Important Safety Information
SJIA Safety Profile & Adverse Events
ACTEMRA Safety Profile in SJIA
AEs=adverse events; PY=patient years; SAEs=serious adverse events; SIEs=serious infectious events.
Multiple occurrences of the same AE in one individual are counted.
Last date for collection of safety data was May 31, 2011.
- The most common SAEs occurring in >1% of patients through 104 weeks were varicella infection, gastroenteritis, macrophage activation syndrome, pneumonia, dehydration, and herpes zoster infection
Summary of infections
- The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media
Macrophage Activation Syndrome
- In the 12-week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment
- In an open-label, long-term extension study (N=112), 3 patients (3%) experienced MAS events. All 3 patients had ACTEMRA dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae
- Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the ACTEMRA SJIA clinical development experience; however, no definitive conclusions can be made
- In the 12-week controlled phase, patients were not routinely premedicated; however, most patients were on concomitant corticosteroids as part of their background treatment for SJIA
- Infusion-related reactions were defined as all events occurring during or within 24 hours after an infusion
- During infusion, 4% of patients on ACTEMRA and 0% of patients on placebo experienced events. One event (angioedema) was considered serious and life-threatening, and the patient was discontinued from study treatment
- Within 24 hours after infusion, 16% of patients in the ACTEMRA treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA group, events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia, and headache. One of these events, urticaria, was considered serious
All 112 patients were tested for anti-tocilizumab antibodies at baseline. Two patients developed positive anti-tocilizumab antibodies: one of these patients experienced serious adverse events of urticaria and angioedema consistent with an anaphylactic reaction which led to withdrawal; the other patient developed MAS while on escape therapy and was discontinued from the study.
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).
ACTEMRA is indicated for the treatment of active polyarticular juvenile idiopathic arthritis (PJIA) in patients 2 years of age and older.
ACTEMRA is indicated for the treatment of active systemic juvenile idiopathic arthritis (SJIA) in patients 2 years of age and older.
IMPORTANT SAFETY INFORMATION
Serious infections leading to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, and other opportunistic infections, have occurred in patients receiving ACTEMRA. ACTEMRA should not be administered during an active infection, including localized infections. If a serious infection develops, ACTEMRA should be interrupted until the infection is controlled.
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. All patients should be monitored for active TB during treatment, even if 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.
ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.
WARNINGS AND PRECAUTIONS
Use ACTEMRA with caution in patients who may be at increased risk for gastrointestinal (GI) perforation. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation.
Laboratory monitoring is recommended due to potential consequences of treatment-related laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications or interruptions may be required. Please see full Prescribing Information for more information.
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, have been reported in association with ACTEMRA and anaphylactic events with a fatal outcome have been reported with intravenous infusion of ACTEMRA. In the postmarketing setting, these events have occurred as early as the first infusion of ACTEMRA. ACTEMRA for intravenous use should only be infused by a healthcare professional with appropriate medical support to manage anaphylaxis. For ACTEMRA subcutaneous injection, advise patients to seek immediate medical attention if they experience any symptoms of a hypersensitivity reaction. If anaphylaxis or other hypersensitivity reaction occurs, stop administration of ACTEMRA immediately and discontinue ACTEMRA permanently. Do not administer ACTEMRA to patients with known hypersensitivity to ACTEMRA.
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 of intravenous ACTEMRA, 0.2% (8 out of 4009) of patients in the intravenous all-exposure RA population, 0.7% (8 out of 1068) in the subcutaneous 6-month controlled RA trials, and in 0.7% (10 out of 1456) of patients in the subcutaneous all-exposure population.
In the PJIA controlled trial with intravenous ACTEMRA, 0 out of 188 patients (0%) in the ACTEMRA all-exposure population experienced hypersensitivity reactions that required treatment discontinuation. Reactions that required treatment discontinuation included generalized erythema, rash, and urticaria.
Monitor patients 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.
Avoid use of live vaccines concurrently with ACTEMRA. Patients should be brought up to date on all recommended vaccinations prior to initiation of ACTEMRA therapy. The interval between live vaccinations and initiation of ACTEMRA therapy should follow current vaccination guidelines for immunosuppressive agents.
