SPL PATIENT PACKAGE INSERT SECTION.

This Patient Information has been approved by the U.S. Food and Drug Administration.Issued 9/2021PATIENT INFORMATIONTALZENNA(R) (Tal-ZEN-ah)(talazoparib)capsulesWhat is the most important information should know about TALZENNATALZENNA may cause serious side effects, including:Bone marrow problems called Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML). Some people who have cancer and who have received previous treatment with chemotherapy or certain other medicines for their cancer have developed MDS or AML during or after treatment with TALZENNA. MDS or AML may lead to death. If you develop MDS or AML, your healthcare provider will stop treatment with TALZENNA.Symptoms of low blood cell counts are common during treatment with TALZENNA, but can be sign of serious problems, including MDS or AML. Tell your healthcare provider if you have any of the following symptoms during treatment with TALZENNA:weaknessweight lossfeverfrequent infectionsblood in urine or stoolshortness of breathfeeling very tiredbruising or bleeding more easilyYour healthcare provider will do blood tests to check your blood cell counts:before treatment with TALZENNAevery month during treatment with TALZENNAweekly if you have low blood cell counts that last long time. Your healthcare provider may stop treatment with TALZENNA until your blood cell counts improve. See What are the possible side effects of TALZENNA below for other side effects of TALZENNA. What is TALZENNATALZENNA is prescription medicine used to treat adults with:a certain type of breast cancer (human epidermal growth factor receptor [HER2]-negative), andan abnormal inherited BRCA gene, andwhose cancer has spread to other parts of the body (locally advanced or metastatic).Your healthcare provider will perform test to make sure that TALZENNA is right for you.It is not known if TALZENNA is safe and effective in children.Before taking TALZENNA, tell your healthcare provider about all of your medical conditions, including if you:have kidney problemsare pregnant or plan to become pregnant. TALZENNA can harm your unborn baby, and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with TALZENNA. Tell your healthcare provider right away if you are pregnant or become pregnant during treatment with TALZENNA.If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with TALZENNA.Females who are able to become pregnant should use effective birth control (contraception) during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you. Males with female partners who are pregnant or are able to become pregnant should use effective birth control during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA. are breastfeeding or plan to breastfeed. It is not known if TALZENNA passes into your breast milk. Do not breastfeed during treatment with TALZENNA and for at least month after receiving the last dose of TALZENNA. Talk to your healthcare provider about the best way to feed your baby during this time.Tell your healthcare provider about all the medicines you take, including prescription medicines, over-the-counter medicines, vitamins, and herbal supplements. Taking TALZENNA and certain other medicines can affect how TALZENNA works and may cause side effects.Know the medicines you take. Keep list of your medicines and show it to your healthcare provider and pharmacist when you get new medicine. How should take TALZENNATake TALZENNA exactly as your healthcare provider tells you.Do not change your dose or stop taking TALZENNA without first talking with your healthcare provider.Take TALZENNA time day.Take TALZENNA with or without food. Swallow TALZENNA capsules whole. Do not dissolve or open TALZENNA capsules. Your healthcare provider may change your dose of TALZENNA or tell you to stop taking TALZENNA depending on how you respond to treatment.If you miss dose of TALZENNA or vomit, take your next dose at your regular time. Do not take an extra dose to make up for missed dose.If you take too much TALZENNA, call your healthcare provider or go to the nearest hospital emergency room right away.What are the possible side effects of TALZENNATALZENNA may cause serious side effects, including: See What is the most important information should know about TALZENNAThe most common side effects of TALZENNA include:tiredness or weaknesslow number of red or white blood cellsnausealow number of plateletsheadacheloss of appetitediarrheavomitinghair loss TALZENNA may cause fertility problems in males. This may affect your ability to father child. Talk to your healthcare provider if this is concern for you. These are not all of the possible side effects of TALZENNA.Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.How should store TALZENNAStore TALZENNA at 68F to 77F (20C to 25C ). Keep TALZENNA and all medicines out of the reach of children. General information about the safe and effective use of TALZENNA.Medicines are sometimes prescribed for purposes other than those listed in Patient Information leaflet. Do not use TALZENNA for condition for which it is not prescribed. Do not give TALZENNA to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TALZENNA that is written for health professionals. What are the ingredients in TALZENNAActive ingredient: talazoparib tosylate Inactive ingredients: silicified microcrystalline cellulose (sMCC). The capsule shells contain hypromellose (HPMC), yellow iron oxide, red iron oxide and titanium dioxide. The printing ink contains shellac, black iron oxide, potassium hydroxide, ammonium hydroxide, and propylene glycol. For more information, go to www.TALZENNA.com or call 1-800-438-1985.LAB-1272-3.0. weakness. weight loss. fever. frequent infections. blood in urine or stool. shortness of breath. feeling very tired. bruising or bleeding more easily. before treatment with TALZENNA. every month during treatment with TALZENNA. weekly if you have low blood cell counts that last long time. Your healthcare provider may stop treatment with TALZENNA until your blood cell counts improve.. certain type of breast cancer (human epidermal growth factor receptor [HER2]-negative), and. an abnormal inherited BRCA gene, and. whose cancer has spread to other parts of the body (locally advanced or metastatic).. have kidney problems. are pregnant or plan to become pregnant. TALZENNA can harm your unborn baby, and may cause loss of pregnancy (miscarriage). You should not become pregnant during treatment with TALZENNA. Tell your healthcare provider right away if you are pregnant or become pregnant during treatment with TALZENNA.If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with TALZENNA.Females who are able to become pregnant should use effective birth control (contraception) during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you. Males with female partners who are pregnant or are able to become pregnant should use effective birth control during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA. If you are able to become pregnant, your healthcare provider may do pregnancy test before you start treatment with TALZENNA.. Females who are able to become pregnant should use effective birth control (contraception) during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA. Talk to your healthcare provider about forms of birth control that may be right for you. Males with female partners who are pregnant or are able to become pregnant should use effective birth control during treatment with TALZENNA and for at least months after receiving the last dose of TALZENNA.. are breastfeeding or plan to breastfeed. It is not known if TALZENNA passes into your breast milk. Do not breastfeed during treatment with TALZENNA and for at least month after receiving the last dose of TALZENNA. Talk to your healthcare provider about the best way to feed your baby during this time.. Take TALZENNA exactly as your healthcare provider tells you.. Do not change your dose or stop taking TALZENNA without first talking with your healthcare provider.. Take TALZENNA time day.. Take TALZENNA with or without food. Swallow TALZENNA capsules whole. Do not dissolve or open TALZENNA capsules. Your healthcare provider may change your dose of TALZENNA or tell you to stop taking TALZENNA depending on how you respond to treatment.. If you miss dose of TALZENNA or vomit, take your next dose at your regular time. Do not take an extra dose to make up for missed dose.. If you take too much TALZENNA, call your healthcare provider or go to the nearest hospital emergency room right away.. tiredness or weakness. low number of red or white blood cells. nausea. low number of platelets. headache. loss of appetite. diarrhea. vomiting. hair loss Logo.

