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Tocilizumab

Pronunciation: TOE-si-LIZ-ue-mab
Class: Immunomodulator

Trade Names

Actemra
- Injection, solution, concentrate 20 mg/mL

Pharmacology

A recombinant humanized antihuman interleukin 6 (IL-6) receptor that binds specifically to both soluble and membrane-bound IL-6 receptors (sIL-6R and mIL-6R), and has been shown to inhibit IL-6–mediated signaling through these receptors.

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Pharmacokinetics

Absorption

For doses of 4 mg/kg given every 4 wk in rheumatoid arthritis (RA) patients, the predicted mean steady-state AUC, C min , and C max were 13,000 mcg•h/mL, 1.49 mcg/mL, and 88.3 mcg/mL, respectively. Steady state was reached following the first administration for C max and AUC, respectively, and after 16 wk for C min .

For doses of 8 mg/kg given every 4 wk in RA patients, the predicted mean steady-state AUC, C min , and C max were 35,000 mcg•h/mL, 9.74 mcg/mL, and 183 mcg/mL, respectively. Steady state was reached following the first administration and after 8 and 20 wk for C max , AUC, and C min , respectively.

Distribution

The mean Vd at steady state is 6.4 L for RA patients and 2.54 L for systemic juvenile idiopathic arthritis patients.

Elimination

At the 10 mg/kg single dose in RA patients, mean Cl was 0.29 mL/h/kg and mean apparent terminal half-life was 151 h (6.3 days). The linear Cl was estimated to be 12.5 mL/h. The concentration-dependent apparent half-life is up to 11 days for 4 mg/kg and up to 13 days for 8 mg/kg every 4 wk at steady state for RA and up to 23 days at wk 12 for systemic juvenile idiopathic arthritis patients.

Special Populations

Renal Function Impairment

Mild renal impairment did not impact the pharmacokinetics of tocilizumab. Tocilizumab has not been studied in patients with moderate to severe renal impairment.

Hepatic Function Impairment

No pharmacokinetic data are available.

Elderly

Age did not affect the pharmacokinetics of tocilizumab.

Gender

Gender did not affect the pharmacokinetics of tocilizumab.

Race

Race did not affect the pharmacokinetics of tocilizumab.

Weight

The body weight–based dose (8 mg/kg) resulted in approximately 86% higher exposure in patients who weighed more than 100 kg in comparison with patients who weighed less than 60 kg.

Indications and Usage

For the treatment of adults with moderately to severely active RA who have had an inadequate response to 1 or more tumor necrosis factor (TNF) antagonist therapies; for the treatment of active systemic juvenile idiopathic arthritis.

Contraindications

Hypersensitivity to tocilizumab.

Dosage and Administration

Rheumatoid Arthritis
Adults

IV 4 mg/kg once every 4 wk. Increase to 8 mg/kg based on clinical response (max, 800 mg per infusion).

Dosage reduction

Reduction of dose from 8 mg/kg to 4 mg/kg is recommended for management of certain dose-related laboratory changes, including elevated liver enzymes, neutropenia, and thrombocytopenia.

Elevated liver enzymes More than 1 to 3 × ULN

Dose modify concomitant disease-modifying antirheumatic drugs (DMARDs) if appropriate. For persistent increases in this range, reduce tocilizumab dose to 4 mg/kg or interrupt tocilizumab until ALT/AST have normalized.

More than 3 to 5 × ULN (confirmed by repeat testing)

Interrupt tocilizumab dosing until less than 3 × ULN and follow recommendations above for more than 1 to 3 × ULN. For persistent increases more than 3 × ULN, discontinue tocilizumab.

More than 5 × ULN

Discontinue tocilizumab.

Neutropenia Absolute neutrophil count (ANC) more than 1,000 cells/mm 3

Maintain dose.

ANC 500 to 1,000 cells/mm 3

Interrupt tocilizumab dosing. When ANC is more than 1,000 cells/mm 3 , resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.

ANC less than 500 cells/mm 3

Discontinue tocilizumab.

Thrombocytopenia Platelets 50,000 to 100,000 cells/mm 3

Interrupt tocilizumab dosing. When platelet count is greater than 100,000 cells/mm 3 resume tocilizumab at 4 mg/kg and increase to 8 mg/kg as clinically appropriate.

Platelets less than 50,000 cells/mm 3

Discontinue tocilizumab.

Systemic Juvenile Idiopathic Arthritis
Children 2 y and older Weighing less than 30 kg

IV 12 mg/kg once every 2 wk.

Weighing 30 kg or more

IV 8 mg/kg once every 2 wk.

Dose adjustment/reduction

A change in dose should not be made based solely on a single visit body weight measurement because weight may fluctuate. Dose reduction has not been studied; however, dose interruptions are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts at levels similar to adult RA patient.

General Advice

  • Administer as a 60-min single IV drip infusion. Do not administer as an IV push or bolus.
  • Must be diluted with sodium chloride 0.9% to 50 or 100 mL. Allow the fully diluted solution to reach room temperature before administration.
  • May be used as monotherapy or concomitantly with methotrexate or other DMARDs.
  • It is recommended that tocilizumab not be initiated in patients with an ANC below 2,000/mm 3 , platelet count below 100,000/mm 3 , or who have ALT or AST more than 1.5 times the ULN.
  • Tocilizumab treatment should be interrupted if a patient develops a serious infection until the infection is controlled.
  • Do not use concomitantly in the same IV line with other drugs.
  • For systemic juvenile idiopathic arthritis patients weighing less than 30 kg, use a 50 mL infusion bag or bottle. For adult RA and systemic juvenile idiopathic arthritis patients weighing 30 kg or more, use a 100 mL infusion bag or bottle.

