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Tocilizumab

Pronunciation

(toe si LIZ oo mab)

Index Terms

  • Atlizumab
  • MRA
  • R-1569
  • RoActemra

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution, Intravenous [preservative free]:

Actemra: 80 mg/4 mL (4 mL); 200 mg/10 mL (10 mL); 400 mg/20 mL (20 mL) [contains polysorbate 80]

Solution Prefilled Syringe, Subcutaneous [preservative free]:

Actemra: 162 mg/0.9 mL (0.9 mL) [contains polysorbate 80]

Brand Names: U.S.

  • Actemra

Pharmacologic Category

  • Antirheumatic, Disease Modifying
  • Interleukin-6 Receptor Antagonist

Pharmacology

Antagonist of the interleukin-6 (IL-6) receptor. Endogenous IL-6 is induced by inflammatory stimuli and mediates a variety of immunological responses. Inhibition of IL-6 receptors by tocilizumab leads to a reduction in cytokine and acute phase reactant production.

Distribution

Vdss: Children: 2.54 L (SJIA), 4.08 L (PJIA); Adults: 6.4 L

Half-Life Elimination

IV: Terminal, single dose: 6.3 days (concentration-dependent; may be increased up to 16-23 days [children] or 11-13 days [adults] at steady state)

SubQ: Concentration dependent: Adults: Up to 5 days (every other week dosing) or 13 days (every week dosing)

Special Populations Note

Weight

For IV administration, the body weight–based dose (8 mg/kg) resulted in ~86% higher exposure in patients who weighed >100 kg in comparison with patients who weighed <60 kg.

Use: Labeled Indications

Polyarticular juvenile idiopathic arthritis: Treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years and older.

Rheumatoid arthritis: Treatment of adults with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs).

Systemic juvenile idiopathic arthritis: Treatment of active systemic juvenile idiopathic arthritis in patients 2 years and older.

Contraindications

Hypersensitivity to tocilizumab or any component of the formulation

Canadian labeling: Additional contraindications (not in U.S. labeling): Active infections

Dosing: Adult

Note: Do not initiate if ANC is <2000/mm3, platelets are <100,000/mm3 or if ALT or AST are >1.5 times ULN.

Rheumatoid arthritis: Note: Methotrexate or other nonbiologic disease-modifying antirheumatic drugs (DMARDs) may be continued for the treatment of rheumatoid arthritis. Tocilizumab should not be used in combination with biologic DMARDs.

IV: Initial: 4 mg/kg every 4 weeks; may be increased to 8 mg/kg based on clinical response (maximum dose: 800 mg).

SubQ:

<100 kg: 162 mg every other week; increase to every week based on clinical response

≥100 kg: 162 mg every week

Transitioning from IV therapy to SubQ therapy: Administer the first SubQ dose instead of the next scheduled IV dose.

Dosing: Pediatric

Note: Do not initiate if ANC is <2000/mm3, platelets are <100,000/mm3 or if ALT or AST are >1.5 times ULN.

Polyarticular juvenile idiopathic arthritis (PJIA): Children ≥2 years: IV: Note: Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate.

<30 kg: 10 mg/kg every 4 weeks

≥30 kg: 8 mg/kg every 4 weeks

Systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years: IV: Note: Dose adjustment should not be made based solely on a single-visit body weight measurement due to fluctuations in body weight. May be used as monotherapy or in combination with methotrexate.

<30 kg: 12 mg/kg every 2 weeks

≥30 kg: 8 mg/kg every 2 weeks

Dosing: Renal Impairment

Mild renal impairment: No dosage adjustment necessary.

Moderate-to-severe renal impairment: There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied).

Dosing: Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling (has not been studied). Not recommended for use in patients with active hepatic disease or hepatic impairment.

Hepatotoxicity during treatment: Rheumatoid arthritis:

>1 to 3 x ULN: Adjust concomitant DMARDs as appropriate. For patients receiving IV therapy with persistent increases >1 to 3 x ULN, reduce dose to 4 mg/kg or interrupt until ALT/AST have normalized. For patients receiving SubQ therapy with persistent increases >1 to 3 x ULN, reduce injection frequency to every other week or interrupt until ALT/AST have normalized; increase frequency to every week as clinically appropriate.

