Actemra (Tocilizumab) is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

Actemra (Tocilizumab) may be used as monotherapy or concomitantly with methotrexate or other DMARDs. The recommended dose of Actemra (Tocilizumab) for adult patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Single-use vials of Actemra (Tocilizumab) (20 mg per mL):

Actemra (Tocilizumab) should not be administered to patients with known hypersensitivity to Actemra (Tocilizumab)

Serious and sometimes fatal infections due to bacterial, mycobacterial, invasive fungal, viral, protozoal, or other opportunistic pathogens have been reported in patients receiving immunosuppressive agents including Actemra (Tocilizumab) for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis . Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with Actemra (Tocilizumab) . Other serious infections, not reported in clinical studies, may also occur (e.g., histoplasmosis, coccidioidomycosis, listeriosis). Patients have presented with disseminated rather than localized disease, and were often taking concomitant immunosuppressants such as methotrexate or corticosteroids which in addition to rheumatoid arthritis may predispose them to infections.

Actemra (Tocilizumab) should not be administered in patients with an active infection, including localized infections. The risks and benefits of treatment should be considered prior to initiating Actemra (Tocilizumab) in patients:

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with Actemra (Tocilizumab) , as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants .

Actemra (Tocilizumab) should be interrupted if a patient develops a serious infection, an opportunistic infection, or sepsis. A patient who develops a new infection during treatment with Actemra (Tocilizumab) should undergo a prompt and complete diagnostic workup appropriate for an immunocompromised patient, appropriate antimicrobial therapy should be initiated, and the patient should be closely monitored.

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. Actemra (Tocilizumab) should be used with caution in patients who may be at increased risk for gastrointestinal perforation. Patients presenting with new onset abdominal symptoms should be evaluated promptly for early identification of gastrointestinal perforation .

Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with infusion of Actemra (Tocilizumab) . Anaphylaxis and other hypersensitivity reactions that required treatment discontinuation were reported in 0.1% (3 out of 2644) of patients in the 6-month controlled trials, and in 0.2% (8 out of 4009) of patients in the all-exposure rheumatoid arthritis population; and in the SJIA controlled trial, 1 out of 112 patients (0.9%). In the postmarketing setting, a patient with a previous infusion reaction and premedicated with steroids and antihistamines experienced fatal anaphylaxis during subsequent treatment with Actemra (Tocilizumab) . Actemra (Tocilizumab) should only be administered by a healthcare professional with appropriate medical support to manage anaphylaxis. If anaphylaxis or other clinically significant hypersensitivity reaction occurs, administration of Actemra (Tocilizumab) should be stopped immediately and Actemra (Tocilizumab) should be permanently discontinued. Do not administer Actemra (Tocilizumab) to patients with known hypersensitivity to Actemra (Tocilizumab) .

The impact of treatment with Actemra (Tocilizumab) on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in RA clinical studies. Patients should be closely monitored for signs and symptoms potentially indicative of demyelinating disorders. Prescribers should exercise caution in considering the use of Actemra (Tocilizumab) in patients with preexisting or recent onset demyelinating disorders.

Live vaccines should not be given concurrently with Actemra (Tocilizumab) as clinical safety has not been established. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving Actemra (Tocilizumab) . No data are available on the effectiveness of vaccination in patients receiving Actemra (Tocilizumab) . Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly systemic juvenile idiopathic arthritis patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating Actemra (Tocilizumab) therapy. The interval between live vaccinations and initiation of Actemra (Tocilizumab) therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not predict the rates observed in a broader patient population in clinical practice.

Population pharmacokinetic analyses did not detect any effect of methotrexate (MTX), non-steroidal anti-inflammatory drugs or corticosteroids on tocilizumab clearance.

Concomitant administration of a single dose of 10 mg per kg Actemra (Tocilizumab) with 10-25 mg MTX once weekly had no clinically significant effect on MTX exposure.

Actemra (Tocilizumab) has not been studied in combination with biological DMARDs such as TNF antagonists .

No studies on the potential for Actemra (Tocilizumab) to cause dependence have been performed. However, there is no evidence from the available data that Actemra (Tocilizumab) treatment results in dependence.

There are limited data available on overdoses with Actemra (Tocilizumab) . One case of accidental overdose was reported 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.

Actemra (Tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1κ (gamma 1, kappa) subclass with a typical HL polypeptide structure. Each light chain and heavy chain consists of 214 and 448 amino acids, respectively. The four polypeptide chains are linked intra- and inter-molecularly by disulfide bonds. Actemra (Tocilizumab) has a molecular weight of approximately 148 kDa.

