HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ACTEMRA safely and effectively. See full prescribing information for ACTEMRA.
ACTEMRA ® (tocilizumab)
injection, for intravenous use
injection, for subcutaneous use
Initial U.S. Approval: 2010
WARNING: RISK OF SERIOUS INFECTIONS
See full prescribing information for complete boxed warning.
Serious infections leading to hospitalization or death including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections have occurred in patients receiving ACTEMRA. (5.1)
If a serious infection develops, interrupt ACTEMRA until the infection is controlled. (5.1)
Perform test for latent TB; if positive, start treatment for TB prior to starting ACTEMRA. (5.1)
Monitor all patients for active TB during treatment, even if initial latent TB test is negative. (5.1)
RECENT MAJOR CHANGES
Indications and Usage (1.2) 04/2013
Dosage and Administration (2.1, 2.2, 2.3, 2.5, 2.6, 2.7) 10/2013
Warnings and Precautions (5.3, 5.5) 10/2013
INDICATIONS AND USAGE
ACTEMRA® (tocilizumab) is an interleukin-6 (IL-6) receptor antagonist indicated for treatment of:
Rheumatoid Arthritis (RA) (1.1)
Adult patients with moderately to severely active rheumatoid arthritis who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
Polyarticular Juvenile Idiopathic Arthritis (PJIA) (1.2)
Patients 2 years of age and older with active polyarticular juvenile idiopathic arthritis.
Systemic Juvenile Idiopathic Arthritis (SJIA) (1.3)
Patients 2 years of age and older with active systemic juvenile idiopathic arthritis.
 DOSAGE AND ADMINISTRATION
ACTEMRA may be used alone or in combination with methotrexate: and in RA, other DMARDs may be used. (2)
Rheumatoid Arthritis (2.1)
Recommended Adult Intravenous (IV) Dosage:
When used in combination with DMARDs or as monotherapy the recommended starting dose is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.
Recommended Adult Subcutaneous (SC) Dosage:
Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight 162 mg administered subcutaneously every week
Polyarticular Juvenile Idiopathic Arthritis (2.2)
Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight 10 mg per kg
Patients at or above 30 kg weight 8 mg per kg
Systemic Juvenile Idiopathic Arthritis (2.3)
Recommended Intravenous SJIA Dosage Every 2 Weeks
Patients less than 30 kg weight 12 mg per kg
Patients at or above 30 kg weight 8 mg per kg
General Dosing Information (2.4)
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). (2.1, 5.3)
ACTEMRA doses exceeding 800 mg per infusion are not recommended in RA patients. (2.1, 12.3)
Administration of Intravenous formulation (2.5)
For adults, PJIA and SJIA patients at or above 30 kg, dilute to 100 mL in 0.9% Sodium Chloride for intravenous infusion using aseptic technique.
For PJIA and SJIA patients less than 30 kg, dilute to 50 mL in 0.9% Sodium Chloride for intravenous infusion using aseptic technique.
Administer as a single intravenous drip infusion over 1 hour; do not administer as bolus or push.
Administration of Subcutaneous formulation (2.6)
Follow the Instructions for Use for prefilled syringe
Dose Modifications (2.7)
Recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia.
 DOSAGE FORMS AND STRENGTHS
Single-use vials of ACTEMRA (20 mg per mL) for intravenous administration:
80 mg per 4 mL (3)
200 mg per 10 mL (3)
400 mg per 20 mL (3)
Prefilled Syringe (PFS) for subcutaneous administration:
A single use PFS providing 162 mg of ACTEMRA in 0.9mL (3)
CONTRAINDICATIONS
ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA. (4)
WARNINGS AND PRECAUTIONS
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. (5.1)
Gastrointestinal (GI) perforation – use with caution in patients who may be at increased risk. (5.2)
