Actemra

Juvenile idiopathic arthritis, Rheumatoid Arthritis (RA)

IV Preparation Withdraw a volume of 0.9% 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% NaCl Children <30 kg: Dilute to 50 mL in 0.9% 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 from refrigerator 30 minutes before administration 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

Parenteral Adult: Rheumatoid Arthritis Indicated for adults with moderate-to-severe active rheumatoid arthritis with inadequate response to 1 or more DMARDs as an IV infusion or SC injection May use alone or in combination with methotrexate or other DMARDs IV infusion 4 mg/kg IV q4wk initially; may increase to 8 mg/kg q4wk based on clinical response Not to exceed 800 mg/dose q4wk SC injection Weight <100 kg: 162 mg SC every other week, followed by an increase to every week based on clinical response Weight >100 kg: 162 mg SC every week Hepatic impairment Not recommended with active hepatic disease or hepatic impairment

Systemic Juvenile Idiopathic Arthritis (SJIA, Still's Disease) <2 years: Safety and efficacy not established >2 years or older (<30 kg): 12 mg/kg IV q2weeks (>30 kg): 8 mg/kg IV q2weeks May be administered as monotherapy or with methotrexate Polyarticular Juvenile Idiopathic Arthritis (PJIA) <2 years: Safety and efficacy not established >2 years or older (<30 kg): 10 mg/kg IV q4weeks (>30 kg or more): 8 mg/kg IV q4weeks May be administered as monotherapy or with methotrexate

Renal impairment Mild: No dosage adjustment required Moderate-to-severe: Has not been studied

Hypersensitivity

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

Serious infections leading to hospitalization or death (ie, tuberculosis; bacterial, invasive fungal, viral, or other opportunistic infections) have occurred with use Stop therapy if serious infection occurs; can restart if infection is controlled Test for latent tuberculosis before initiating; if positive, initiate tuberculosis therapy before starting tocilizumab Continue to monitor all patients for active tuberculosis during therapy Lactation: unknown whether distributed in breast milk, do not breast feed

>10% SC injection site reactions (7.1-10.1%) 1-10% Upper respiratory tract infections,Nasopharyngitis,Headache,Hypertension,Increased ALT,Infusion related skin reactions (eg, rash, pruritus, urticaria),Dose related adverse reactions including decreased neutrophil count <1000/cu.mm, decreased platelets <100,000/cu.mm,Lipid elevations,Mouth ulcerations,Gastritis,Upper abdominal pain

Interactions with Other Medications and Other Forms of Interaction: Population pharmacokinetic analyses did not detect any effect of MTX, nonsteroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance. Tocilizumab has not been studied in combination with other biological DMARDs. The expression of hepatic CYP450 enzymes is suppressed by cytokines, eg, IL-6, that stimulate chronic inflammation. Thus, CYP450 expression may be reversed when potent cytokine inhibitory therapy, eg, tocilizumab is introduced. In vitro studies with cultured human hepatocytes demonstrated that IL-6 caused a reduction in CYP1A2, CYP2C9, CYP2C19, and CYP3A4 enzyme expression. Tocilizumab normalizes expression of these enzymes. The effect of tocilizumab on CYP enzymes (except CYP2C19 and CYP2D6) is clinically relevant for CYP450 substrates with a narrow therapeutic index, and/or where the dose is individually adjusted. In a study in RA patients, levels of simvastatin (CYP3A4) were decreased by 57% one week following a single dose of tocilizumab, to the level similar or slightly higher than those observed in healthy subjects. When starting or stopping therapy with tocilizumab, patients taking medications, which are individually dose-adjusted and are metabolised via CYP450 3A4, 1A2, or 2C9 (eg, atorvastatin, calcium channel blockers, theophylline, warfarin, phenytoin, ciclosporin, or benzodiazepines) should be monitored as doses of these products may need to be adjusted to maintain their therapeutic effect. Given its long elimination t½, the effect of tocilizumab on CYP450 enzyme activity may persist for several weeks after stopping therapy.