WARNING: SERIOUS MENINGOCOCCAL INFECTIONS
Eculizumab products, complement inhibitors, increase the risk of serious infections caused by Neisseria meningitidis. Life-threatening and fatal meningococcal infections have occurred in patients treated with complement inhibitors. These infections may become rapidly life-threatening or fatal if not recognized and treated early.
- Complete or update vaccination for meningococcal bacteria (for serogroups A, C, W, Y, and B) at least 2 weeks prior to the first dose of EPYSQLI, unless the risks of delaying therapy with EPYSQLI outweigh the risk of developing a serious infection. Comply with the most current Advisory Committee on Immunization Practices (ACIP) recommendations for vaccinations against meningococcal bacteria in patients receiving a complement inhibitor. Initiate prophylactic antibacterial drug therapy. Vaccinate as soon as possible.
- Patients receiving eculizumab products are at increased risk for invasive disease caused by Neisseria meningitidis, even if they develop antibodies following vaccination. Monitor patients for early signs and symptoms of serious meningococcal infections and evaluate immediately if infection is suspected.
Because of the risk of serious meningococcal infections, EPYSQLI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called EPYSQLI REMS.
CONTRAINDICATIONS
EPYSQLI is contraindicated for initiation in patients with unresolved serious Neisseria meningitidis infection.
WARNINGS AND PRECAUTIONS
Serious Meningococcal Infections
Eculizumab products, complement inhibitors, increase a patient's susceptibility to serious, life-threatening, or fatal infections caused by meningococcal bacteria (septicemia and/or meningitis) in any serogroup, including non-groupable strains. Life-threatening and fatal meningococcal infections have occurred in both vaccinated and unvaccinated patients treated with complement inhibitors.
Complete or update meningococcal vaccination (for serogroups A, C, W, Y, and B) at least 2 weeks prior to administration of the first dose of EPYSQLI, according to current ACIP recommendations for patients receiving a complement inhibitor. Revaccinate patients in accordance with ACIP recommendations, considering the duration of therapy with EPYSQLI. Note that ACIP recommends an administration schedule in patients receiving complement inhibitors that differs from the administration schedule in the vaccine prescribing information. If urgent EPYSQLI therapy is indicated in a patient who is not up to date with meningococcal vaccines according to ACIP recommendations, provide the patient with antibacterial drug prophylaxis and administer meningococcal vaccines as soon as possible. Various durations and regimens of antibacterial drug prophylaxis have been considered, but the optimal durations and drug regimens for prophylaxis and their efficacy have not been studied in unvaccinated or vaccinated patients receiving complement inhibitors, including eculizumab products. The benefits and risks of treatment with EPYSQLI, as well as the benefits and risks of antibacterial drug prophylaxis in unvaccinated or vaccinated patients, must be considered against the known risks for serious infections caused by Neisseria meningitidis.
Vaccination does not eliminate the risk of serious meningococcal infections, despite development of antibodies following vaccination.
Closely monitor patients for early signs and symptoms of meningococcal infection and evaluate patients immediately if infection is suspected. Inform patients of these signs and symptoms and instruct patients to seek immediate medical care if these signs and symptoms occur. Promptly treat known infections. Meningococcal infection may become rapidly life-threatening or fatal if not recognized and treated early. Consider interruption of EPYSQLI in patients who are undergoing treatment for serious meningococcal infection, depending on the risks of interrupting treatment in the disease being treated.
EPYSQLI REMS
EPYSQLI is available only through a restricted program under a REMS called EPYSQLI REMS, because of the risk of serious meningococcal infections.
Notable requirements of the EPYSQLI REMS include the following:
- Prescribers must enroll in the REMS.
- Prescribers must counsel patients about the risk of serious meningococcal infection.
- Prescribers must provide the patients with the REMS educational materials.
- Prescribers must assess patient vaccination status for meningococcal vaccines (against serogroups A, C, W, Y and B) and vaccinate if needed according to current ACIP recommendations two weeks prior to the first dose of EPYSQLI.
- Prescribers must provide a prescription for antibacterial drug prophylaxis if treatment must be started urgently and the patient is not up to date with meningococcal vaccines according to current ACIP recommendations at least two weeks prior to the first dose of EPYSQLI.
- Healthcare settings and pharmacies that dispense EPYSQLI must be certified in the REMS and must verify prescribers are certified.
- Patients must receive counseling from the prescriber about the need to receive meningococcal vaccines per ACIP recommendations, the need to take antibiotics as directed by the prescriber, and the signs and symptoms of meningococcal infection.
