ACTEMRA is indicated for the treatment of adult patients with moderately to severely active rheumatoid arthritis (RA) who have had an inadequate response to one or more Disease-Modifying Anti-Rheumatic Drugs (DMARDs).
Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral and other opportunistic infections, have occurred in patients receiving ACTEMRA. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. Among opportunistic infections, tuberculosis (TB), cryptococcus, aspergillosis, candidiasis and pneumocystosis were reported with ACTEMRA.
ACTEMRA should not be administered during an active infection, including localized infections. Prior to initiating ACTEMRA, a test for latent TB should be performed. If the test is positive, treatment for TB should be started prior to starting ACTEMRA. Antituberculosis therapy should also be considered prior to initiation of ACTEMRA in patients with a past history of latent or active TB in whom an adequate course of treatment cannot be confirmed, and for patients with a negative test for latent TB but having risk factors for TB infection. All patients should be monitored for active TB during treatment, even if the initial latent TB test is negative.
The benefits and risks of treatment should be considered prior to initiating ACTEMRA in patients:
- with chronic or recurrent infection
- who have been exposed to TB
- who have a history of serious or opportunistic infections
- who have resided or traveled in areas of endemic TB or mycoses
- with underlying conditions that may predispose them to infection
Patients should be closely monitored for 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. If a serious infection, opportunistic infection or sepsis develops, ACTEMRA should be interrupted until the infection is controlled. 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.
ACTEMRA should not be administered to patients with known hypersensitivity to ACTEMRA.
Events of gastrointestinal perforation have been reported in clinical trials, primarily as complications of diverticulitis. ACTEMRA should be used with caution in patients who may be at increased risk for gastrointestinal (GI) perforation. Patients presenting with new-onset abdominal symptoms should be evaluated promptly for early identification of GI perforation
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 an absolute neutrophil count (ANC) <2000/mm3. In patients who develop an ANC <500/mm3, treatment is not recommended. Neutrophils should be monitored every 4 to 8 weeks. Dosage modifications based on ANC may be required. Please see full Prescribing Information for more information.Platelets
Treatment with ACTEMRA was associated with a reduction in platelet counts. It is not recommended to initiate ACTEMRA treatment in patients with a platelet count <100,000/mm3. In patients who develop a platelet count <50,000/mm3, treatment is not recommended. Platelets should be monitored every 4 to 8 weeks. Dosage modifications based on platelet counts may be required. Please see full Prescribing Information for more information.Liver Function Tests
Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations. Increased frequency and magnitude of these elevations was observed when potentially hepatotoxic drugs (eg, methotrexate) were used in combination with ACTEMRA. It is not recommended to initiate ACTEMRA treatment in patients with elevated transaminases ALT or AST >1.5x ULN. In patients who develop elevated ALT or AST >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. Dosage modifications based on transaminases may be required. Please see full Prescribing Information for more information.Lipids
Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterol and/or HDL cholesterol. Assessment of lipid parameters should be performed approximately 4 to 8 weeks following initiation of ACTEMRA therapy, then at approximately 6-month intervals. Patients should be managed according to clinical guidelines for the management of hyperlipidemia.
The impact of treatment with ACTEMRA on the development of malignancies is not known, but malignancies were observed in clinical studies with ACTEMRA. ACTEMRA is an immunosuppressant, and treatment with immunosuppressants may result in an increased risk of malignancies.
Hypersensitivity reactions, including anaphylaxis and death, have occurred with infusion of ACTEMRA. ACTEMRA should only be administered by a healthcare professional with appropriate medical support to immediately 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.
Clinically significant hypersensitivity reactions, including anaphylaxis associated with ACTEMRA and requiring treatment discontinuation, were reported in 0.1% (3 out of 2644) in the 24-week controlled trials and in 0.2% (8 out of 4009) in the all-exposure population. In the postmarketing setting, these events have occurred as early as the first infusion of ACTEMRA.
The impact of treatment with ACTEMRA on demyelinating disorders is not known, but multiple sclerosis and chronic inflammatory demyelinating polyneuropathy were reported rarely in clinical studies. Patients should be closely monitored for signs and symptoms 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.
Live vaccines should not be given concurrently with ACTEMRA. No data are available on the secondary transmission of infection from persons receiving live vaccines to patients receiving ACTEMRA or on the effectiveness of vaccination in patients receiving ACTEMRA. Patients should be brought up to date on all recommended vaccinations, except for live vaccines, prior to initiation of ACTEMRA therapy.
The most common serious adverse reactions were serious infections. In the ACTEMRA monotherapy clinical study, the rate of serious infections was 3.6 per 100 patient-years in the ACTEMRA group and 1.5 per 100 patient-years in the methotrexate group. The rate of serious infections in the 4 mg/kg and 8 mg/kg ACTEMRA plus DMARD groups was 4.4 and 5.3 events per 100 patient-years, respectively, compared to 3.9 events per 100 patient-years in the placebo plus DMARD group.
In the 5 Phase III clinical trials the most common adverse reactions (≥5% of patients treated with ACTEMRA) through 6 months were:
|Reaction||ACTEMRA 8mg/kg Monotherapy (%)||Methotrexate (%)||ACTEMRA 4 mg/kg + DMARDS (%)||ACTEMRA 8 mg/kg + DMARDS (%)||Placebo + DMARDS (%)|
Cytochrome P450s in the liver are down-regulated by infection and inflammation stimuli including cytokines such as IL-6. Inhibition of IL-6 signaling in RA patients treated with tocilizumab may restore CYP450 activities to higher levels than those in the absence of tocilizumab leading to increased metabolism of drugs that are CYP450 substrates. Prescribers should exercise caution when ACTEMRA is coadministered with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, eg, oral contraceptives, lovastatin, atorvastatin, etc.
USE IN PREGNANCY
There are no adequate and well-controlled studies in pregnant women. ACTEMRAshould be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. To monitor the outcomes of pregnant women exposed to ACTEMRA, a pregnancy registry has been established. Physicians are encouraged to register patients by calling 1-877-311-8972.
PATIENT COUNSELING INFORMATION
Patients 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. Inform patients that ACTEMRA may lower their resistance to infections and instruct patients of the importance of contacting their doctor immediately when symptoms of an infection appear. Inform patients that some patients receiving ACTEMRA have had serious side effects in the stomach and intestines and instruct patients of the importance of contacting their doctor immediately when symptoms of severe, persistent abdominal pain appear.
Please see full Prescribing Information including Boxed Warning for additional important safety information.