USE IN SPECIFIC POPULATIONS SECTION.

8 USE IN SPECIFIC POPULATIONS. Lactation: Advise women not to breastfeed. (8.2)Severe Renal Impairment: Reduce TALZENNA dose and monitor for potential increased adverse reactions as appropriate. (8.6, 12.3). Lactation: Advise women not to breastfeed. (8.2). Severe Renal Impairment: Reduce TALZENNA dose and monitor for potential increased adverse reactions as appropriate. (8.6, 12.3). 8.1 Pregnancy. Risk SummaryBased on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1)], TALZENNA can cause embryo-fetal harm when administered to pregnant woman. There are no available data on TALZENNA use in pregnant women to inform drug-associated risk. In an animal reproduction study, the administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations and embryo-fetal death at maternal exposures that were 0.24 times the AUC in patients receiving the recommended dose of mg daily (see Data). Apprise pregnant women and females of reproductive potential of the potential risk to fetus.The background risk of major birth defects and miscarriage for the indicated population is unknown. In the general U.S. population, the estimated background risks of major birth defects and miscarriage in clinically recognized pregnancies are 2% to 4% and 15% to 20%, respectively.. Data. Animal DataIn an embryo-fetal development toxicity study, pregnant rats received oral doses of 0.015, 0.05, and 0.15 mg/kg/day talazoparib during the period of organogenesis. Talazoparib caused embryo-fetal death at doses >=0.015 mg/kg/day (approximately 0.24 times the AUC in patients at the recommended dose). dose of 0.015 mg/kg/day caused decreased fetal body weights and an increased incidence of fetal malformations (depressed eye bulge, small eye, split sternebra, and fused cervical vertebral arch) and structural variations including misshapen or incomplete ossification of the sternebra, skull, rib, and vertebra.. 8.2 Lactation. Risk SummaryThere are no data on the presence of talazoparib in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for at least month after the final dose.. 8.3 Females and Males of Reproductive Potential. Pregnancy TestingA pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment.. Contraception. FemalesTALZENNA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment and for at least months following the last dose of TALZENNA.. MalesBased on genotoxicity and animal reproduction studies, advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception during treatment with TALZENNA and for at least months following the last dose [see Use in Specific Populations (8.1), Nonclinical Toxicology (13.1)].. Infertility. MalesBased on animal studies, TALZENNA may impair fertility in males of reproductive potential [see Nonclinical Toxicology (13.1)]. 8.4 Pediatric Use. The safety and effectiveness of TALZENNA have not been established in pediatric patients.. 8.5 Geriatric Use. In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA mg daily as monotherapy, 85 (17%) patients were >=65 years of age, and this included 19 (4%) patients who were >=75 years old. There were patients >=85 years old. No overall differences in safety or effectiveness of TALZENNA were observed between these patients and younger patients, but greater sensitivity of some older individuals cannot be ruled out.. 8.6Renal Impairment. Patients with moderate or severe renal impairment have higher exposure to TALZENNA than patients with normal renal function. Reduce the recommended dose of TALZENNA in patients with moderate (CLcr 30 59 mL/min) and severe (CLcr 15 29 mL/min) renal impairment. Monitor patients with severe renal impairment for potential increased adverse reactions and adjust dosing accordingly [see Dosage and Administration (2.4), Clinical Pharmacology (12.3)]. No dose adjustment is required for patients with mild renal impairment (CLcr 60 89 mL/min). TALZENNA has not been studied in patients requiring hemodialysis [see Clinical Pharmacology (12.3)].. 8.7Hepatic Impairment. No dose modification is recommended for patients with mild, moderate, or severe hepatic impairment (based on NCI criteria) [see Clinical Pharmacology (12.3)].

ADVERSE REACTIONS SECTION.

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)] 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. 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). 6.1Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of 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. EMBRACAThe 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 lines of chemotherapy for the treatment of locally advanced/metastatic disease. EMBRACA was randomized, open-label, multi-center study in which 412 patients received either TALZENNA mg once daily (n=286) or chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare providers 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 and Table summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.Table 3.Adverse ReactionsGraded according to NCI CTCAE 4.03. (in >=20% of Patients Receiving TALZENNA) in EMBRACA TALZENNAN=286 (%)ChemotherapyN=126 (%)Adverse ReactionsGrades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4Abbreviations: AR=adverse reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute; N=number of patients.Blood and lymphatic system disordersAnemiaIncludes anemia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased. 533811841NeutropeniaIncludes febrile neutropenia, neutropenia and neutrophil count decreased. 35183432016ThrombocytopeniaIncludes thrombocytopenia and platelet count decreased. 27114720Metabolism and nutrition disordersDecreased appetite21<102210Nervous system disordersHeadache33202210Gastrointestinal disordersNausea49<104720Vomiting25202320Diarrhea22102660Skin and subcutaneous tissue disordersAlopeciaFor TALZENNA, Grade in 23%, and Grade in 2%. For the chemotherapy arm, Grade in 20%, and Grade in 8%. 25002800General disorders and administration site conditionsFatigueIncludes fatigue and asthenia. 62305050The 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 4Laboratory Abnormalities Reported in >=25% of Patients in EMBRACA EMBRACA StudyTALZENNANThis 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 (%)ChemotherapyN=126 (%)ParameterGrades 1-4Grade 3Grade 4Grades 1-4Grade 3Grade 4Abbreviation: N=number of patients.Decrease in hemoglobin903907760Decrease in leukocytes84140.373222Decrease in neutrophils68173702117Decrease in lymphocytes76170.75380.8Decrease in platelets551142920Increase in glucoseThis number represents non-fasting glucose. 54205120Increase in aspartate aminotransferase37204830Increase in alkaline phosphatase36203420Increase in alanine aminotransferase33103720Decrease in calcium28101600.

