients: 18.3-18.9 days (162 mg SC every week); 4.2-7.9 days (162 mg SC every other week)

            Clearance: 0.0125 L/hr

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            Administration

            IV Compatibility

            0.9% or 0.45% NaCl

            IV Preparation

            Withdraw a volume of 0.9% or 0.45% NaCl from bag/bottle equal to volume of the solution required for the patient's dose

            Adults and children weighing ≥30 kg: Dilute to 100 mL in 0.9% or 0.45% NaCl

            Children <30 kg: Dilute to 50 mL in 0.9% or 0.45% NaCl

            Slowly add dose to infusion bag or bottle and gently invert to mix (prevent foaming)

            IV Administration

            Administer as single IV infusion over 1 hr

            Do NOT administer as bolus or push

            Do not infuse with any other drugs as no compatibility studies have been conducted

            SC Preparation

            Remove prefilled SC syringe/autoinjector from refrigerator 30 minutes before administration

            SC injection is not intended for IV drip infusion

            Do not use prefilled syringes or autoinjectors exhibiting particulate matter, cloudiness, or discoloration; solution for SC administration should appear clear and colorless to pale yellow

            SC Administration

            Indicated only in adults with rheumatoid arthritis

            Rotate SC injection sites (ie, thighs, abdomen, outer area of upper arm [caregiver only]) and inject full amount of the syringe (0.9 mL)

            Transition from IV to SC: Administer first SC dose instead of next scheduled IV dose

            Storage

            Undiluted vials and prefilled SC syringes/autoinjectors: Store refrigerated between 2-8°C (36-46°F) in original container and protect from light

            After dilution for IV administration: Store refrigerated between 2-8°C (36-46°F) or room temperature for up to 24 hr; protect from light

            Do not freeze

            Do not save unused, reconstituted drug in vials because product contains no preservatives

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            Formulary

            FormularyPatient Discounts

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            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
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