ACTEMRA® (tocilizumab)

ACTEMRA (tocilizumab) is a recombinant humanized anti-human interleukin 6 (IL-6) receptor monoclonal antibody of the immunoglobulin IgG1 (gamma 1, kappa) subclass with a typical H2L2 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 has a molecular weight of approximately 148 kDa.

ACTEMRA is supplied as a sterile, preservative-free solution for intravenous (IV) infusion at a concentration of 20 mg per mL. ACTEMRA 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. Injectable solutions of ACTEMRA 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).

Rheumatoid Arthritis (RA)
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.

Systemic Juvenile Idiopathic Arthritis (SJIA)
ACTEMRA® (tocilizumab) is indicated for the treatment of active systemic juvenile idiopathic arthritis in patients 2 years of age and older.

• Serious Infections – do not administer ACTEMRA during an active infection, including localized infections. If a serious infection develops, interrupt ACTEMRA until the infection is controlled.
• Gastrointestinal (GI) perforation – use with caution in patients who may be at increased risk.
• Laboratory monitoring – recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests.
• Hypersensitivity reactions, including anaphylaxis and death have occurred
• Live vaccines – should not be given with ACTEMRA.

Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT.

To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch

Rheumatoid Arthritis

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

• Reduction of dose from 8 mg per kg to 4 mg per kg is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
• Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)].

Systemic Juvenile Idiopathic Arthritis

ACTEMRA may be used alone or in combination with methotrexate. The recommended dose of ACTEMRA for SJIA patients given once every 2 weeks as a 60-minute single intravenous drip infusion is:

• A change in dose should not be made based solely on a single visit body weight measurement, as weight may fluctuate.
• Interruption of dosing may be needed for management of dose-related laboratory abnormalities including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration].

General Considerations for Administration:

• ACTEMRA has not been studied and its use should be avoided in combination with biological DMARDs such as TNF antagonists, IL-1R antagonists, anti-CD20 monoclonal antibodies and selective co-stimulation modulators because of the possibility of increased immunosuppression and increased risk of infection.
• It is recommended that ACTEMRA not be initiated in patients with an absolute neutrophil count (ANC) below 2000 per mm3, platelet count below 100,000 per mm3, or who have ALT or AST above 1.5 times the upper limit of normal (ULN).

ACTEMRA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

• Systemic Juvenile Idiopathic Arthritis Patients less than 30 kg: utilize a 50 mL infusion bag or bottle, then follow steps 1 and 2 below.
• Adult Rheumatoid Arthritis and SJIA patients at or above 30 kg weight: utilize a 100 mL infusion bag or bottle, then follow steps 1 and 2 below.

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  Step 1. Withdraw a volume of 0.9% Sodium Chloride Injection, USP, equal to the volume of the ACTEMRA solution required for the patient's dose from the infusion bag or bottle.

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  Step 2. Slowly add ACTEMRA for intravenous infusion from each vial into the infusion bag or bottle. To mix the solution, gently invert the bag to avoid foaming.

• The fully diluted ACTEMRA solutions for infusion may be stored at 2° to 8°C (36° to 46°F) or room temperature for up to 24 hours and should be protected from light. ACTEMRA solutions do not contain preservatives; therefore, unused product remaining in the vials should not be used.
• Allow the fully diluted ACTEMRA solution to reach room temperature prior to infusion.
• The infusion should be administered over 60 minutes, and must be administered with an infusion set. Do not administer as an intravenous push or bolus.
• ACTEMRA should not be infused concomitantly in the same intravenous line with other drugs. No physical or biochemical compatibility studies have been conducted to evaluate the co-administration of ACTEMRA with other drugs.
• Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If particulates and discolorations are noted, the product should not be used. Fully diluted ACTEMRA solutions are compatible with polypropylene, polyethylene and polyvinyl chloride infusion bags and polypropylene, polyethylene and glass infusion bottles.

Dosage Modifications-----------------------------------------------

ACTEMRA treatment should be interrupted if a patient develops a serious infection until the infection is controlled.

Rheumatoid Arthritis

Systemic Juvenile Idiopathic Arthritis:
Dose reduction of ACTEMRA has not been studied in the SJIA population. Dose interruptions of ACTEMRA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with SJIA at levels similar to what is outlined above for patients with RA. If appropriate, concomitant methotrexate and/or other medications should be dose modified or stopped and ACTEMRA dosing interrupted until the clinical situation has been evaluated. In SJIA the decision to discontinue ACTEMRA for a laboratory abnormality should be based upon the medical assessment of the individual patient.

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

80 mg per 4 mL
200 mg per 10 mL
400 mg per 20 mL

HOW SUPPLIED/STORAGE AND HANDLING
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

Storage and Stability: Do not use beyond expiration date on the container. ACTEMRA must be refrigerated at 2°C to 8°C (36°F to 46°F). Do not freeze. Protect the vials from light by storage in the original package until time of use. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit. If visibly opaque particles, discoloration or other foreign particles are observed, the solution should not be used.