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IMPORTANT SAFETY INFORMATION
RISK OF SERIOUS INFECTIONS:
Patients treated with ACTEMRA are at increased risk for developing serious infections that may lead to hospitalization or death, including tuberculosis (TB), bacterial, invasive fungal, viral, or other opportunistic infections. If a serious infection develops, interrupt ACTEMRA until the infection is controlled.
Reported infections include:
- Active tuberculosis, which may present with pulmonary or extrapulmonary disease. Patients should be tested for latent tuberculosis before ACTEMRA use and during therapy. Treatment for latent infection should be initiated prior to ACTEMRA use.
- Invasive fungal infections, including candidiasis, aspergillosis, and pneumocystis. Patients with invasive fungal infections may present with disseminated, rather than localized, disease.
- Bacterial, viral and other infections due to opportunistic pathogens.
The risks and benefits of treatment with ACTEMRA should be carefully considered prior to initiating therapy in patients with chronic or recurrent infection.
Patients should be closely monitored for the development of signs and symptoms of infection during and after treatment with ACTEMRA, including the possible development of tuberculosis in patients who tested negative for latent tuberculosis infection prior to initiating therapy.
ACTEMRA is contraindicated in patients with known hypersensitivity to ACTEMRA.
WARNINGS AND PRECAUTIONS
Events of gastrointestinal (GI) perforation have been reported in clinical trials, primarily as complications of diverticulitis in RA patients. Use ACTEMRA with caution in patients who may be at increased risk for GI perforation. Promptly evaluate patients presenting with new-onset abdominal symptoms for early identification of GI perforation.
Serious cases of hepatic injury have been observed in patients taking intravenous or subcutaneous ACTEMRA. Some of these cases have resulted in liver transplant or death. Time to onset for cases ranged from months to years after treatment initiation. Most cases presented with marked elevations of transaminases (> 5 times ULN), and some cases presented with signs or symptoms of liver dysfunction and only mildly elevated transaminases.
Treatment with ACTEMRA was associated with a higher incidence of transaminase elevations; increased frequency and magnitude of these elevations were observed when ACTEMRA was used in combination with potentially hepatotoxic drugs (e.g., methotrexate).
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 discontinue ACTEMRA.
Measure liver tests promptly in patients who report symptoms that may indicate liver injury. If the patient is found to have abnormal liver tests, ACTEMRA treatment should be interrupted. ACTEMRA should only be restarted in patients with another explanation for the liver test abnormalities after normalization of the liver tests.
Laboratory monitoring is recommended due to potential consequences of treatment-related laboratory abnormalities in neutrophils, platelets, lipids, and liver function tests. Dosage modifications may be required.
Neutropenia: Treatment with ACTEMRA was associated with a higher incidence of neutropenia. 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 ANC less than 500 per mm3 treatment is not recommended.
Thrombocytopenia: Treatment with ACTEMRA was associated with a reduction in platelet counts. It is not recommended to initiate ACTEMRA 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.
Elevated Liver Enzymes: 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.
Lipid Abnormalities: Treatment with ACTEMRA was associated with increases in lipid parameters such as total cholesterol, triglycerides, LDL cholesterols, and/or HDL cholesterol.
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. 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 1465) of patients in the subcutaneous all-exposure population. In the SJIA controlled trial with intravenous ACTEMRA, 1 out of 112 patients (0.9%) experienced hypersensitivity reactions that required treatment discontinuation. 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.
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. 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. 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 prior to initiation of ACTEMRA therapy.
RHEUMATOID ARTHRITIS (RA)
The most common serious adverse reactions were serious infections. The most common serious infections included pneumonia, urinary tract infection, cellulitis, herpes zoster, gastroenteritis, diverticulitis, sepsis and bacterial arthritis. 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.
GIANT CELL ARTERITIS (GCA)
The overall safety profile observed in the ACTEMRA treatment groups was generally consistent with the known safety profile of ACTEMRA. There was an overall higher incidence of infections in GCA patients relative to RA patients.
