warnings and cautions
5 WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML occurred in patients exposed to ZEJULA, and some cases were fatal. Monitor patients for hematological toxicity and discontinue if MDS/AML is confirmed. ( 5.1 ) Bone Marrow Suppression: Test complete blood counts weekly for the first month, monthly for the next 11 months and periodically thereafter for clinically significant changes. ( 5.2 ) Cardiovascular Effects: Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year, and periodically thereafter during treatment with ZEJULA. Manage with antihypertensive medications as well as adjustment of the ZEJULA dose, if necessary. ( 5.3 ) Embryo-Fetal Toxicity: ZEJULA can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.4 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received ZEJULA. In 1902 patients treated with ZEJULA in clinical trials, MDS/AML occurred in 14 patients (0.7%). The duration of therapy with ZEJULA in patients who developed secondary MDS/cancer therapy-related AML varied from <2 months to >4 years. All of these patients had received previous chemotherapy with platinum agents and/or other DNA-damaging agents including radiotherapy. Discontinue ZEJULA if MDS/AML is confirmed. 5.2 Bone Marrow Suppression Hematologic adverse reactions (thrombocytopenia, anemia and neutropenia) have been reported in patients treated with ZEJULA. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 29%, 25%, and 20% of patients receiving ZEJULA in NOVA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 3%, 1%, and 2% of patients. Grade ≥3 thrombocytopenia, anemia and neutropenia were reported, respectively, in 28%, 27%, and 13% of patients receiving ZEJULA in QUADRA. Discontinuation due to thrombocytopenia, anemia, and neutropenia occurred, respectively, in 4%, 2%, and 1% of patients. Do not start ZEJULA until patients have recovered from hematological toxicity caused by previous chemotherapy (≤ Grade 1). Monitor complete blood counts weekly for the first month, monthly for the next 11 months of treatment, and periodically after this time. If hematological toxicities do not resolve within 28 days following interruption, discontinue ZEJULA, and refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics [see Dosage and Administration (2.3) ]. 5.3 Cardiovascular Effects Hypertension and hypertensive crisis have been reported in patients treated with ZEJULA. Grade 3-4 hypertension occurred in 9% of ZEJULA treated patients compared to 2% of placebo treated patients in NOVA with a median time from first dose to first onset of 77 days (range: 4 to 504 days) and with a median duration of 15 days (range: 1 to 86 days). Discontinuation due to hypertension occurred in <1% of patients. Grade 3-4 hypertension occurred in 5% of ZEJULA-treated patients in QUADRA with a median time from first dose to first onset of 15 days (range: 1 to 316 days) and with a median duration of 7 days (range: 1 to 118 days). Discontinuation due to hypertension occurred in <0.2% of patients. Monitor blood pressure and heart rate at least weekly for the first two months, then monthly for the first year and periodically thereafter during treatment with ZEJULA. Closely monitor patients with cardiovascular disorders, especially coronary insufficiency, cardiac arrhythmias, and hypertension. Medically manage hypertension with antihypertensive medications and adjustment of the ZEJULA dose, if necessary [see Dosage and Administration (2.3) and Nonclinical Toxicology (13.2) ]. 5.4 Embryo-Fetal Toxicity Based on its mechanism of action, ZEJULA can cause fetal harm when administered to a pregnant woman [see Clinical Pharmacology (12.1) ]. ZEJULA has the potential to cause teratogenicity and/or embryo-fetal death since niraparib is genotoxic and targets actively dividing cells in animals and patients (e.g., bone marrow) [see Warnings and Precautions (5.2) and Nonclinical Toxicology (13.1) ] . Due to the potential risk to a fetus based on its mechanism of action, animal developmental and reproductive toxicology studies were not conducted with niraparib. Apprise pregnant women of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for 6 months after the last dose of ZEJULA [see Use in Specific Populations (8.1 , 8.3) ].