Included as part of the PRECAUTIONS section.

Serious Infections

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 for rheumatoid arthritis. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis [see ADVERSE REACTIONS]. Among opportunistic infections, tuberculosis, cryptococcus, aspergillosis, candidiasis, and pneumocystosis were reported with ACTEMRA. 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 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 in patients:

• with chronic or recurrent infection;
• who have been exposed to tuberculosis;
• with a history of serious or an opportunistic infection;
• who have resided or traveled in areas of endemic tuberculosis or endemic mycoses; or
• with underlying conditions that may predispose them to infection.

Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, as signs and symptoms of acute inflammation may be lessened due to suppression of the acute phase reactants [see DOSAGE AND ADMINISTRATION, ADVERSE REACTIONS, and PATIENT INFORMATION].

ACTEMRA 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 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.

Tuberculosis

Patients should be evaluated for tuberculosis risk factors and tested for latent infection prior to initiating ACTEMRA.

Anti-tuberculosis therapy should also be considered prior to initiation of ACTEMRA in patients with a past history of latent or active tuberculosis in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent tuberculosis but having risk factors for tuberculosis infection. Consultation with a physician with expertise in the treatment of tuberculosis is recommended to aid in the decision whether initiating anti-tuberculosis therapy is appropriate for an individual patient.

Patients should be closely monitored for the development of signs and symptoms of tuberculosis including patients who tested negative for latent tuberculosis infection prior to initiating therapy.

It is recommended that patients be screened for latent tuberculosis infection prior to starting ACTEMRA. The incidence of tuberculosis in worldwide clinical development programs is 0.1%. Patients with latent tuberculosis should be treated with standard antimycobacterial therapy before initiating ACTEMRA.

Viral Reactivation

Viral reactivation has been reported with immunosuppressive biologic therapies and cases of herpes zoster exacerbation were observed in clinical studies with ACTEMRA. No cases of Hepatitis B reactivation were observed in the trials; however patients who screened positive for hepatitis were excluded.

Gastrointestinal Perforations

Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. ACTEMRA 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 [see ADVERSE REACTIONS].

Laboratory Parameters

Rheumatoid Arthritis

Neutrophils

Treatment with ACTEMRA was associated with a higher incidence of neutropenia. Infections have been uncommonly reported in association with treatment-related neutropenia in long-term extension studies and postmarketing clinical experience.

• It is not recommended to initiate ACTEMRA treatment in patients with a low neutrophil count, i.e., absolute neutrophil count (ANC) less than 2000 per mm³ . In patients who develop an absolute neutrophil count less than 500 per mm³ treatment is not recommended.
• Neutrophils should be monitored every 4 to 8 weeks [see CLINICAL PHARMACOLOGY]. For recommended modifications based on ANC results see [DOSAGE AND ADMINISTRATION].

Platelets

Treatment with ACTEMRA was associated with a reduction in platelet counts. Treatment-related reduction in platelets was not associated with serious bleeding events in clinical trials [see ADVERSE REACTIONS].

• It is not recommended to initiate ACTEMRA treatment in patients with a platelet count below 100,000 per mm³ . In patients who develop a platelet count less than 50,000 per mm³ treatment is not recommended.
• Platelets should be monitored every 4 to 8 weeks. For recommended modifications based on platelet counts see [DOSAGE AND ADMINISTRATION].

Liver Function Tests

Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. These elevations did not result in apparent permanent or clinically evident hepatic injury in clinical trials [see ADVERSE REACTIONS]. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (e.g., MTX) were used in combination with ACTEMRA.

In one case, a patient who had received ACTEMRA 8 mg per kg monotherapy without elevations in transaminases experienced elevation in AST to above 10x ULN and elevation in ALT to above 16x ULN when MTX was initiated in combination with ACTEMRA. Transaminases normalized when both treatments were held, but elevations recurred when MTX and ACTEMRA were restarted at lower doses. Elevations resolved when MTX and ACTEMRA were discontinued.

• It is not recommended to initiate ACTEMRA treatment in patients with elevated transaminases ALT or AST greater than 1.5x ULN. In patients who develop elevated ALT or AST greater than 5x ULN treatment is not recommended.
• ALT and AST levels should be monitored every 4 to 8 weeks. When clinically indicated, other liver function tests such as bilirubin should be considered. For recommended modifications based on transaminases see [DOSAGE AND ADMINISTRATION].

Lipids

Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol, and/or HDL cholesterol [see ADVERSE REACTIONS].

• Assessment of lipid parameters should be performed approximately 4 to 8 weeks following initiation of ACTEMRA therapy, then at approximately 24 week intervals.
• Patients should be managed according to clinical guidelines [e.g., National Cholesterol Educational Program (NCEP)] for the management of hyperlipidemia.

Polyarticular and Systemic Juvenile Idiopathic Arthritis

A similar pattern of liver enzyme elevation, low neutrophil count, low platelet count and lipid elevations is noted with ACTEMRA treatment in the PJIA and SJIA populations. Neutrophils, Platelets, ALT and AST should be monitored at the time of the second infusion and thereafter every 4 to 8 weeks for PJIA and every 2 to 4 weeks for SJIA. Lipids should be monitored as above for RA [see DOSAGE AND ADMINISTRATION].

Immunosuppression

The impact of treatment with ACTEMRA on the development of malignancies is not known but malignancies were observed in clinical studies [see ADVERSE REACTIONS]. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.

