Tocilizumab

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 Auto-injector, Subcutaneous [preservative free]:

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

Solution Prefilled Syringe, Subcutaneous [preservative free]:

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

Pharmacology

Mechanism of Action

Tocilizumab is an 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.

Pharmacokinetics/Pharmacodynamics

Distribution

V_dss: Children and Adolescents: Systemic juvenile idiopathic arthritis (SJIA): 4.01 L; Polyarticular juvenile idiopathic arthritis (PJIA): 4.08 L; Adults: Rheumatoid arthritis (RA): 6.4 L; Giant cell arteritis (GCA): 7.46 L

Onset of Action

Cytokine release syndrome (CRS): Median time to defervescence: 4 hours (Fitzgerald 2017); Fever and hypotension typically resolve within a few hours (Lee 2014); Blood pressure stabilization: 1 to 3 days (Abboud 2016; Maude 2014b). A median of 1 dose (range: 1 to 4) was required for management of CRS due to chimeric antigen receptor T-cell therapy.

Time to Peak

SubQ: ~3 days (for every-week dosing); ~4.5 days (for every-2-week dosing)

Half-Life Elimination

IV: Concentration dependent: Steady state: Children and Adolescents: SJIA: Up to 16 days; PJIA: Up to 17 days; Adults: RA: Up to 11 to 13 days

SubQ: Concentration dependent: Children and Adolescents: SJIA: Up to 14 days; PJIA: Up to 10 days; Adults: RA: Up to 5 days (every-other-week dosing) or up to 13 days (every-week dosing); GCA: 4.2 to 7.9 days (every other week dosing) or 18.3 to 18.9 days (every-week dosing)

Use in Specific Populations

Special Populations Note

Body weight:

RA: 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.

GCA: Higher exposure was observed in patients with lower body weight. For the 162 mg every week dosing regimen, the steady-state C_avg was 51% higher in patients with body weight <60 kg compared with patients weighing between 60 to 100 kg. For the 162 mg every-other-week regimen, the steady-state C_avg was 129% higher in patients with body weight <60 kg compared with patients weighing between 60 to 100 kg.

Use: Labeled Indications

Cytokine release syndrome, severe or life-threatening: Treatment of chimeric antigen receptor (CAR) T-cell induced severe or life-threatening cytokine release syndrome in patients ≥2 years of age

Giant cell arteritis: Treatment of giant cell arteritis (GCA) in adult patients

Polyarticular juvenile idiopathic arthritis: Treatment of active polyarticular juvenile idiopathic arthritis (pJIA) in patients ≥2 years of age

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 (SJIA) in patients ≥2 years of age

Use: Off Label

Cytokine release syndrome (severe or life-threatening; due to BiTE therapy)c

Clinical experience suggests that tocilizumab may be effective for the management of severe or life-threatening cytokine release syndrome associated with bi-specific T-cell engaging (BiTE) cancer treatment Lee 2014, Maude 2014a. Additional data may be necessary to further define the role of tocilizumab in the treatment of this condition.

Contraindications

Known hypersensitivity to tocilizumab or any component of the formulation

Canadian labeling: Additional contraindications (not in the US labeling): Active infections

Dosage and Administration

Dosing: Adult

Note: In patients with giant cell arteritis (GCA) or rheumatoid arthritis (RA), do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³ or if ALT or AST are >1.5 times ULN. Patients with severe or life-threatening cytokine release syndrome frequently have cytopenias or elevated liver transaminases due to the underlying disease state and/or its treatment; evaluate risk versus benefit of tocilizumab treatment in patients with severe or life-threatening cytokine release syndrome.

Cytokine release syndrome (due to chimeric antigen receptor-T cell therapy), severe or life-threatening: Note: If clinical improvement does not occur after the first dose, up to 3 additional doses may be administered (with at least an 8 hour interval between consecutive doses). Tocilizumab may be administered as monotherapy or in combination with corticosteroids.

