tocilizumab (Rx)

Brand and Other Names:Actemra
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Dosing & Uses

AdultPediatricGeriatric

Dosage Forms & Strengths

injectable solution

  • 20mg/mL (4-, 10-, and 20-mL single-dose 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)

May use alone or in combination with methotrexate or other DMARDs

IV infusion

4 mg/kg IV q4Weeks initially; may increase to 8 mg/kg q4Weeks based on clinical response  

Not to exceed 800 mg/dose q4weeks

SC injection

  • Weight <100 kg: 162 mg SC every other week, followed by an increase to weekly based on clinical response
  • Weight ≥100 kg: 162 mg SC weekly

Giant Cell Arteritis

Indicated for treatment of giant cell arteritis (GCA)

162 mg SC 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)

Not approved for IV administration

Cytokine Release Syndrome

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

8 mg/kg IV once; may be administered as alone or in combination with corticosteroids

If no clinical improvement in the signs and symptoms of CRS occurs after initial dose, may administer up to 3 additional doses; allow 8-hr interval between consecutive doses

Not approved for SC administration

Coronavirus Disease 2019 (COVID-19) (Off-label)

Data available as of March 24, 2020

Note: Limited data available; no drug is FDA approved to treat COVID-19

Tocilizumab may be considered for use as part of an investigational protocol for patients with COVID-19

For more information, see the CDC website (link https://www.cdc.gov/coronavirus/2019-ncov/hcp/therapeutic-options.html)

Additional Medscape COVID-19 references are available

Dosage Modifications

Renal impairment

  • Mild-to-moderate (eGFR ≥30 mL/min): No dosage adjustment required
  • Severe (eGFR <30 mL/min): Not studied

Hepatic impairment

  • Not recommended with active hepatic disease or hepatic impairment

Liver enzyme abnormalities for RA and GCA

  • >1 to ≤3x ULN
    • Modify dose concomitant DMARDs (RA) or immunomodulatory agents (GCA) if appropriate
    • Persistent increases (IV infusion): Reduce tocilizumab dose to 4 mg/kg OR hold dose and restart until ALT/AST return to normal
    • Persistent increases (SC injection): Reduce injection frequency to every other week OR hold dose until ALT/AST return to normal, resume at every other week and increase frequency to every week as clinically appropriate
  • >3 to ≤5x ULN
    • Hold dose until <3x ULN and follow recommendations above for >1 to ≤3x ULN
    • Persistent increases >3x ULN: Discontinue tocilizumab
  • >5x ULN
    • Discontinue therapy

Neutropenia for RA and GCA

ANC >1000 cells/mm3: Maintain dose

  • ANC 500-1000 cells/mm3
    • Hold dose, resume when 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 weekly as clinically appropriate
  • ANC <500 cell/mm3
    • Discontinue therapy

Thrombocytopenia for RA and GCA

  • 50,000-10,000 cells/mm3
    • Hold dose, resume when platelet count >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 weekly as clinically appropriate
  • <50,000 cells/mm3
    • Discontinue therapy

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

injectable solution

  • 20mg/mL (4-, 10-, and 20-mL single-dose 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) 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

SC injection

  • ≥2 years (<30 kg): 162 mg SC q2weeks
  • ≥2 years (≥30 kg): 162 mg SC weekly

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

SC injection

  • ≥2 years (<30 kg): 162 mg SC q3weeks
  • ≥2 years (≥30 kg): 162 mg SC q2weeks

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
  • ≥30 kg: 8 mg/kg IV once
  • May be administered as monotherapy or with corticosteroids
  • If no clinical improvement in the signs and symptoms of CRS occurs after initial dose, may administer up to 3 additional doses; allow 8-hr interval between consecutive doses
  • Not to exceed 800 mg/dose
  • Not approved for SC administration

Dosage Modifications

Dose reduction has not been studied in PJIA and SJIA populations

PJIA or SJIA: Dose interruptions are recommended for liver enzyme abnormalities, low ANC, and low platelet counts in outlined for adults with RA and GCA

If appropriate, modify dose or stop concomitant methotrexate and/or other medications and hold tocilizumab until clinical situation has been evaluated

Discontinue tocilizumab should be based upon medical assessment of the patient

Renal impairment

  • Mild-to-moderate (eGFR ≥30 mL/min): No dosage adjustment required
  • Severe (eGFR <30 mL/min): Not studied

Hepatic impairment

  • Not recommended with active hepatic disease or hepatic impairment

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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     activity indicator 
    No Interactions Found
    Interactions Found

    Contraindicated

      Serious - Use Alternative

        Significant - Monitor Closely

          Minor

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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)

            Do not administer in patients with an active infection, including localized infections; consider the risk versus benefits before initiating in patients with chronic or recurrent infection, who have been exposed to tuberculosis, with a history of serious or an opportunistic infection, who have resided or traveled in areas of endemic tuberculosis or endemic mycoses, or with underlying conditions that may predispose them to infection