RHEUMATOID ARTHRITIS (RA)
The most common serious adverse reactions were serious infections. In the ACTEMRA-IV 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-IV) through 6 months were:
+ DMARDs (%)
+ DMARDs (%)
+ DMARDs (%)
The safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection-site reactions, which were more common with ACTEMRA-SC compared with placebo-SC injections (IV-arm).
In the 6-month control period, in SC-I, the frequency of injection-site reactions was 10.1% (64/631) and 2.4% (15/631) for the weekly ACTEMRA-SC and placebo-SC (IV-arm) group, respectively. In SC-II, the frequency of injection-site reactions was 7.1% (31/437) and 4.1% (9/218) for the every other week ACTEMRA-SC and placebo-SC groups, respectively. These injection-site reactions were mild to moderate in severity. The majority resolved without any treatment and none necessitated drug discontinuation.
POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS (PJIA)
The most common adverse events seen in ACTEMRA-treated patients in the all-exposure population included: upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.
The rate of infections in the ACTEMRA all-exposure population was 163.7 per 100 patient-years. The most common events observed were nasopharyngitis and upper respiratory tract infections. The rate of serious infections was numerically higher in patients weighing less than 30 kg treated with 10 mg/kg ACTEMRA (12.2 per 100 patient-years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg ACTEMRA (4.0 per 100 patient-years). The incidence of infections leading to dose interruptions was also numerically higher in patients weighing less than 30 kg treated with 10 mg/kg ACTEMRA (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg ACTEMRA (8%).
In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the ACTEMRA all-exposure population, 11 patients (6%) experienced an event during the infusion, and 38 patients (20.2%) experienced an event within 24 hours of an infusion. The most common events occurring during infusion were headache, nausea and hypotension, and occurring within 24 hours of infusion were dizziness and hypotension.
SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA)
The most common adverse events (at least 5%) seen in ACTEMRA-treated patients in the 12-week controlled portion of the study were: upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.
In the 12-week controlled phase, the rate of all infections in the ACTEMRA group was 345 per 100 patient-years and 287 per 100 patient-years in the placebo group. In the open-label extension over an average duration of 73 weeks of treatment, the overall rate of infections was 304 per 100 patient-years.
In the 12-week controlled phase, the rate of serious infections in the ACTEMRA group was 11.5 per 100 patient-years. In the open-label extension over an average duration of 73 weeks of treatment, the overall rate of serious infections was 11.4 per 100 patient-years. The most commonly reported serious infections included pneumonia, gastroenteritis, varicella, and otitis media.
Macrophage Activation Syndrome
In the 12-week controlled study, no patient in any treatment group experienced macrophage activation syndrome (MAS) while on assigned treatment; 3 per 112 (3%) developed MAS during open-label treatment with ACTEMRA. One patient in the placebo group escaped to ACTEMRA 12 mg per kg at Week 2 due to severe disease activity, and ultimately developed MAS at Day 70. Two additional patients developed MAS during the long-term extension. All 3 patients had ACTEMRA dose interrupted (2 patients) or discontinued (1 patient) for the MAS event, received treatment, and the MAS resolved without sequelae. Based on a limited number of cases, the incidence of MAS does not appear to be elevated in the ACTEMRA SJIA clinical development experience; however, no definitive conclusions can be made.
In the 12-week controlled phase, 4% of ACTEMRA and 0% of placebo-treated patients experienced events occurring during infusion.
Within 24 hours after infusion, 16% of patients in the ACTEMRA treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA group the events included rash, urticaria, diarrhea, epigastric discomfort, arthralgia, and headache. One of these events, urticaria, was considered serious.
Anaphylaxis was reported in 1 out of 112 patients (less than 1%) treated with ACTEMRA during the controlled and open-label extension study.
USE IN PREGNANCY: Pregnancy Category C
Adequate and well-controlled studies with ACTEMRA have not been conducted in pregnant women. ACTEMRA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to ACTEMRA during pregnancy. Physicians are encouraged to register patients and pregnant women are encouraged to register themselves by calling 1-877-311-8972.
PATIENT COUNSELING INFORMATION
Advise patients and parents or guardians of minors with PJIA or SJIA 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. Assess patient suitability for home use for SC injection. Inform patients that some patients have had serious allergic reactions including anaphylaxis and advise them to seek immediate medical attention if symptoms occur.