IV: Maximum dose: 800 mg per dose

<30 kg: 12 mg/kg

≥30 kg: 8 mg/kg

Giant cell arteritis: SubQ: 162 mg once every week (in combination with a tapering course of glucocorticoids); based on clinical considerations, may consider 162 mg once every other week (with a tapering course of glucocorticoids). Tocilizumab may be administered as monotherapy following discontinuation of glucocorticoids.

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

SubQ:

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

≥100 kg: 162 mg once every week

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

Cytokine release syndrome (due to bi-specific T-cell engaging therapy), severe or life-threatening (off-label use): IV: 4 mg/kg once; may repeat the dose if clinical improvement does not occur within 24 to 48 hours (Lee 2014). Additional data may be necessary to further define the role of tocilizumab in the treatment of this condition.

Dosing: Pediatric

Cytokine release syndrome (CRS) due to chimeric antigen receptor T-cell therapy; severe or life-threatening: Children ≥2 years and Adolescents: May be used alone or in combination with corticosteroids

<30 kg: IV: 12 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses.

≥30 kg: IV: 8 mg/kg/dose once; if no clinical improvement after initial dose, may repeat dose every 8 hours for up to 3 additional doses; maximum single dose: 800 mg/dose

Cytokine release syndrome (CRS) due to bi-specific T-cell engaging therapy, severe or life-threatening: Very limited data available (Barrett 2014; Maude 2014a); optimal dose not established: Children ≥2 years and Adolescents: IV: 8 mg/kg/dose once; some experts suggest may repeat the dose if clinical improvement does not occur within 24 to 48 hours (Lee 2014; Teachey 2013); dosing based on expert recommendations and a case report of a 7-year old who received blinatumomab as part of a Phase I clinical trial and developed CRS; a single 8 mg/kg dose of tocilizumab was used (patient weight was not provided) and within 12 hours a significant clinical response observed (Teachey 2013); other reports of experience in pediatric patients are lacking.

Polyarticular juvenile idiopathic arthritis (PJIA): Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³, or if ALT or AST are >1.5 times ULN. 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. Variable routes of administration (IV, SubQ) and dosing; use precaution to ensure appropriate dose/route.

IV:

<30 kg: 10 mg/kg/dose every 4 weeks

≥30 kg: 8 mg/kg/dose every 4 weeks; maximum dose: 800 mg/dose

SubQ:

<30 kg: 162 mg/dose once every 3 weeks

≥30 kg: 162 mg/dose once every 2 weeks

Conversion from IV to SubQ dosing: Administer the first SubQ dose instead of the next scheduled IV dose.

Systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years and Adolescents: Note: Do not initiate if ANC is <2,000/mm³, platelets are <100,000/mm³ or if ALT or AST are >1.5 times ULN. 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.

IV:

<30 kg: 12 mg/kg/dose every 2 weeks

≥30 kg: 8 mg/kg/dose every 2 weeks; maximum dose: 800 mg/dose

SubQ:

<30 kg: 162 mg/dose once every 2 weeks

≥30 kg: 162 mg/dose once every week

Conversion from IV to SubQ dosing: Administer the first SubQ dose instead of the next scheduled IV dose.

Dosing adjustment for toxicity:

Polyarticular and systemic juvenile idiopathic arthritis (SJIA): Children ≥2 years and Adolescents:

Non-hematologic toxicity: Dose reductions have not been studied; however, dose interruptions are recommended for liver enzyme abnormalities (see Hepatic Impairment). In addition, consider interrupting or discontinuing concomitant methotrexate and/or other medications and hold tocilizumab dosing until the clinical situation has been assessed. For hypersensitivity reactions, stop the infusion immediately and discontinue permanently. For infection (serious, opportunistic, or sepsis), interrupt treatment until infection resolved.

Hematologic toxicity: Dose reductions have not been studied; however, dose interruptions are recommended for low neutrophil counts and low platelets similar to recommendations provided for adult rheumatoid arthritis patients (see the following):

Adults:

Neutropenia:

ANC >1,000/mm³: Maintain dose.

