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warnings and cautions
5 WARNINGS AND PRECAUTIONS Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies. Monitor patients for hematological toxicity at baseline and monthly thereafter. Discontinue if MDS/AML is confirmed. ( 5.1 ) Myelosuppression: TALZENNA may affect hematopoiesis and can cause anemia, neutropenia, and/or thrombocytopenia. ( 5.2 ) Embryo-Fetal Toxicity: TALZENNA can cause fetal harm. Advise of the potential risk to the fetus and to use effective contraception. ( 5.3 , 8.1 , 8.3 ) 5.1 Myelodysplastic Syndrome/Acute Myeloid Leukemia Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML) have been reported in patients who received TALZENNA. Overall, MDS/AML has been reported in 2 out of 584 (0.3%) solid tumor patients treated with TALZENNA in clinical studies. The duration of TALZENNA treatment in these two patients prior to developing MDS/AML was 4 months and 24 months, respectively. Both patients had received previous chemotherapy with platinum agents and/or other DNA damaging agents including radiotherapy. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor complete blood counts for cytopenia at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA. 5.2 Myelosuppression Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia, have been reported in patients treated with TALZENNA [see Adverse Reactions (6) ] . Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients. Monitor complete blood count for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If this occurs, dose modifications (dosing interruption with or without dose reduction) are recommended [see Dosing Modifications (2.3) ] . 5.3 Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations, and embryo-fetal death at exposures that were 0.24 times the area under the concentration-time curve (AUC) in patients receiving the recommended human dose of 1 mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of TALZENNA [see Use in Specific Populations (8.1 , 8.3) , Clinical Pharmacology (12.1) ] . Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for at least 4 months following the last dose of TALZENNA [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .
6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Myelodysplastic Syndrome/Acute Myeloid Leukemia [see Warnings and Precautions (5.1) ] Myelosuppression [see Warnings and Precautions (5.2) ] Most common (≥20%) adverse reactions of any grade were: Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite. ( 6.1 ) Most common laboratory abnormalities (≥25%) were: Decreases in hemoglobin, platelets, neutrophils, lymphocytes, leukocytes, and calcium. Increases in glucose, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Pfizer, Inc. at 1-800-438-1985 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Treatment of gBRCAm HER2-negative Locally Advanced or Metastatic Breast Cancer EMBRACA The safety of TALZENNA as monotherapy was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than 3 lines of chemotherapy for the treatment of locally advanced/metastatic disease. EMBRACA was a randomized, open-label, multi-center study in which 412 patients received either TALZENNA 1 mg once daily (n=286) or a chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare provider's choice (n=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA and 50% of those receiving chemotherapy; dose reductions due to any cause occurred in 53% of TALZENNA patients and 40% of chemotherapy patients. Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients and 6% chemotherapy patients. Table 3 and Table 4 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study. Table 3. Adverse Reactions Graded according to NCI CTCAE 4.03. (in ≥20% of Patients Receiving TALZENNA) in EMBRACA TALZENNA N=286 (%) Chemotherapy N=126 (%) Adverse Reactions Grades 1–4 Grade 3 Grade 4 Grades 1–4 Grade 3 Grade 4 Abbreviations: AR=adverse reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; N=number of patients. Blood and lymphatic system disorders Anemia Includes anemia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased. 53 38 1 18 4 1 Neutropenia Includes febrile neutropenia, neutropenia and neutrophil count decreased. 35 18 3 43 20 16 Thrombocytopenia Includes thrombocytopenia and platelet count decreased. 27 11 4 7 2 0 Metabolism and nutrition disorders Decreased appetite 21 <1 0 22 1 0 Nervous system disorders Headache 33 2 0 22 1 0 Gastrointestinal disorders Nausea 49 <1 0 47 2 0 Vomiting 25 2 0 23 2 0 Diarrhea 22 1 0 26 6 0 Skin and subcutaneous tissue disorders Alopecia For TALZENNA, Grade 1 in 23%, and Grade 2 in 2%. For the chemotherapy arm, Grade 1 in 20%, and Grade 2 in 8%. 25 0 0 28 0 0 General disorders and administration site conditions Fatigue Includes fatigue and asthenia. 62 3 0 50 5 0 The following adverse reactions have been identified in <20% of the 286 patients receiving TALZENNA, and thus were not included in Table 3: abdominal pain (19%), dizziness (17%), leukopenia (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and lymphopenia (7%). Table 4 Laboratory Abnormalities Reported in ≥25% of Patients in EMBRACA EMBRACA Study TALZENNA N This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter. =286 (%) Chemotherapy N =126 (%) Parameter Grades 1–4 Grade 3 Grade 4 Grades 1–4 Grade 3 Grade 4 Abbreviation: N=number of patients. Decrease in hemoglobin 90 39 0 77 6 0 Decrease in leukocytes 84 14 0.3 73 22 2 Decrease in neutrophils 68 17 3 70 21 17 Decrease in lymphocytes 76 17 0.7 53 8 0.8 Decrease in platelets 55 11 4 29 2 0 Increase in glucose This number represents non-fasting glucose. 54 2 0 51 2 0 Increase in aspartate aminotransferase 37 2 0 48 3 0 Increase in alkaline phosphatase 36 2 0 34 2 0 Increase in alanine aminotransferase 33 1 0 37 2 0 Decrease in calcium 28 1 0 16 0 0