CLINICAL PHARMACOLOGY SECTION.

12 CLINICAL PHARMACOLOGY. 12.1Mechanism of Action. Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (PARP) enzymes, including PARP1 and PARP2, which play role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA and BRCA 2, have shown that talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes resulting in DNA damage, decreased cell proliferation, and apoptosis. Talazoparib anti-tumor activity was observed in human patient-derived xenograft breast cancer tumor models bearing mutated BRCA or mutated BRCA or wild-type BRCA and BRCA 2.. 12.2 Pharmacodynamics. Cardiac ElectrophysiologyThe effect of talazoparib on cardiac repolarization was evaluated in 37 patients with advanced solid tumors. Talazoparib had no large QTc prolongation (i.e., >20 ms) at the recommended dose.. 12.3 Pharmacokinetics. After oral administration of mg TALZENNA once daily in patients, the recommended dose, the geometric mean [% coefficient of variation (CV%)] of AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) ng.hr/mL and 16.4 (32%) ng/mL, respectively. The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to mg (2 times the recommended dose). The median accumulation ratio of talazoparib following repeated oral administration of mg once daily was in the range of 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within to weeks.. AbsorptionFollowing oral administration of talazoparib, the median time to Cmax (Tmax) was generally between to hours after dosing.. Food Effect Following single oral dose of 0.5 mg TALZENNA with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean Cmax of talazoparib was decreased by 46%, the median Tmax was delayed from to hours, and AUCinf was not affected.. DistributionThe mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.. EliminationThe mean terminal plasma half-life (+-standard deviation) of talazoparib is 90 (+-58) hours, and the mean apparent oral clearance (inter-subject variability) is 6.45 L/h (31.1%) in cancer patients.. MetabolismTalazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways of talazoparib in humans include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.. ExcretionExcretion of talazoparib in urine was the major route of elimination. Approximately 68.7% (54.6% unchanged) of the total administered radioactive dose [14C]talazoparib was recovered in urine, and 19.7% (13.6% unchanged) was recovered in feces.. Specific PopulationsAge (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment based on NCI criteria had no clinically relevant effect on the PK of talazoparib.. Pediatric PatientsThe PK of talazoparib have not been evaluated in patients <18 years of age.. Patients with Renal Impairment Talazoparib steady-state total exposure (AUC0-24) increased by 12%, 43%, and 163% in patients with mild (eGFR 60 89 mL/min/1.73 m2), moderate (eGFR 30 59 mL/min/1.73 m2), and severe (eGFR 15 29 mL/min/1.73 m2) renal impairment, respectively, relative to patients with normal renal function (eGFR >= 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 11%, 32%, and 89% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis. There was no evidence of relationship between the protein binding of talazoparib and renal function.. Drug Interaction Studies Effect of Other Drugs on TalazoparibEffect of P-gp inhibitors: In patients with advanced solid tumors, coadministration of P-gp inhibitor (multiple 100 mg twice-daily doses of itraconazole) with single 0.5 mg talazoparib dose increased talazoparib AUCinf and Cmax by approximately 56% and 40%, respectively. Population PK analysis showed that coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil in clinical studies increased talazoparib exposure by 45% [see Dosage and Administration (2.5), Drug Interactions (7.1)]. Coadministration with P-gp inhibitors including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin in clinical studies increased talazoparib exposure by 8% [see Dosage and Administration (2.5), Drug Interactions (7)].Effect of P-gp inducers: In patients with advanced solid tumors, coadministration of P-gp inducer (multiple 600 mg once-daily doses of rifampin) with single mg talazoparib dose increased talazoparib Cmax by 37% with no effect on talazoparib exposure.Effect of BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied. Coadministration with BCRP inhibitors may increase talazoparib exposure [see Drug Interactions (7)].Effect of acid-reducing agents on talazoparib: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor antagonists (H2RA), or other acid reducing agents has no effect on the absorption of talazoparib.. In Vitro StudiesTalazoparib is substrate of P-gp and BCRP transporters. Talazoparib is not substrate of organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationic transporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP], multidrug and toxin extrusion [MATE]1, and MATE2-K.Talazoparib is not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5, or inducer of CYP1A2, CYP2B6, or CYP3A4.Talazoparib is not an inhibitor of transporters including P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, and MATE2-K.Talazoparib is not an inhibitor of uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15).