>3 to 5 x ULN (confirmed with repeat testing): Interrupt until ALT/AST <3 x ULN and follow dosage adjustments recommended for liver enzyme abnormalities >1 to 3 x ULN. For persistent increases >3 x ULN, discontinue.

>5 x ULN: Discontinue.

Dosing: Adjustment for Toxicity

Hypersensitivity (anaphylaxis or other clinically-significant hypersensitivity reaction): Stop immediately and discontinue permanently.

Infection (serious infection, opportunistic infection or sepsis): Interrupt treatment until the infection is controlled.

Polyarticular and systemic juvenile idiopathic arthritis: Dose reductions have not been studied; however, dose interruptions are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelets similar to recommendations provided for rheumatoid arthritis. In addition, consider interrupting or discontinuing concomitant methotrexate and/or other medications and hold tocilizumab dosing until the clinical situation has been assessed.

Rheumatoid arthritis (RA):

Low absolute neutrophil counts (ANC):

ANC >1000 cells/mm3: Maintain dose.

ANC 500-1000 cells/mm3: Interrupt therapy; when ANC >1000 cells/mm3, resume IV tocilizumab at 4 mg/kg (may increase to 8 mg/kg as clinically appropriate). or resume SubQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).

ANC <500 cells/mm3: Discontinue.

Low platelet counts:

Platelets 50,000-100,000 cells/mm3: Interrupt therapy; when platelet count is >100,000 cells/mm3, resume IV tocilizumab at 4 mg/kg (may increase to 8 mg/kg as clinically appropriate) or resume SubQ tocilizumab at every other week dosing (increase frequency to every week as clinically appropriate).

Platelets <50,000 cells/mm3: Discontinue.

Reconstitution

IV: Prior to administration, dilute to 50 mL (children <30 kg) or 100 mL (children ≥30 kg and adults) by slowly adding to 0.9% sodium chloride. Use vials for IV to prepare infusion solutions; do not use prefilled SubQ syringes to prepare IV solutions. Withdraw equal volume of 0.9% sodium chloride to the volume of tocilizumab required for dose; slowly add tocilizumab dose into infusion bag or bottle. Gently invert to mix (avoid foaming). Diluted solutions may be stored under refrigeration or at room temperature for up to 24 hours (protected from light) and are compatible with polypropylene, polyethylene (PE), polyvinyl chloride (PVC), and glass infusion containers. Allow diluted solution to reach room temperature prior to infusion.

Administration

IV: Allow diluted solution for infusion to reach room temperature prior to administration; infuse over 60 minutes using a dedicated IV line. Do not infuse other agents through same IV line. Do not administer IV push or IV bolus. Do not use if opaque particles or discoloration is visible.

SubQ: Rheumatoid arthritis: When transitioning from IV administration to SubQ administration, give the first SubQ dose instead of the next scheduled IV dose. Administer the full amount in the prefilled syringe. Allow to reach room temperature prior to use. Do not use if particulate matter or discoloration is visible; solution should be clear and colorless to pale yellow. Rotate injection sites; avoid injecting into moles, scars, or tender, bruised, red, or hard skin. Prefilled syringe is available for use by patients (self-administration).

Storage

Store intact vials/syringes at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials and syringes from light (store in the original package until time of use); keep syringes dry. Solutions diluted for IV infusion may be stored at 2°C to 8°C (36°F to 46°F) or room temperature for up to 24 hours and should be protected from light. Discard unused product remaining in the vials.

Drug Interactions

Abatacept: Tocilizumab may enhance the adverse/toxic effect of Abatacept. Avoid combination

Anti-TNF Agents: Tocilizumab may enhance the immunosuppressive effect of Anti-TNF Agents. Avoid combination

BCG (Intravesical): Immunosuppressants may diminish the therapeutic effect of BCG (Intravesical). Avoid combination

Belimumab: Monoclonal Antibodies may enhance the adverse/toxic effect of Belimumab. Avoid combination

Coccidioides immitis Skin Test: Immunosuppressants may diminish the diagnostic effect of Coccidioides immitis Skin Test. Monitor therapy

CYP3A4 Substrates: Tocilizumab may decrease the serum concentration of CYP3A4 Substrates. Monitor therapy

Denosumab: May enhance the adverse/toxic effect of Immunosuppressants. Specifically, the risk for serious infections may be increased. Monitor therapy