            Not 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 IV or SC therapy; some cases have resulted in liver transplant or death; onset for cases ranged from months to years after initiating tocilizumab
            • For RA and GCA patients, obtain a liver test panel (ALT, AST, alkaline phosphatase, and total bilirubin) before initiating therapy, every 4-8 weeks after start of therapy for the first 6 months of treatment and every 3 months thereafter
            • Not recommended to initiate 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 (eg, ALT >3x ULN, total bilirubin >2x ULN)
            • Interrupt treatment and establish probable cause; once liver tests normalize, restart in patients with another explanation for liver test abnormalities

            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

            Insufficient data available in pregnant women to determine whether there is a drug-associated risk for major birth defects and miscarriage

            Pregnancy registry

            • Monitors pregnancy outcomes in women exposed to tocilizumab during pregnancy
            • Register or encourage patients and pregnant women to register themselves by calling 1-877-311-8972

            Fetal/neonatal adverse reactions

            • Monoclonal antibodies (eg, tocilizumab) are actively transported across the placenta during the third trimester of pregnancy and may affect immune response in the in utero exposed infant
            • Consider risks and benefits before administering live or live-attenuated vaccines to infants exposed in utero

            Lactation

            No data available on the presence of tocilizumab in human milk, effects of the drug on the breastfed infant, or effects of the 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 the gastrointestinal tract and potential limited systemic exposure in the infant to tocilizumab are unknown

            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

            Peak plasma concentration

            • RA (4 mg/kg IV q4Weeks): 86.1 mcg/mL
            • RA (8 mg/kg IV q4Weeks): 176 mcg/mL
            • RA (162 mg SC every other week): 12.1 mcg/mL
            • RA (162 mg SC weekly): 49.8 mcg/mL
            • GCA (162 SC every other week): 17.2 mcg/mL
            • GCA (162 SC weekly): 72.1 mcg/mL
            • PJIA (8 mg/kg IV q4Weeks): 181 mcg/mL
            • PJIA (10 mg/kg IV q4Weeks): 167 mcg/mL
            • PJIA (162 mg SC q2Weeks): 29.7 mcg/mL
            • PJIA (162 mg SC q3Weeks): 62.4 mcg/mL
            • SJIA (8 mg/kg IV q2Weeks): 253 mcg/mL
            • SJIA (12 mg/kg IV q2Weeks): 274 mcg/mL
            • SJIA (162 mg SC weekly): 89.8 mcg/mL
            • SJIA (162 mg SC q2Weeks): 127 mcg/mL

            Plasma trough concentration

            • RA (4 mg/kg IV q4Weeks): 0.1 mcg/mL
            • RA (8 mg/kg IV q4Weeks): 13.4 mcg/mL
            • RA (162 mg SC every other week): 4.1 mcg/mL
            • RA (162 mg SC weekly): 42.9 mcg/mL
            • GCA (162 SC every other week): 7.7 mcg/mL
            • GCA (162 SC weekly): 9.6 mcg/mL
            • PJIA (8 mg/kg IV q4Weeks): 3.28 mcg/mL
            • PJIA (10 mg/kg IV q4Weeks): 0.35 mcg/mL
            • PJIA (162 mg SC q2Weeks): 12.7 mcg/mL
            • PJIA (162 mg SC q3Weeks): 13.4 mcg/mL
            • SJIA (8 mg/kg IV q2Weeks): 70.7 mcg/mL
            • SJIA (12 mg/kg IV q2Weeks): 65.9 mcg/mL
            • SJIA (162 mg SC weekly): 72.4 mcg/mL
            • SJIA (162 mg SC q2Weeks): 64.2 mcg/mL

            Peak plasma time

            • RA (weekly): 2.8 days
            • RA (every other week): 4.7 days
            • GCA (weekly): 3 days
            • GCA (every other week): 4.5 days

            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 2-8ºC (36-46ºF) in original container and protect from light

            After dilution for IV administration: Store refrigerated between 2-8ºC (36-46ºF) 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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            Images

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            Formulary

            FormularyPatient Discounts

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            The above information is provided for general informational and educational purposes only. Individual plans may vary and formulary information changes. Contact the applicable plan provider for the most current information.

            Tier Description
            1 This drug is available at the lowest co-pay. Most commonly, these are generic drugs.
            2 This drug is available at a middle level co-pay. Most commonly, these are "preferred" (on formulary) brand drugs.
            3 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs.
            4 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            5 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            6 This drug is available at a higher level co-pay. Most commonly, these are "non-preferred" brand drugs or specialty prescription products.
            NC NOT COVERED – Drugs that are not covered by the plan.
            Code Definition
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