Laboratory monitoring – recommended due to potential consequences of treatment-related changes in neutrophils, platelets, lipids, and liver function tests. (2.7, 5.3)
Hypersensitivity reactions, including anaphylaxis and death have occurred. (5.5)
Live vaccines – Avoid use with ACTEMRA. (5.8, 7.3)
ADVERSE REACTIONS
Most common adverse reactions (incidence of at least 5%): upper respiratory tract infections, nasopharyngitis, headache, hypertension, increased ALT, injection site reactions. (6.1)
To report SUSPECTED ADVERSE REACTIONS, contact Genentech at 1-888-835-2555 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
 USE IN SPECIFIC POPULATIONS
Pregnancy: Based on animal data, may cause fetal harm. (8.1)
Nursing Mothers: Discontinue drug or nursing taking into consideration importance of drug to mother. (8.3)
See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.
Revised: 11/2014
FULL PRESCRIBING INFORMATION: CONTENTS*
WARNING: RISK OF SERIOUS INFECTIONS
1 INDICATIONS AND USAGE
1.1 Rheumatoid Arthritis (RA)
1.2 Polyarticular Juvenile Idiopathic Arthritis (PJIA)
1.3 Systemic Juvenile Idiopathic Arthritis (SJIA)
2 DOSAGE AND ADMINISTRATION
2.1 Rheumatoid Arthritis
2.2 Polyarticular Juvenile Idiopathic Arthritis
2.3 Systemic Juvenile Idiopathic Arthritis
2.4 General Considerations for Administration
2.5 Preparation and Administration Instructions for Intravenous Infusion
2.6 Preparation and Administration Instructions for Subcutaneous Injection for RA
2.7 Dosage Modifications due to Serious Infections or Laboratory Abnormalities
3 DOSAGE FORMS AND STRENGTHS
4 CONTRAINDICATIONS
5 WARNINGS AND PRECAUTIONS
5.1 Serious Infections
5.2 Gastrointestinal Perforations
5.3 Laboratory Parameters
5.4 Immunosuppression
5.5 Hypersensitivity Reactions, Including Anaphylaxis
5.6 Demyelinating Disorders
5.7 Active Hepatic Disease and Hepatic Impairment
5.8 Vaccinations
6 ADVERSE REACTIONS
6.1 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV)
6.2 Clinical Trials Experience in Rheumatoid Arthritis Patients Treated with Subcutaneous ACTEMRA (ACTEMRA-SC)
6.3 Clinical Trials Experience in Polyarticular Juvenile Idiopathic Arthritis Patients Treated With Intravenous ACTEMRA (ACTEMRA-IV)
6.4 Clinical Trials Experience in Systemic Juvenile Idiopathic Arthritis Patients Treated with Intravenous ACTEMRA (ACTEMRA-IV)
6.5 Postmarketing Experience
7 DRUG INTERACTIONS
7.1 Other Drugs for Treatment of Rheumatoid Arthritis
7.2 Interactions with CYP450 Substrates
7.3 Live Vaccines
8 USE IN SPECIFIC POPULATIONS
8.1 Pregnancy
8.3 Nursing Mothers
8.4 Pediatric Use
8.5 Geriatric Use
8.6 Hepatic Impairment
8.7 Renal Impairment
9 DRUG ABUSE AND DEPENDENCE
10 OVERDOSAGE
11 DESCRIPTION
12 CLINICAL PHARMACOLOGY
12.1 Mechanism of Action
12.2 Pharmacodynamics
12.3 Pharmacokinetics
13 NONCLINICAL TOXICOLOGY
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility
14 CLINICAL STUDIES
14.1 Rheumatoid Arthritis –Intravenous Administration
14.2 Rheumatoid Arthritis–Subcutaneous Administration
14.3 Polyarticular Juvenile Idiopathic Arthritis-Intravenous Administration
14.4 Systemic Juvenile Idiopathic Arthritis-Intravenous Administration
16 HOW SUPPLIED/STORAGE AND HANDLING
17 PATIENT COUNSELING INFORMATION
Sections or subsections omitted from the full prescribing information are not listed.
1 INDICATIONS AND USAGE
1.1 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 Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
1.2 Polyarticular Juvenile Idiopathic Arthritis (PJIA)
ACTEMRA® (tocilizumab) is indicated for the treatment of active polyarticular juvenile idiopathic arthritis in patients 2 years of age and older.
1.3 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.