The rate of infections was 200.2 per 100 patient-years in the ACTEMRA SC weekly group and 160.2 per 100 patient-years in the ACTEMRA SC every other week group, as compared to 156.0 per 100 patient-years in the placebo + 26 week prednisone taper and 210.2 per 100 patient-years in the placebo + 52 week taper groups.
The rate of serious infections was 9.7 per 100 patient-years in the ACTEMRA SC weekly group and 4.4 per 100 patient-years in the ACTEMRA SC every other week group, as compared to 4.2 per 100 patient-years in the placebo + 26 week prednisone taper and 12.5 per 100 patient-years in the placebo + 52 week prednisone taper groups.
POLYARTICULAR JUVENILE IDIOPATHIC ARTHRITIS (PJIA)
The most common adverse events seen in ACTEMRA-IV all-exposure population included: upper respiratory tract infections, headache, nasopharyngitis, and diarrhea.
The rate of infections in the ACTEMRA-IV 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-IV (12.2 per 100 patient-years) compared to patients weighing at or above 30 kg, treated with 8 mg/kg ACTEMRA-IV (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-IV (21%) compared to patients weighing at or above 30 kg, treated with 8 mg/kg ACTEMRA-IV (8%).
In PJIA patients, infusion-related reactions are defined as all events occurring during or within 24 hours of an infusion. In the ACTEMRA-IV 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.
In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of injection site reactions (ISRs), and neutropenia.
During the 1-year study, a frequency of 28.8% (15/52) ISRs was observed in ACTEMRA-SC treated PJIA patients. These ISRs occurred in a greater proportion of patients at or above 30 kg (44.0%) compared with patients below 30 kg (14.8%). All ISRs were mild in severity and none of the ISRs required patient withdrawal from treatment or dose interruption.
During routine laboratory monitoring in the ACTEMRA-SC all exposure population, a decrease in neutrophil counts below 1 × 109 per L occurred in 15.4% of patients, and was more frequently observed in the patients less than 30 kg (25.9%) compared to patients at or above 30 kg (4.0%). There was no clear relationship between decreases in neutrophils below 1 x 109 per L and the occurrence of serious infections.
SYSTEMIC JUVENILE IDIOPATHIC ARTHRITIS (SJIA)
The most common adverse events (at least 5%) seen in ACTEMRA-IV 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-IV 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-IV 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-IV. One patient in the placebo group escaped to ACTEMRA-IV 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-IV 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-IV SJIA clinical development experience; however, no definitive conclusions can be made.
In the 12-week controlled phase, 4% of ACTEMRA-IV and 0% of placebo-treated patients experienced events occurring during infusion.
Within 24 hours after infusion, 16% of patients in the ACTEMRA-IV treatment group and 5% of patients in the placebo group experienced an event. In the ACTEMRA-IV 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-IV during the controlled and open-label extension study.
In general, the safety observed for ACTEMRA administered subcutaneously was consistent with the known safety profile of intravenous ACTEMRA, with the exception of Injection Site Reactions (ISRs).
A total of 41.2% (21/51) SJIA patients experienced ISRs to ACTEMRA-SC. The most common ISRs were erythema, pruritus, pain, and swelling at the injection site. The majority of ISRs reported were Grade 1 events and all ISRs reported were non-serious and none required patient withdrawal from treatment or dose interruption.
In GCA patients, no effect of concomitant corticosteroid on ACTEMRA exposure was observed.
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 ACTEMRA may restore CYP450 activities to higher levels than those in the absence of ACTEMRA leading to increased metabolism of drugs that are CYP450 substrates.
Exercise caution when coadministering ACTEMRA with CYP3A4 substrate drugs where decrease in effectiveness is undesirable, e.g., oral contraceptives, lovastatin, atorvastatin, etc.
USE IN PREGNANCY
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.
The limited available data with ACTEMRA in pregnant women are not sufficient to determine whether there is a drug-associated risk for major birth defects and miscarriage.
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 giant cell arteritis (GCA) in adult patients.
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.
ACTEMRA is indicated for slowing the rate of decline in pulmonary function in adult patients with systemic sclerosis-associated interstitial lung disease (SSc-ILD).