ANC 500 to 1,000/mm³: Interrupt therapy; when ANC >1,000/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/mm³: Discontinue.

Thrombocytopenia:

Platelets 50,000 to 100,000/mm³: Interrupt therapy; when platelet count is >100,000/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/mm³: 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.

Rheumatoid arthritis and giant cell arteritis:

Neutropenia:

ANC >1,000/mm³: Maintain dose.

ANC 500 to 1,000/mm³: Interrupt therapy; when ANC >1,000/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/mm³: Discontinue.

Thrombocytopenia:

Platelets 50,000 to 100,000/mm³: Interrupt therapy; when platelet count is >100,000/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/mm³: Discontinue.

Reconstitution

IV: Prior to administration, dilute to 100 mL by slowly adding to NS or ¹/₂ NS. Use only the vials to prepare IV infusion solutions; do not use SubQ formulations (prefilled syringes, autoinjectors) to prepare IV solutions. Withdraw equal volume of NS or ¹/₂ NS 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 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. If additional doses are necessary for the management of cytokine release syndrome, the interval between doses should be at least 8 hours. Do not use if opaque particles or discoloration is visible.

SubQ: Allow to reach room temperature (30 minutes for prefilled syringe; 45 minutes for autoinjector) prior to use. Do not use if particulate matter or discoloration is visible; solution should be clear and colorless to pale yellow. Administer the full amount in the prefilled syringe or autoinjector. Rotate injection sites; avoid injecting into moles, scars, or tender, bruised, red, or hard skin. After proper training, patients may self-inject, or the patient's caregiver may administer tocilizumab.

Rheumatoid arthritis, polyarticular juvenile idiopathic arthritis, systemic juvenile idiopathic arthritis: When transitioning from IV administration to SubQ administration, give the first SubQ dose instead of the next scheduled IV dose.

Giant cell arteritis: Should only be administered subQ (IV administration is not approved for giant cell arteritis).

Storage

Store intact vials, prefilled syringes, and autoinjectors at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect vials, prefilled syringes, and autoinjectors from light (store in the original package until time of use); keep prefilled syringes and autoinjectors dry. Solutions diluted for IV infusion in NS may be stored at 2°C to 8°C (36°F to 46°F) or room temperature for up to 24 hours; solutions diluted for IV infusion in ¹/₂NS may be stored at 2°C to 8°C (36°F to 46°F) for up to 24 hours or at room temperature for up to 4 hours; protect from light. Discard unused product remaining in the vials.

Drug Interactions

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: May enhance the immunosuppressive effect of Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Biologic Disease-Modifying Antirheumatic Drugs (DMARDs): May enhance the immunosuppressive effect of other Biologic Disease-Modifying Antirheumatic Drugs (DMARDs). Avoid combination

Cladribine: May enhance the immunosuppressive effect of Immunosuppressants. Avoid combination

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

CYP3A4 Substrates (High risk with Inducers): Tocilizumab may decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). 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

Ocrelizumab: May enhance the immunosuppressive effect of Immunosuppressants. Monitor therapy

Pidotimod: Immunosuppressants may diminish the therapeutic effect of Pidotimod. Monitor therapy

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

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

Siponimod: Immunosuppressants may enhance the immunosuppressive effect of Siponimod. Monitor therapy

Sipuleucel-T: Immunosuppressants may diminish the therapeutic effect of Sipuleucel-T. Management: Evaluate patients to see if it is medically appropriate to reduce or discontinue therapy with immunosuppressants prior to initiating sipuleucel-T therapy. Consider therapy modification

Smallpox and Monkeypox Vaccine (Live): Immunosuppressants may diminish the therapeutic effect of Smallpox and Monkeypox Vaccine (Live). Monitor therapy

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

Tertomotide: Immunosuppressants may diminish the therapeutic effect of Tertomotide. Monitor therapy

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. Exceptions: Smallpox and Monkeypox Vaccine (Live). Avoid combination

Adverse Reactions

Incidence as reported for adults unless otherwise noted. Incidence as reported for monotherapy and combination therapy. Combination therapy refers to use in rheumatoid arthritis with nonbiological disease-modifying antirheumatic drugs or use in systemic juvenile idiopathic arthritis or polyarticular juvenile idiopathic arthritis in trials where most patients (~70% to 80%) were taking methotrexate at baseline.

