Uses of Actemra: - Ankylosing spondylitis - Rheumatoid arthritis - Psoriasis - Ulcerative Colitis - Crohn’s disease Juvenile idiopathic arthritis, Rheumatoid Arthritis (RA) Hypersensitivity

Drugs used for Rheumatoid Arthritis

Tocilizumab is a recombinant humanized anti-human interleukin 6 (IL 6) receptor monoclonal antibody of the immunoglobulin (Ig) IgG1 subclass. Tocilizumab binds specifically to both soluble and membrane-bound IL 6 receptors (sIL 6R and mIL 6R), and has been shown to inhibit sIL 6R and mIL 6R-mediated signaling. Interleukin-6 is a multi-functional cytokine, produced by a variety of cell types involved in local paracrine function as well as regulation of systemic physiological and pathological processes eg, induction of immunoglobulin secretion, T-cell activation, induction of hepatic acute phase proteins and stimulation of haematopoiesis. Interleukin-6 has been implicated in the pathogenesis of diseases including inflammatory diseases, osteoporosis and neoplasia. The possibility exists for tocilizumab to affect host defences against infections and malignancies. The role of IL-6 receptor inhibition in the development of malignancies is not known.

How to use Tocilizumab: Your doctor or nurse will give you this medicine. Kindly do not self administer. Administration: 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 Adult 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 Child Dose: 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 Dose: Renal impairment Mild: No dosage adjustment required Moderate-to-severe: Has not been studied

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.

Hypersensitivity

Common - Headache - High blood pressure - Upper respiratory tract infection - Increased liver enzymes - Nasopharyngitis (inflammation of the throat and nasal passages) >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

Pregnancy Category- C. Animal reproduction studies have shown an adverse effect on the fetus and there are no adequate and well-controlled studies in humans, but potential benefits may warrant use of the drug in pregnant women despite potential risksLactation: Unknown whether distributed in breast milk, do not breast feed

Precaution: 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

There are limited data available on overdoses with tocilizumab. One case of accidental overdose was reported with intravenous tocilizumab in which a patient with multiple myeloma received a dose of 40 mg per kg. No adverse drug reactions were observed. No serious adverse drug reactions were observed in healthy volunteers who received single doses of up to 28 mg per kg, although all 5 patients at the highest dose of 28 mg per kg developed dose-limiting neutropenia. In case of an overdose, it is recommended that the patient be monitored for signs and symptoms of adverse reactions. Patients who develop adverse reactions should receive appropriate symptomatic treatment.

Tocilizumab must be refrigerated at 2ºC to 8ºC. Do not freeze. Protect the vials, syringes, and autoinjectors from light by storage in the original package until time of use, and keep syringes and autoinjectors dry.

Drugs used for Rheumatoid Arthritis

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

Based on animal data, may cause fetal harm. Discontinue drug or nursing taking into consideration importance of drug to mother.