CLINICAL STUDIES SECTION.

14 CLINICAL STUDIES. EMBRACA Study (NCT01945775). Deleterious or Suspected Deleterious Germline BRCA-mutated (gBRCAm) HER2-negative Locally Advanced or Metastatic Breast CancerEMBRACA (NCT01945775) was an open-label study in which patients (N=431) with gBRCAm HER2-negative locally advanced or metastatic breast cancer were randomized 2:1 to receive TALZENNA mg or healthcare providers choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) until disease progression or unacceptable toxicity. Randomization was stratified by prior lines of chemotherapy for metastatic disease (0 versus 1, 2, or 3), by triple-negative disease status (triple-negative breast cancer [TNBC] versus non-TNBC), and history of central nervous system (CNS) metastasis (yes versus no).Patients received no more than prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or taxane (unless contraindicated) in the neoadjuvant, adjuvant, and/or metastatic treatment setting. First-line treatment for advanced or metastatic disease with no prior adjuvant chemotherapy was allowed if the investigator determined that of the chemotherapy choices in the control arm would be an appropriate treatment option for the patient. Patients with prior platinum therapy for advanced disease were required to have no evidence of disease progression during platinum therapy. No prior treatment with PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have deleterious or suspected deleterious gBRCAm using clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx(R). BRCA mutation status (breast cancer susceptibility gene [BRCA1] positive or breast cancer susceptibility gene [BRCA2] positive) was similar across both treatment arms.The median age of patients treated with TALZENNA was 46 years (range 28 to 84) and 51 years (range 24 to 89) among patients treated with chemotherapy. Among all randomized patients, 1% versus 2% were males, 67% versus 75% were White; 11% versus 11% were Asian, and 4% versus 1% were Black or African American in the TALZENNA and chemotherapy arms, respectively. Almost all patients (98%) in both arms had an Eastern Cooperative Oncology Group (ECOG) performance status of or 1. Approximately 56% of patients had estrogen receptor-positive and/or progesterone receptor-positive disease; 44% of patients had triple-negative disease, and the proportions were balanced across both treatment arms. Fifteen percent (15%) of patients in the TALZENNA arm and 14% of patients in the chemotherapy arm had history of CNS metastases. Ninety-one percent (91%) of patients in the TALZENNA arm had received prior taxane therapy, and 85% had received prior anthracycline therapy in any setting. Sixteen percent (16%) of patients in the TALZENNA arm and 21% of patients in the chemotherapy arm had received prior platinum treatment in any setting. The median number of prior cytotoxic regimens for patients with advanced breast cancer was one; 38% received no prior cytotoxic regimens for advanced or metastatic disease, 37% received one, 20% received two, and 5% received three or more prior cytotoxic regimens.The major efficacy outcome measure was progression-free survival (PFS) evaluated according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by blinded independent central review (BICR). statistically significant improvement in PFS was demonstrated for TALZENNA compared with chemotherapy. sensitivity analysis of investigator-assessed PFS was consistent with the BICR-assessed PFS results. Consistent PFS results were observed across patient subgroups defined by study stratification factors (prior lines of chemotherapy, TNBC status, and history of CNS metastases). Efficacy data from the EMBRACA study are summarized in Table 5, and the Kaplan-Meier curves for PFS are shown in Figure and final overall survival (OS) in Figure 2.Table 5.Summary of Efficacy Results EMBRACA StudyTALZENNAChemotherapyAbbreviations: BICR=blinded independent central review; CI=confidence interval; DOR=duration of response; ITT=intent-to-treat; ORR=objective response rate; OS=overall survival; PFS=progression-free survival.PFS by BICRN=287N=144 Disease Progression or Deaths, (%)186 (65)83 (58) Median months (95% CI)8.6 (7.2, 9.3)5.6 (4.2, 6.7) Hazard Ratio (95% CI)Hazard ratio is estimated from Cox proportional hazards model stratified by prior use of chemotherapy for metastatic disease (0 versus 1, 2, or 3), by triple-negative disease status (triple-negative breast cancer [TNBC] versus non TNBC), and by history of central nervous system metastasis (yes versus no) and was relative to overall chemotherapy with <1 favoring talazoparib. 0.54 (0.41, 0.71) p-valueP-values (2-sided) from the log-rank test stratified by number of prior cytotoxic chemotherapy regimens, triple negative status and history of central nervous system metastasis. p<0.0001Patients with Measurable Disease by InvestigatorConducted in ITT population with measurable disease at baseline. N=219N=114 ORR, (95% CI)Response rate based on confirmed responses. 50.2 (43.4, 57.0)18.4 (11.8, 26.8) MedianMedian estimated from Kaplan-Meier probabilities. DOR months (95% CI)6.4 (5.4, 9.5)3.9 (3.0, 7.6)OSN=287N=144 Deaths, (%)216 (75)108 (75) Median months (95% CI)19.3 (16.6, 22.5)19.5 (17.4, 22.4) Hazard ratio (95% CI) 0.85 (0.67, 1.07) p-value p=0.1693Figure 1.Kaplan-Meier Curves of PFS EMBRACA StudyAbbreviation: PFS=progression-free survival.Figure 2.Kaplan-Meier Curves of OS EMBRACA Study (ITT Population)Abbreviation: OS=overall survival.. Figure 1. Figure 2.