>10%:

Endocrine & metabolic: Increased serum cholesterol (19% to 20%; children and adolescents: ≤2%)

Hepatic: Increased serum alanine aminotransferase (≤36%), increased serum aspartate aminotransferase (≤22%)

Local: Injection site reaction (SubQ: children and adolescents: 15% to 44% [higher incidence occurred in weight <30 kg]; adults: 4% to 10%)

Miscellaneous: Infusion-related reaction (4% to 20%)

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 (1%)

Endocrine & metabolic: Increased LDL cholesterol (9% to 10%; children and adolescents ≤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 (children and adolescents <30 kg: 26%; adults, grade 3: 2% to 7%; children and adolescents ≥30 kg: 4%; adults, grade 4: <1%), thrombocytopenia (1% to 2%), leukopenia (<2%)

Hepatic: Increased serum bilirubin (<2%)

Immunologic: Antibody development (children and adolescents: ≤6%; adults: <2%; neutralizing, adults: ≤1%)

Infection: Herpes simplex infection (<2%)

Ophthalmic: Conjunctivitis (<2%)

Renal: Nephrolithiasis (<2%)

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

Frequency not defined:

Infection: Infection, infection due to an organism in genus Pneumocystis, serious infection, varicella zoster infection

Otic: Otitis media

<1%, postmarketing, and/or case reports: Active tuberculosis, anaphylaxis, angioedema, aspergillosis, candidiasis, cellulitis, chronic inflammatory demyelinating polyneuropathy, cryptococcosis, diverticulitis of the gastrointestinal tract, gastroenteritis, gastrointestinal perforation, hepatic failure, hepatic injury (Genovese 2017), hepatitis, hepatotoxicity, hypersensitivity reaction, hypertriglyceridemia, hypotension, increased HDL cholesterol, jaundice, malignant neoplasm, multiple sclerosis, nausea, opportunistic infection, pancreatitis, pneumonia, pneumonia due to Pneumocystis jirovecii, septic arthritis, sepsis, Stevens-Johnson syndrome, urinary tract infection, viral infection

Warnings/Precautions

Concerns related to adverse effects:

• GI perforation: Use with caution in patients at increased risk for GI 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 giant cell arteritis (GCA), polyarticular juvenile idiopathic arthritis, rheumatoid arthritis (RA), or systemic juvenile idiopathic arthritis with an ANC <2,000/mm³ or platelet count <100,000/mm³; discontinue treatment for ANC <500/mm³ or platelet count <50,000/mm³.
• Hepatic effects: Hepatic injury, resulting in liver transplant or death, has been reported. May occur months to years after treatment initiation and may present with marked elevations of hepatic transaminases (>5 × ULN) or signs or symptoms of hepatic dysfunction with mildly elevated transaminases. May require treatment interruption, dose or interval modification, or discontinuation. Monitor LFTs prior to therapy initiation and during treatment. It is not recommended to initiate treatment in RA or GCA patients with baseline ALT or AST >1.5 × ULN; discontinue treatment for ALT or AST >5 × ULN. Patients with symptoms that indicate hepatic injury during therapy should have LFTs evaluated; interrupt therapy with abnormal LFTs (eg, ALT >3 × ULN, serum total bilirubin >2 × ULN); do not reinitiate therapy unless there is another explanation for abnormal hepatic tests and LFTs have normalized. Patients receiving concomitant hepatotoxic drugs (eg, methotrexate) are at an increased risk of developing elevated transaminases.
• 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 to 8 weeks after initiation, then subsequently according to current guidelines.
• Hypersensitivity: 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 SubQ 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.
• Infections: [US 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.
• 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: [US 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 preexisting or recent onset CNS demyelinating disorders; rare cases of CNS demyelinating disorders (multiple sclerosis and chronic inflammatory demyelinating polyneuropathy) 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. Initiation of therapy in RA and GCA patients with baseline ALT or AST >1.5 × ULN is not recommended.