2 DOSAGE AND ADMINISTRATION
2.1 Rheumatoid Arthritis
ACTEMRA may be used as monotherapy or concomitantly with methotrexate or other non-biologic DMARDs as an intravenous infusion or as a subcutaneous injection.
Recommended Intravenous (IV) Dosage Regimen:

The recommended dosage of ACTEMRA for adult patients given as a 60-minute single intravenous drip infusion is 4 mg per kg every 4 weeks followed by an increase to 8 mg per kg every 4 weeks based on clinical response.

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 [see Dosage and Administration (2.7), Warnings and Precautions (5.3), and Adverse Reactions (6.1)].
Doses exceeding 800 mg per infusion are not recommended in RA patients [see Clinical Pharmacology (12.3)].
Recommended Subcutaneous (SC) Dosage Regimen:

Patients less than 100 kg weight 162 mg administered subcutaneously every other week, followed by an increase to every week based on clinical response
Patients at or above 100 kg weight 162 mg administered subcutaneously every week

When transitioning from ACTEMRA intravenous therapy to subcutaneous administration administer the first subcutaneous dose instead of the next scheduled intravenous dose.

Interruption of dose or reduction in frequency of administration of subcutaneous dose from every week to every other week dosing is recommended for management of certain dose-related laboratory changes including elevated liver enzymes, neutropenia, and thrombocytopenia [see Dosage and Administration (2.7), Warnings and Precautions (5.3), and Adverse Reactions (6.2)].

2.2 Polyarticular Juvenile Idiopathic Arthritis
ACTEMRA may be used alone or in combination with methotrexate. The recommended dosage of ACTEMRA for PJIA patients given once every 4 weeks as a 60-minute single intravenous drip infusion is:

Recommended Intravenous PJIA Dosage Every 4 Weeks
Patients less than 30 kg weight 10 mg per kg
Patients at or above 30 kg weight 8 mg per kg

Do not change dose 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 (2.7)].
Subcutaneous administration is not approved for PJIA.
2.3 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:

Recommended Intravenous SJIA Dosage Every 2 Weeks
Patients less than 30 kg weight 12 mg per kg
Patients at or above 30 kg weight 8 mg per kg

Do not change a dose 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 (2.7)].
Subcutaneous administration is not approved for SJIA.
2.4 General Considerations for Administration
ACTEMRA has not been studied 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. Avoid using ACTEMRA with biological DMARDs.
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).
2.5 Preparation and Administration Instructions for Intravenous Infusion
ACTEMRA for intravenous infusion should be diluted by a healthcare professional using aseptic technique as follows:

PJIA and SJIA patients less than 30 kg: use a 50 mL infusion bag or bottle of 0.9% Sodium Chloride, and then follow steps 1 and 2 below.
Adult RA, PJIA and SJIA patients at or above 30 kg weight: use a 100 mL infusion bag or bottle, and then follow steps 1 and 2 below.
–
Step 1. Withdraw a volume of 0.9% Sodium Chloride injection, equal to the volume of the ACTEMRA injection required for the patient's dose from the infusion bag or bottle [see Dosage and Administration (2.1, 2.2, 2.3)]. For Intravenous Use: Volume of ACTEMRA Injection per kg of Body Weight
Dosage Indication Volume of ACTEMRA injection per kg of body weight
4 mg/kg Adult RA 0.2mL/kg
8 mg/kg Adult RA
SJIA and PJIA (≥30 kg of body weight) 0.4mL/kg
10 mg/kg PJIA (< 30 kg of body weight) 0.5 mL/kg
12 mg/kg SJIA (< 30 kg of body weight) 0.6mL/kg

–
Step 2. Withdraw the amount of ACTEMRA for intravenous infusion from the vial(s) and add slowly into the Sodium Chloride 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 eva luate 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.
2.6 Preparation and Administration Instructions for Subcutaneous Injection for RA
ACTEMRA for subcutaneous injection is only indicated in the treatment in patients with adult RA and is not indicated for the treatment of patients with PJIA or SJIA. ACTEMRA for subcutaneous injection is not intended for intravenous drip infusion.