Hypersensitivity Reactions, Including Anaphylaxis

Hypersensitivity reactions, including anaphylaxis and death, have been reported in association with infusion of ACTEMRA [see ADVERSE REACTIONS]. 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, events of clinically significant hypersensitivity and anaphylaxis, including events with a fatal outcome, have occurred in patients treated with a range of doses of ACTEMRA, with or without concomitant arthritis therapies. Events have occurred in patients who received premedication. Clinically significant hypersensitivity and anaphylaxis events have occurred both with and without previous hypersensitivity reactions and as early as the first infusion of ACTEMRA [see ADVERSE REACTIONS]. ACTEMRA 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 should be stopped immediately and ACTEMRA should be permanently discontinued. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA [see CONTRAINDICATIONS and ADVERSE REACTIONS].

Demyelinating Disorders

The impact of treatment with ACTEMRA 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 in patients with preexisting or recent onset demyelinating disorders.

Active Hepatic Disease and Hepatic Impairment

Treatment with ACTEMRA is not recommended in patients with active hepatic disease or hepatic impairment [see ADVERSE REACTIONS, Use In Specific Populations].

Vaccinations

Live vaccines should not be given concurrently with ACTEMRA 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. No data are available on the effectiveness of vaccination in patients receiving ACTEMRA. Because IL-6 inhibition may interfere with the normal immune response to new antigens, it is recommended that all patients, particularly PJIA and SJIA patients, if possible, be brought up to date with all immunizations in agreement with current immunization guidelines prior to initiating ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.

Patient Counseling Information

See FDA-approved patient labeling (Medication Guide)

Patient Counseling

Patients and parents or guardians of minors with PJIA or SJIA should be advised of the potential benefits and risks of ACTEMRA. Physicians should instruct their patients to read the Medication Guide before starting ACTEMRA therapy.

• Infections:
  Inform patients that ACTEMRA may lower their resistance to infections. Instruct the patient of the importance of contacting their doctor immediately when symptoms suggesting infection appear in order to assure rapid evaluation and appropriate treatment.
• Gastrointestinal Perforation:
  Inform patients that some patients who have been treated with ACTEMRA have had serious side effects in the stomach and intestines. Instruct the patient of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear to assure rapid evaluation and appropriate treatment.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

No long-term animal studies have been performed to establish the carcinogenicity potential of tocilizumab.

Mutagenesis

Tocilizumab was negative in the in vitro Ames bacterial reverse mutation assay and the in vitro chromosomal aberrations assay using human peripheral blood lymphocytes.

Impairment of Fertility

Fertility studies conducted in male and female mice using a murine analogue of tocilizumab showed no impairment of fertility.

Use In Specific Populations

Pregnancy

Teratogenic Effects - Pregnancy Category C

There are no adequate and well-controlled studies in pregnant women. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

An embryo-fetal developmental toxicity study was performed in which pregnant cynomolgus monkeys were treated intravenously with tocilizumab (daily doses of 2, 10, or 50 mg per kg from gestation day 20-50) during organogenesis. Although there was no evidence for a teratogenic/dysmorphogenic effect at any dose, tocilizumab produced an increase in the incidence of abortion/embryo-fetal death at 10 mg per kg and 50 mg per kg doses (1.25 and 6.25 times the human dose of 8 mg per kg every 2 to 4 weeks based on a mg per kg comparison).

Nonteratogenic Effects

Testing of a murine analogue of tocilizumab in mice did not yield any evidence of harm to offspring during the pre- and postnatal development phase when dosed at 50 mg per kg intravenously with treatment every three days from implantation until day 21 after delivery (weaning). There was no evidence for any functional impairment of the development and behavior, learning ability, immune competence and fertility of the offspring.

Pregnancy Registry

To monitor the outcomes of pregnant women exposed to ACTEMRA, a pregnancy registry has been established. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.

Nursing Mothers

It is not known whether tocilizumab is excreted in human milk or absorbed systemically after ingestion. Because many drugs are excreted in human milk, and because of the potential for serious adverse reactions in nursing infants from ACTEMRA, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

Safety and effectiveness of ACTEMRA in pediatric patients with conditions other than PJIA or SJIA have not been established. Children under the age of two have not been studied. Testing of a murine analogue of tocilizumab did not exert toxicity in juvenile mice. In particular, there was no impairment of skeletal growth, immune function and sexual maturation.

Geriatric Use

Of the 2644 patients who received ACTEMRA in Studies I to V [see Clinical Studies], a total of 435 rheumatoid arthritis patients were 65 years of age and older, including 50 patients 75 years and older. The frequency of serious infection among ACTEMRA treated subjects 65 years of age and older was higher than those under the age of 65. As there is a higher incidence of infections in the elderly population in general, caution should be used when treating the elderly.

Hepatic Impairment

The safety and efficacy of ACTEMRA have not been studied in patients with hepatic impairment, including patients with positive HBV and HCV serology [see WARNINGS AND PRECAUTIONS].

Renal Impairment

No dose adjustment is required in patients with mild renal impairment. ACTEMRA has not been studied in patients with moderate to severe renal impairment [see CLINICAL PHARMACOLOGY].

Last reviewed on RxList: 5/16/2013
This monograph has been modified to include the generic and brand name in many instances.