Echinacea: May diminish the therapeutic effect of Immunosuppressants. Consider therapy modification

Fingolimod: Immunosuppressants may enhance the immunosuppressive effect of Fingolimod. Management: Avoid the concomitant use of fingolimod and other immunosuppressants when possible. If combined, monitor patients closely for additive immunosuppressant effects (eg, infections). Consider therapy modification

Leflunomide: Immunosuppressants may enhance the adverse/toxic effect of Leflunomide. Specifically, the risk for hematologic toxicity such as pancytopenia, agranulocytosis, and/or thrombocytopenia may be increased. Management: Consider not using a leflunomide loading dose in patients receiving other immunosuppressants. Patients receiving both leflunomide and another immunosuppressant should be monitored for bone marrow suppression at least monthly. Consider therapy modification

Natalizumab: Immunosuppressants may enhance the adverse/toxic effect of Natalizumab. Specifically, the risk of concurrent infection may be increased. Avoid combination

Nivolumab: Immunosuppressants may diminish the therapeutic effect of Nivolumab. Consider therapy modification

Pimecrolimus: May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Roflumilast: May enhance the immunosuppressive effect of Immunosuppressants. Consider therapy modification

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Monitor therapy

Tacrolimus (Topical): May enhance the adverse/toxic effect of Immunosuppressants. Avoid combination

Tofacitinib: Tocilizumab may enhance the adverse/toxic effect of Tofacitinib. Avoid combination

Trastuzumab: May enhance the neutropenic effect of Immunosuppressants. Monitor therapy

Vaccines (Inactivated): Immunosuppressants may diminish the therapeutic effect of Vaccines (Inactivated). Management: Vaccine efficacy may be reduced. Complete all age-appropriate vaccinations at least 2 weeks prior to starting an immunosuppressant. If vaccinated during immunosuppressant therapy, revaccinate at least 3 months after immunosuppressant discontinuation. Consider therapy modification

Vaccines (Live): Immunosuppressants may enhance the adverse/toxic effect of Vaccines (Live). Immunosuppressants may diminish the therapeutic effect of Vaccines (Live). Management: Avoid use of live organism vaccines with immunosuppressants; live-attenuated vaccines should not be given for at least 3 months after immunosuppressants. Avoid combination

Adverse Reactions

Incidence as reported for monotherapy, except where noted. Combination therapy refers to use in rheumatoid arthritis with nonbiological DMARDs or use in SJIA or PJIA in trials where most patients (~70% to 80%) were taking methotrexate at baseline.

>10%:

Endocrine & metabolic: Increased serum cholesterol (>240 mg/dL; 19% to 20%; >1.5-2 x ULN; combination therapy; children and adolescents <1% to 2%)

Hepatic: Increased serum ALT (≤36%; grades 3/4: <1%), increased serum AST (≤22%; grades 3/4: <1%)

Miscellaneous: Infusion-related reaction (combination therapy; 4% to 16%)

1% to 10%:

Cardiovascular: Hypertension (1% to 6%), peripheral edema (<2%)

Central nervous system: Headache (1% to 7%), dizziness (3%)

Dermatologic: Skin rash (2%), dermatological reaction (combination therapy; 1% [includes pruritus, urticaria])

Endocrine & metabolic: Increased LDL cholesterol (9% to 10%; >1.5-2 x ULN; combination therapy; children and adolescents <1% to 2%), hypothyroidism (<2%)

Gastrointestinal: Diarrhea (children and adolescents ≤5%), abdominal pain (2%), oral mucosa ulcer (2%), gastric ulcer (<2%), stomatitis (<2%), weight gain (<2%), gastritis (1%)

Hematologic & oncologic: Neutropenia (combination therapy; grade 3: 2% to 7%; grade 4: <1%), thrombocytopenia (combination therapy; 1% to 2%), leukopenia (<2%)

Hepatic: Increased serum bilirubin (<2%)

Immunologic: Antibody development (<2%)

Infection: Herpes simplex infection (<2%)

Local: Injection site reaction (SubQ: Including erythema, pruritus, pain, and hematoma; 4% to 10%)

Ophthalmic: Conjunctivitis (<2%)

Renal: Nephrolithiasis (<2%)

Respiratory: Upper respiratory tract infection (7%), nasopharyngitis (7%), bronchitis (3%), cough (<2%), dyspnea (<2%)