ACTEMRA subcutaneous injection is intended for use under the guidance of a healthcare practitioner. After proper training in subcutaneous injection technique, a patient may self-inject ACTEMRA or the patient's caregiver may administer ACTEMRA if a healthcare practitioner determines that it is appropriate. Patients, or patient caregivers, should be instructed to follow the directions provided in the Instructions for Use (IFU) for additional details on medication administration.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. Do not use ACTEMRA prefilled syringes (PFS) exhibiting particulate matter, cloudiness, or discoloration. ACTEMRA for subcutaneous administration should be clear and colorless to pale yellow. Do not use if any part of the PFS appears to be damaged.
Patients using ACTEMRA for subcutaneous administration should be instructed to inject the full amount in the syringe (0.9 mL), which provides 162 mg of ACTEMRA, according to the directions provided in the IFU.
Injection sites should be rotated with each injection and should never be given into moles, scars, or areas where the skin is tender, bruised, red, hard, or not intact.
2.7 Dosage Modifications due to Serious Infections or Laboratory Abnormalities
Hold ACTEMRA treatment if a patient develops a serious infection until the infection is controlled.

Rheumatoid Arthritis

Liver Enzyme Abnormalities [see Warnings and Precautions (5.3)]:
Lab Value Recommendation
Greater than 1 to 3× ULN Dose modify concomitant DMARDs if appropriate
  For persistent increases in this range:
For patients receiving intravenous ACTEMRA, reduce dose to 4 mg per kg or hold ACTEMRA until ALT or AST have normalized
For patients receiving subcutaneous ACTEMRA, reduce injection frequency to every other week or hold dosing until ALT or AST have normalized. Resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate.
 
Greater than 3 to 5× ULN Hold ACTEMRA dosing until less than 3× ULN and follow recommendations above for greater than 1 to 3× ULN
(confirmed by repeat testing) For persistent increases greater than 3× ULN, discontinue ACTEMRA
Greater than 5× ULN Discontinue ACTEMRA
Low Absolute Neutrophil Count (ANC) [see Warnings and Precautions (5.3)]:
Lab Value
(cells per mm3) Recommendation
ANC greater than 1000 Maintain dose
ANC 500 to 1000 Hold ACTEMRA dosing
  When ANC greater than 1000 cells per mm3:
For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate
For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate
 
ANC less than 500 Discontinue ACTEMRA

Low Platelet Count [see Warnings and Precautions (5.3)]:
Lab Value
(cells per mm3) Recommendation
50,000 to 100,000 Hold ACTEMRA dosing
  When platelet count is greater than 100,000 cells per mm3:
For patients receiving intravenous ACTEMRA, resume ACTEMRA at 4 mg per kg and increase to 8 mg per kg as clinically appropriate
For patients receiving subcutaneous ACTEMRA, resume ACTEMRA at every other week and increase frequency to every week as clinically appropriate
 
Less than 50,000 Discontinue ACTEMRA

Polyarticular and Systemic Juvenile Idiopathic Arthritis:

Dose reduction of ACTEMRA has not been studied in the PJIA and SJIA populations. Dose interruptions of ACTEMRA are recommended for liver enzyme abnormalities, low neutrophil counts, and low platelet counts in patients with PJIA and SJIA at levels similar to what is outlined above for patients with RA. If appropriate, dose modify or stop concomitant methotrexate and/or other medications and hold ACTEMRA dosing until the clinical situati