Concurrent drug therapy issues:

• Biological disease-modifying antirheumatic drugs (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 with 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: SubQ administration is only indicated for adult patients with RA and GCA and pediatric patients with polyarticular juvenile idiopathic arthritis. Do not use SubQ injection for IV infusion. Do not administer IV for the treatment of GCA.
• 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 (all patients); neutrophils, platelets (prior to therapy, 4 to 8 weeks after start of therapy, and every 3 months thereafter [rheumatoid arthritis {RA}, giant cell arteritis {GCA}]); ALT/AST, alkaline phosphatase, and total bilirubin (prior to therapy, every 4 to 8 weeks after start of therapy for the first 6 months, and every 3 months thereafter [RA, GCA]); neutrophils, platelets, ALT/AST (prior to therapy, at second administration, and every 2 to 4 weeks [systemic juvenile idiopathic arthritis] or 4 to 8 weeks [polyarticular juvenile idiopathic arthritis] thereafter); additional liver function tests (eg, bilirubin) as clinically indicated; lipid panel (prior to and 4 to 8 weeks following initiation of therapy, then subsequently according to current guidelines); monitor all patients for signs and symptoms of infection (prior to, during, and after therapy); signs and symptoms of CNS demyelinating disorders

Pregnancy

Pregnancy Considerations

Tocilizumab is a humanized monoclonal antibody (IgG₁). Potential placental transfer of human IgG is dependent upon the IgG subclass and gestational age, generally increasing as pregnancy progresses. The lowest exposure would be expected during the period of organogenesis (Palmeira 2012; Pentsuk 2009).

Immune response in infants exposed to tocilizumab in utero may be affected. Consider risks:benefits prior to administering live or live-attenuated vaccines to infants exposed to tocilizumab in utero.

A pregnancy registry has been established to monitor outcomes of women exposed to tocilizumab during pregnancy. Health care providers or pregnant patients are encouraged to register (877-311-8972).

Patient Education

What is this drug used for?

• It is used to treat some types of arthritis.
• It is used to treat a certain artery problem called giant cell arteritis (GCA).
• It is used to treat cytokine release syndrome (CRS).
• It may be given to you for other reasons. Talk with the doctor.

Frequently reported side effects of this drug

• Injection site irritation
• Common cold symptoms
• Stuffy nose
• Sore throat

Other side effects of this drug: Talk with your doctor right away if you have any of these signs of:

• Infection
• Bleeding like 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 severe or persistent bleeding.
• Liver problems like dark urine, fatigue, lack of appetite, nausea, abdominal pain, light-colored stools, vomiting, or yellow skin.
• Behavioral changes
• Mood changes
• Confusion
• Neck rigidity
• Sensitivity to lights
• Severe muscle weakness
• Severe headache
• Severe dizziness
• Passing out
• Vision changes
• Mole changes
• Shortness of breath
• Chest pain
• Severe nausea
• Vomiting
• Severe abdominal pain
• Severe abdominal edema
• Skin growths
• Burning or numbness feeling
• Bowel changes
• Signs of a significant reaction like 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. Talk to your doctor if you have questions.

Consumer Information Use and Disclaimer: This information should not be used to decide whether or not to take this medicine or any other medicine. Only the healthcare provider has the knowledge and training to decide which medicines are right for a specific patient. This information does not endorse any medicine as safe, effective, or approved for treating any patient or health condition. This is only a brief summary of general information about this medicine. It does NOT include all information about the possible uses, directions, warnings, precautions, interactions, adverse effects, or risks that may apply to this medicine. This information is not specific medical advice and does not replace information you receive from the healthcare provider. You must talk with the healthcare provider for complete information about the risks and benefits of using this medicine.