- Patients must be instructed to carry the Patient Safety Card with them at all times during and for 3 months following treatment with EPYSQLI.
Further information is available at www.EPYSQLIREMS.com or 1-866-318-0342.
Other Infections
Serious infections with Neisseria species (other than Neisseria meningitidis), including disseminated gonococcal infections, have been reported.
Eculizumab products block terminal complement activation; therefore, patients may have increased susceptibility to infections, especially with encapsulated bacteria, such as infections with Neisseria meningitidis but also Streptococcus pneumoniae, Haemophilus influenzae, and to a lesser extent, Neisseria gonorrhoeae. Additionally, Aspergillus infections have occurred in immunocompromised and neutropenic patients. Children treated with eculizumab products may be at increased risk of developing serious infections due to Streptococcus pneumoniae and Haemophilus influenzae type b (Hib). Administer vaccinations for the prevention of Streptococcus pneumoniae and Haemophilus influenzae type b (Hib) infections according to ACIP recommendations. Patients receiving eculizumab products are at increased risk for infections due to these organisms, even if they develop antibodies following vaccination.
Monitoring Disease Manifestations after EPYSQLI Discontinuation
Treatment Discontinuation for PNH
Monitor patients after discontinuing EPYSQLI for at least 8 weeks to detect hemolysis.
Treatment Discontinuation for aHUS
After discontinuing EPYSQLI, monitor patients with aHUS for signs and symptoms of thrombotic microangiopathy (TMA) complications for at least 12 weeks. In aHUS clinical trials, 18 patients (5 in the prospective studies) discontinued eculizumab treatment. TMA complications occurred following a missed dose in 5 patients, and eculizumab was reinitiated in 4 of these 5 patients.
Clinical signs and symptoms of TMA include changes in mental status, seizures, angina, dyspnea, or thrombosis. In addition, the following changes in laboratory parameters may identify a TMA complication: occurrence of two, or repeated measurement of any one of the following: a decrease in platelet count by 25% or more compared to baseline or the peak platelet count during EPYSQLI treatment; an increase in serum creatinine by 25% or more compared to baseline or nadir during EPYSQLI treatment; or, an increase in serum LDH by 25% or more over baseline or nadir during EPYSQLI treatment.
If TMA complications occur after EPYSQLI discontinuation, consider reinstitution of EPYSQLI treatment, plasma therapy [plasmapheresis, plasma exchange, or fresh frozen plasma infusion (PE/PI)], or appropriate organ-specific supportive measures.
Thrombosis Prevention and Management
The effect of withdrawal of anticoagulant therapy during eculizumab products treatment has not been established. Therefore, treatment with eculizumab products should not alter anticoagulant management.
Infusion-Related Reactions
Administration of eculizumab products may result in infusion-related reactions, including anaphylaxis or other hypersensitivity reactions. In clinical trials, no patients experienced an infusion-related reaction which required discontinuation of eculizumab. Interrupt EPYSQLI infusion and institute appropriate supportive measures if signs of cardiovascular instability or respiratory compromise occur.
ADVERSE REACTIONS
The most frequently reported adverse reactions in the PNH randomized trial (≥10% overall and greater than placebo) are: headache, nasopharyngitis, back pain, and nausea.
The most frequently reported adverse reactions in aHUS single arm prospective trials (≥20%) are: headache, diarrhea, hypertension, upper respiratory infection, abdominal pain, vomiting, nasopharyngitis, anemia, cough, peripheral edema, nausea, urinary tract infections, pyrexia.
The most frequently reported adverse reaction in the gMG placebo-controlled clinical trial (≥10%) is: musculoskeletal pain.
DRUG INTERACTIONS
Plasmapheresis, Plasma Exchange, or Fresh Frozen Plasma Infusion
Concomitant use of eculizumab products with plasma exchange (PE), plasmapheresis (PP) or fresh frozen plasma infusion (PE/PI) treatment can reduce serum eculizumab product concentrations and requires a supplemental dose of EPYSQLI.
Neonatal Fc Receptor Blockers
Concomitant use of eculizumab products with neonatal Fc receptor (FcRn) blockers may lower systemic exposures and reduce effectiveness of eculizumab products. Closely monitor for reduced effectiveness of EPYSQLI.
To report SUSPECTED ADVERSE REACTIONS, contact Teva Pharmaceuticals at 1-888-483-8279 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