Storage/Stability

Store between 36° and 46°F. Do not freeze. Keep in original carton to protect from light until time of use. Store fully diluted solutions between 36° and 46°F or at room temperature for up to 24 h and protect from light. Unused product remaining in the vials should not be used.

Drug Interactions

Anti-CD20 monoclonal antibodies (eg, rituximab), IL-1R antagonists (eg, anakinra), selective costimulation modulators (eg, abatacept), TNF antagonists (eg, infliximab)

There is a possibility of increased immunosuppression and increased risk of infection. Avoid coadministration of these agents with tocilizumab.

Cyclosporine, theophylline

The pharmacologic effect of these agents may be decreased. Closely measure cyclosporine and theophylline concentrations when starting or stopping tocilizumab. Adjust the dose as needed.

Dextromethorphan, HMG-CoA reductase inhibitors (eg, lovastatin, simvastatin), proton pump inhibitors (eg, omeprazole)

The pharmacologic effect of these agents may be decreased. Monitor the response of the patient when starting or stopping tocilizumab and adjust the dose of these agents as needed.

Hormonal contraceptives

The pharmacologic effect of the hormonal contraceptive may be decreased. Inform women of the possible increased risk of hormonal contraceptive failure. An alternative nonhormonal contraceptive or an additional method of contraception should be considered.

Immunosuppressants (eg, corticosteroids, methotrexate)

May predispose patients to infections. Monitor the patient and adjust treatment as needed.

Warfarin

The anticoagulant effect of warfarin may be decreased. Monitor coagulation parameters more closely when starting or stopping tocilizumab. Adjust the warfarin dose as needed.

Adverse Reactions

Cardiovascular

Hypertension (6%).

CNS

Headache (7%); dizziness (3%).

GI

Diarrhea (at least 5%); mouth ulceration, upper abdominal pain (2%); gastric ulcer, stomatitis (less than 2%); gastritis (1%); GI perforation.

Hematologic

Neutropenia (17%); decreased platelet count (4%); leukopenia (less than 2%).

Hepatic

Elevated ALT (36%); elevated AST (22%); increased total bilirubin (less than 2%); transaminase increased (1%).

Hypersensitivity

Fatal anaphylaxis (postmarketing).

Local

Infusion reactions (16%); skin reactions (eg, pruritis, urticaria) (1%).

Metabolic-Nutritional

Hypothyroidism, peripheral edema, weight increased (less than 2%); elevated total cholesterol and LDL (2%).

Respiratory

Nasopharyngitis, upper respiratory tract infection (7%); bronchitis (3%); cough, dyspnea (less than 2%).

Miscellaneous

Infection (5% to 8%); macrophage activation syndrome (3%); antibody formation, rash (2%); conjunctivitis, nephrolithiasis, oral herpes simplex (less than 2%); malignancy.

Precautions

Warnings

Patients treated with tocilizumab are at 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 active tuberculosis (TB); invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis; and bacterial, viral, and other infections caused by opportunistic pathogens. Carefully consider the risks and benefits of treatment 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 TB in patients who tested negative for latent TB infection prior to initiating therapy.


Monitor

Monitor neutrophils, platelets, ALT, and AST every 4 to 8 wk for RA patients; for systemic juvenile idiopathic arthritis patients monitor at the time of the second infusion and every 2 to 4 wk thereafter. Monitor lipid panel 4 to 8 wk following initiation of therapy, then at 6-month intervals. Closely monitor for development of signs or symptoms of infection during and after treatment. Closely monitor patients for signs and symptoms potentially indicative of demyelinating disorders. Monitor for signs and symptoms of TB, including patients who tested positive for latent TB infection prior to initiating therapy.


Pregnancy

Category C .

Lactation

Undetermined.

Children

Safety and efficacy not established in children younger than 2 y for the treatment of systemic juvenile idiopathic arthritis.

Hypersensitivity

Serious hypersensitivity reactions, including anaphylaxis and death, have occurred.

Renal Function

No dosage adjustment is required in mild renal impairment. Use in moderate to severe renal impairment has not been studied.

Hepatic Function

Not recommended in active hepatic disease or hepatic impairment.

Demyelinating disorders

Use caution in treating patients with preexisting or recent-onset demyelinating disorders.

GI perforations

May occur; primarily as complications of diverticulitis.

Hematologic effects

Neutropenia, thrombocytopenia, and transaminase elevations may occur.

Hepatic effects

Transaminase elevations may occur.

Immunogenicity

Anti-tocilizumab antibodies may occur.

Lipids

Treatment with tocilizumab was associated with increases in lipid parameters, such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol.

Malignancies

May occur.

Tuberculosis

Evaluate patients for TB infection and test for latent infection prior to initiating treatment.

Viral reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with tocilizumab.

Overdosage

Symptoms

Neutropenia.

Patient Information

  • Advise patient to review Medication Guide before starting therapy and to review it periodically.
  • Instruct patients to notify their health care provider if they develop any symptoms of infection.
  • Instruct patients to seek immediate medical attention if they experience any symptom of severe allergic reaction.
  • Advise patient to report intolerable injection-site reactions or unusual symptoms to health care provider.
  • Warn patient not to receive live vaccines while undergoing tocilizumab therapy.
  • Counsel patients about the risk of malignancies while receiving tocilizumab.
  • Inform patients that serious side effects in the stomach and intestines may occur and to report symptoms of severe, persistent abdominal pain.

Copyright © 2009 Wolters Kluwer Health.

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