<1% (Limited to important or life-threatening): Anaphylaxis, anaphylactoid reaction, angioedema, aspergillosis, candidiasis, cellulitis, chronic inflammatory demyelinating polyneuropathy, cryptococcosis, diverticulitis, gastroenteritis, gastrointestinal perforation, herpes zoster, hypersensitivity, hypersensitivity pneumonitis, hypertriglyceridemia, hypotension, increased HDL cholesterol, malignant neoplasm (including breast and colon cancer), multiple sclerosis, otitis media, pneumonia, pneumocystosis, reactivation of latent Epstein-Barr virus, septic arthritis, sepsis, Stevens-Johnson syndrome, tuberculosis, urinary tract infection, varicella

ALERT: U.S. Boxed Warning

Risk of serious infections:

Patients treated with tocilizumab are at an increased risk for developing serious infections that may lead to hospitalization or death. Most patients who developed these infections were taking concomitant immunosuppressants, such as methotrexate or corticosteroids.

If a serious infection develops, interrupt tocilizumab until the infection is controlled.

Reported infections include the following:

Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Test patients for latent tuberculosis before tocilizumab use and during therapy. Initiate treatment for latent infection prior to tocilizumab use.

Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated rather than localized disease.

Bacterial, viral, and other infections caused by opportunistic pathogens.

Carefully consider the risks and benefits of treatment with tocilizumab prior to initiating therapy in patients with chronic or recurrent infection.

Closely monitor patients for the development of signs and symptoms of infection during and after treatment with tocilizumab, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.

Warnings/Precautions

Concerns related to adverse effects:

• Anaphylaxis/hypersensitivity reactions: May cause hypersensitivity or anaphylaxis; anaphylactic events including fatalities have been reported with IV administration; hypersensitivity reactions have occurred in patients who were premedicated, in patients with and without a prior history of hypersensitivity, and as early as the first infusion. Medications for the treatment of hypersensitivity reactions should be available for immediate use. Patients should seek medical attention if symptoms of hypersensitivity reaction occur with subcutaneous use. Stop immediately and permanently discontinue treatment in patients who develop a hypersensitivity reaction to tocilizumab. In clinical studies, reactions requiring treatment discontinuation included generalized erythema, rash, and urticaria.

• Elevated liver enzymes: Monitor transaminases. Treatment should be discontinued in patients who develop elevated ALT or AST >5 x ULN. Patients receiving concomitant hepatotoxic drugs (eg, methotrexate) are at an increased risk of developing elevated transaminases; elevations are typically reversible and do not result in clinically evident hepatic injury.

• Fatal infections: [U.S. Boxed Warning]: Serious and potentially fatal infections (including active tuberculosis, invasive fungal, bacterial, viral, protozoal, and other opportunistic infections) have been reported in patients receiving tocilizumab; infection may lead to hospitalization or death. Most of the serious infections have occurred in patients on concomitant immunosuppressive therapy. Patients should be closely monitored for signs and symptoms of infection during and after treatment. If serious infection occurs during treatment, withhold tocilizumab until infection is controlled. Prior to treatment initiation, carefully consider risk versus benefit in patients with chronic or recurrent infections, tuberculosis exposure, history of or current opportunistic infection, underlying conditions predisposing to infection, or patients residing in or with travel to areas of endemic tuberculosis or endemic mycosis. The most common serious infections occurring have included pneumonia, UTI, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis, and bacterial arthritis. Do not administer tocilizumab to a patient with an active infection, including localized infection. Interrupt treatment for serious infection, opportunistic infection or sepsis.

• Gastrointestinal perforation: Use with caution in patients at increased risk for gastrointestinal perforation; perforation has been reported, typically secondary to diverticulitis. Monitor for new-onset abdominal symptoms; promptly evaluate if new symptoms occur.

• Hematologic effects: Neutropenia and thrombocytopenia may occur; may require treatment interruption, dose or interval modification, or discontinuation. Monitor neutrophils and platelets. Do not initiate treatment in patients with an ANC <2,000/mm3 or platelet count <100,000/mm3; discontinue treatment for ANC <500/mm3 or platelet count <50,000/mm3.

• Herpes zoster reactivation: Herpes zoster reactivation has been reported.

