tocilizumab

tocilizumab

Actemra

Pharmacologic class: Interleukin-6 (IL-6) receptor inhibitor

Therapeutic class: Immunomodulator

Pregnancy risk category C

FDA Box Warning

Serious infections leading to hospitalization or death, including tuberculosis (TB) and bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving tocilizumab.

If a serious infection develops, interrupt therapy until infection is controlled.

Perform test for latent TB; if positive, start treatment for TB before starting tocilizumab.

Monitor all patients for active TB during treatment, even if initial latent TB test is negative.

Action

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; decreases levels of C-reactive protein to within normal range; decreases rheumatoid factor, erythrocyte sedimentation rate, serum amyloid A; increases hemoglobin

Availability

Solution for injection, concentrate: 80 mg/4 ml, 200 mg/10 ml, 400 mg/20 ml (20 mg/ml) in single-use vials

Indications and dosages

➣ Moderate to severe active rheumatoid arthritis in patients who have had inadequate response to one or more tumor necrosis factor (TNF) antagonists

Adults: Initially (when used in combination with disease-modifying antirheumatic drugs [DMARDs] or as monotherapy), 4 mg/kg by I.V. infusion over 60 minutes q 4 weeks; may increase to 8 mg/kg by I.V. infusion over 60 minutes q 4 weeks based on clinical response. Maximum dosage, 800 mg/infusion.

➣ Active systemic juvenile idiopathic arthritis (SJIA)

Children age 2 and older weighing 30 kg (66 lb) or more: 8 mg/kg (alone or with methotrexate) by I.V. infusion over 60 minutes q 2 weeks

Children age 2 and older weighing less than 30 kg: 12 mg/kg (alone or with methotrexate) by I.V. infusion over 60 minutes q 2 weeks

Dosage adjustment

• Elevated liver enzyme levels

• Neutropenia, thrombocytopenia

Contraindications

• Hypersensitivity to drug

Precautions

Use cautiously in:

• active hepatic disease or hepatic impairment (use not recommended)

• absolute neutrophil count less than 2,000/mm³, platelet count less than 100,000/mm³, ALT or AST more than 1.5 times the upper limit of normal (use not recommended)

• patients who may be at increased risk for GI perforation (such as patients with diverticulitis)

• patients at risk for infection

• demyelinating disorders (such as multiple sclerosis and chronic inflammatory demyelinating polyneuropathy)

• active infection (don't use)

• concurrent use of biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies, selective co-stimulation modulators, and live vaccines (avoid use)

• concurrent use of CYP3A4 substrates when decrease in effectiveness is undesirable (such as oral contraceptives, lovastatin, atorvastatin)

• concurrent use of immunosuppressants and corticosteroids

• elderly patients

• pregnant or breastfeeding patients

• children younger than age 2 and for conditions other than SJIA (safety and efficacy not established).

Administration

Be aware that drug should only be administered by healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other clinically significant hypersensitivity reaction occurs, stop drug immediately and permanently.

• Evaluate patient for TB risk factors; test for latent infection before starting therapy.

• Consider risks and benefits of treatment before starting therapy in patients with chronic or recurrent infection, in those who have been exposed to TB, in those with history of serious or opportunistic infection, in those who have resided or traveled in areas of endemic TB or endemic mycoses, and in those with underlying conditions that may predispose to infection.

• For adults and SJIA patients who weigh 30 kg or more, dilute concentrated solution to 100 ml in 0.9% sodium chloride for I.V. infusion using 100-ml infusion bag.

• For SJIA patients weighing less than 30 kg, dilute to 50 ml in 0.9% sodium chloride for I.V. infusion using 50-ml infusion bag.

• Withdraw a volume of 0.9% sodium chloride injection from infusion bag or bottle equal to volume of drug required for dose.

• Slowly add drug for I.V. infusion from each vial into infusion bag. Gently invert bag to avoid foaming to mix solution. Allow fully diluted solution to reach room temperature before infusing. Don't mix or infuse with other drugs. Discard unused product.