Actemra (Tocilizumab) is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg per mL. Actemra (Tocilizumab) is a colorless to pale yellow liquid, with a pH of about 6.5. Single-use vials are available containing 80 mg per 4 mL, 200 mg per 10 mL, or 400 mg per 20 mL of Actemra (Tocilizumab) . Injectable solutions of Actemra (Tocilizumab) are formulated in an aqueous solution containing disodium phosphate dodecahydrate and sodium dihydrogen phosphate dehydrate (as a 15 mmol per L phosphate buffer), polysorbate 80 (0.5 mg per mL), and sucrose (50 mg per mL).

In clinical studies with the 4 mg per kg and 8 mg per kg doses of Actemra (Tocilizumab) , decreases in levels of C-reactive protein (CRP) to within normal ranges were seen as early as week 2. Changes in pharmacodynamic parameters were observed (i.e., decreases in rheumatoid factor, erythrocyte sedimentation rate (ESR), serum amyloid A and increases in hemoglobin) with both doses, however the greatest improvements were observed with 8 mg per kg Actemra (Tocilizumab) . Pharmacodynamic changes were also observed to occur after Actemra (Tocilizumab) administration in SJIA patients (decreases in CRP, ESR, and increases in hemoglobin). The relationship between these pharmacodynamic findings and clinical efficacy is not known.

In healthy subjects administered Actemra (Tocilizumab) in doses from 2 to 28 mg per kg, absolute neutrophil counts decreased to the nadir 3 to 5 days following Actemra (Tocilizumab) administration. Thereafter, neutrophils recovered towards baseline in a dose dependent manner. Rheumatoid arthritis patients demonstrated a similar pattern of absolute neutrophil counts following Actemra (Tocilizumab) administration .

Rheumatoid Arthritis
The efficacy and safety of Actemra (Tocilizumab) was assessed in five randomized, double-blind, multicenter studies in patients greater than 18 years with active rheumatoid arthritis diagnosed according to American College of Rheumatology (ACR) criteria. Patients had at least 8 tender and 6 swollen joints at baseline. Actemra (Tocilizumab) was given intravenously every 4 weeks as monotherapy (Study I), in combination with methotrexate (MTX) (Studies II and III) or other disease-modifying anti-rheumatic drugs (DMARDs) (Study IV) in patients with an inadequate response to those drugs, or in combination with MTX in patients with an inadequate response to TNF antagonists (Study V).

Study I
Study II
Study III
Study IV
Study V
Systemic Juvenile Idiopathic Arthritis (SJIA)
The efficacy of Actemra (Tocilizumab) for the treatment of active SJIA was assessed in a 12-week randomized, double blind, placebo-controlled, parallel group, 2-arm study. Patients treated with or without MTX, were randomized (Actemra (Tocilizumab) :placebo = 2:1) to one of two treatment groups: 75 patients received Actemra (Tocilizumab) infusions every two weeks at either 8 mg per kg for patients at or above 30 kg or 12 mg per kg for patients less than 30 kg and 37 were randomized to receive placebo infusions every two weeks. Corticosteroid tapering could occur from week six for patients who achieved a JIA ACR70 response. After 12 weeks or at the time of escape, due to disease worsening, patients were treated with Actemra (Tocilizumab) in the open-label extension phase at weight appropriate dosing.

The primary endpoint was the proportion of patients with at least 30% improvement in JIA ACR core set (JIA ACR30 response) at Week 12 and absence of fever (no temperature at or above 37.5°C in the preceding 7 days). JIA ACR (American College of Rheumatology) responses are defined as the percentage improvement (e.g., 30%, 50%, 70%) in 3 of any 6 core outcome variables compared to baseline, with worsening in no more than 1 of the remaining variables by 30% or more. Core outcome variables consist of physician global assessment, parent per patient global assessment, number of joints with active arthritis, number of joints with limitation of movement, erythrocyte sedimentation rate (ESR), and functional ability (childhood health assessment questionnaire-CHAQ).

Primary endpoint result and JIA ACR response rates at Week 12 are shown in.

The treatment effect of Actemra (Tocilizumab) was consistent across all components of the JIA ACR response core variables. JIA ACR scores and absence of fever responses in the open label extension were consistent with the controlled portion of the study (data available through 44 weeks).

Actemra (Tocilizumab) is supplied in single-use vials as a preservative-free, sterile concentrate (20 mg per mL) solution for intravenous infusion. The following packaging configurations are available:

Individually packaged, single-use vials:

NDC 50242-135-01 providing 80 mg per 4 mL

NDC 50242-136-01 providing 200 mg per 10 mL

NDC 50242-137-01 providing 400 mg per 20 mL

Box of 4 single-use vials:

NDC 50242-135-04 providing 80 mg per 4 mL

NDC 50242-136-04 providing 200 mg per 10 mL

NDC 50242-137-04 providing 400 mg per 20 mL

Patient Counseling
Patients and parents or guardians of minors with SJIA should be advised of the potential benefits and risks of Actemra (Tocilizumab) . Physicians should instruct their patients to read the Medication Guide before starting Actemra (Tocilizumab) therapy.

Medication Guide