• Hyperlipidemia: Therapy is associated with increases in total cholesterol, triglycerides, LDL , and/or HDL; monitor ~4-8 weeks after initiation, then approximately every 6 months. Hyperlipidemia should be managed according to current guidelines.

• Malignancy: Use of tocilizumab may affect defenses against malignancies; impact on the development and course of malignancies is not fully defined, however, malignancies were observed in clinical trials.

• Tuberculosis: [U.S. Boxed Warning]: Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving tocilizumab; both reactivation of latent infection and new infections have been reported. Patients should be tested for latent tuberculosis infection before and during therapy; consider treatment of latent tuberculosis used prior to tocilizumab treatment. Some patients who test negative prior to therapy may develop active infection; monitor for signs and symptoms of tuberculosis during and after treatment in all patients. Patients should be evaluated for tuberculosis risk factors with a tuberculin skin test prior to starting therapy. Consider antituberculosis treatment in patients with a history of latent or active tuberculosis if adequate treatment course cannot be confirmed, and for patients with risk factors for tuberculosis despite a negative test.

Disease-related concerns:

• Demyelinating CNS disease: Use with caution in patients with pre-existing or recent onset CNS demyelinating disorders; rare cases of CNS demyelinating disorders (eg, multiple sclerosis) have occurred. All patients should be monitored for signs and symptoms of demyelinating disorders.

• Hepatic impairment: Use is not recommended in patients with active hepatic disease or hepatic impairment. Monitor ALT and AST. Do not initiate treatment if ALT or AST is >1.5 times ULN.

Concurrent drug therapy issues:

• Biological DMARDs: Concomitant use with other biological DMARDs (eg, TNF blockers, IL-1 receptor blockers, anti-CD20 monoclonal antibodies, selective costimulation modulators) has not been studied and should be avoided due to the increased risk of infection.

• Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.

Special populations:

• Elderly: Infection has been reported at a higher incidence in elderly patients compared to younger adults; use with caution in elderly patients.

Dosage form specific issues:

• Polysorbate 80: Some dosage forms may contain polysorbate 80 (also known as Tweens). Hypersensitivity reactions, usually a delayed reaction, have been reported following exposure to pharmaceutical products containing polysorbate 80 in certain individuals (Isaksson, 2002; Lucente 2000; Shelley, 1995). Thrombocytopenia, ascites, pulmonary deterioration, and renal and hepatic failure have been reported in premature neonates after receiving parenteral products containing polysorbate 80 (Alade, 1986; CDC, 1984). See manufacturer’s labeling.

Other warnings/precautions:

• Appropriate use: Subcutaneous administration is only indicated for adult patients with rheumatoid arthritis. Do not use subcutaneous injection for IV infusion.

• Immunizations: Patients should be brought up to date with all immunizations before initiating therapy. Live vaccines should not be given concurrently; there is no data available concerning secondary transmission of infection from live vaccines in patients receiving therapy.

Monitoring Parameters

Latent TB screening prior to therapy initiation; neutrophils, platelets, ALT/AST (prior to therapy, 4-8 weeks after start of therapy, and every 3 months thereafter [RA]); neutrophils, platelets, ALT/AST (prior to therapy, at second infusion, and every 2-4 weeks [SJIA, U.S. labeling; SJIA and PJIA, Canadian labeling] or 4-8 weeks [PJIA, U.S. labeling] thereafter); additional liver function tests (eg, bilirubin) as clinically indicated; lipid panel (prior to, at 4-8 weeks following initiation, and every ~6 months during therapy); signs and symptoms of infection (prior to, during, and after therapy); signs and symptoms of CNS demyelinating disorders

Pregnancy Risk Factor

C

Pregnancy Considerations

Adverse events have been observed in some animal reproduction studies. Monoclonal antibodies cross the placenta, with the largest amount transferred during the third trimester. A pregnancy registry has been established to monitor outcomes of women exposed to tocilizumab during pregnancy (877-311-8972).

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)

• Patient may experience injection site irritation, rhinorrhea, or rhinitis. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any bleeding that is very bad or that will not stop), signs of liver problems (dark urine, feeling tired, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin or eyes), swelling of hands or feet, severe headache, severe dizziness, passing out, severe abdominal pain, skin growths, burning or numbness feeling, or bowel changes (HCAHPS).

• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for healthcare professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience and judgment in diagnosing, treating and advising patients.

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