Administer as single I.V. drip infusion over 1 hour; don't administer as bolus or push.

• Interrupt therapy if patient develops serious infection, opportunistic infection, or sepsis until infection has been controlled.

Be aware that interruption or discontinuation of drug may be needed for management of dose-related laboratory abnormalities, including elevated liver enzyme levels, neutropenia, and thrombocytopenia. If appropriate, concomitant methotrexate or other drugs should be dose-modified or stopped.

• On initiation or discontinuation of tocilizumab in patients being treated with CYP450 substrates with narrow therapeutic indices, monitor therapeutic effect of drugs such as warfarin or drug concentration of drugs such as cyclosporine or theophylline.

Adverse reactions

CNS: headache, dizziness

CV: hypertension

EENT: nasopharyngitis

GI: gastroenteritis, diverticulitis, mouth ulcerations, upper abdominal pain, gastritis, GI perforation

GU: urinary tract infection

Hematologic: neutropenia, decreased platelets

Hepatic: abnormal liver function test results, increased lipids

Musculoskeletal: bacterial arthritis

Respiratory: upper respiratory tract infection, pneumonia, bronchitis

Skin: cellulitis, rash

Other: herpes zoster exacerbation, other serious and opportunistic infections, sepsis, malignancies, infusion reactions, hypersensitivity reactions including anaphylaxis

Interactions

Drug-drug. CYP450 substrates with narrow therapeutic indices (such as cyclosporine, theophylline, warfarin): increased metabolism of these drugs

Omeprazole, simvastatin: decreased exposure of these drugs

Drug-diagnostic tests. ALT, AST, HDL, LDL, total cholesterol, triglycerides: increased levels

Neutrophils, platelets: decreased counts

Patient monitoring

• Monitor CBC with differential, particularly neutrophils and platelets, and hepatic function tests, particularly ALT and AST, every 4 to 8 weeks. Monitor ALT, AST, neutrophils, and platelets every 2 to 4 weeks in children with SJIA. Monitor lipid levels approximately 4 to 8 weeks after initiation of therapy, then at approximately 24-week intervals in adults and children.

Continue to closely watch for signs and symptoms of hypersensitivity, demyelinating disorders, serious infection, and sepsis.

• Be aware that patients who develop new infection during treatment should undergo prompt and complete diagnostic workup appropriate for immunocompromised patients, receive appropriate antimicrobial therapy, and undergo close monitoring.

• Continue to closely monitor patients for signs and symptoms of TB, including patients who tested negative for latent TB before start of therapy.

Monitor patients who may be at increased risk for GI perforation. Promptly evaluate for early identification of GI perforation in patients who present with new-onset abdominal signs and symptoms.

Be aware that treatment with immunosuppressants may increase risk of malignancies.

Patient teaching

• Instruct patient or caregiver about importance of telling prescriber about known infections before starting drug.

• Tell patient or caregiver that TB test will be done before start of therapy and tests for blood counts and liver function will be done frequently.

Instruct patient to immediately seek medical attention if hives, rash, throat swelling, or difficulty breathing occurs.

Instruct patient or caregiver of importance of immediately contacting prescriber if severe, persistent abdominal pain; change in bowel habits; infection (fever, chills, cough, or burning on urination); or other new signs and symptoms occur.

• Instruct patient or caregiver that patient shouldn't receive live vaccines during therapy.

• Advise female patient of childbearing age to inform prescriber if she becomes pregnant during therapy.

• Advise breastfeeding patient that she should decide whether to discontinue breastfeeding or discontinue drug, taking into account importance of drug for her treatment.

• As appropriate, review all other significant and life-threatening adverse reactions and interactions, especially those related to the drugs and tests mentioned above.

McGraw-Hill Nurse's Drug Handbook, 7th Ed. Copyright © 2013 by The McGraw-Hill Companies, Inc. All rights reserved