DESCRIPTION SECTION.

11 DESCRIPTION. Talazoparib is an inhibitor of mammalian polyadenosine 5-diphosphoribose polymerase (PARP) enzyme. The chemical name of talazoparib tosylate is (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one 4-methylbenzenesulfonate (1:1). The chemical formula of talazoparib tosylate is C26H22F2N6O4S, and the relative molecular mass is 552.56 Daltons. The chemical structure of talazoparib tosylate is shown below:Talazoparib tosylate is white to yellow solid. TALZENNA capsules for oral use are available as:0.25 mg hard hypromellose (HPMC) capsule that contains 0.363 mg talazoparib tosylate equivalent to 0.25 mg talazoparib free base, or0.5 mg HPMC capsule that contains 0.727 mg talazoparib tosylate equivalent to 0.5 mg talazoparib free base, or0.75 mg HPMC capsule that contains 1.09 mg talazoparib tosylate equivalent to 0.75 mg talazoparib free base, or1 mg HPMC capsule that contains 1.453 mg talazoparib tosylate equivalent to mg talazoparib free base.Inactive ingredients: silicified microcrystalline cellulose (sMCC). The capsule shells contain HPMC, yellow iron oxide, red iron oxide and titanium dioxide; and the printing ink contains shellac, black iron oxide, potassium hydroxide, ammonium hydroxide, and propylene glycol.. 0.25 mg hard hypromellose (HPMC) capsule that contains 0.363 mg talazoparib tosylate equivalent to 0.25 mg talazoparib free base, or. 0.5 mg HPMC capsule that contains 0.727 mg talazoparib tosylate equivalent to 0.5 mg talazoparib free base, or. 0.75 mg HPMC capsule that contains 1.09 mg talazoparib tosylate equivalent to 0.75 mg talazoparib free base, or. mg HPMC capsule that contains 1.453 mg talazoparib tosylate equivalent to mg talazoparib free base.. Chemical Structure.

DOSAGE & ADMINISTRATION SECTION.

2 DOSAGE AND ADMINISTRATION. The recommended dose of TALZENNA is mg taken as single oral daily dose, with or without food. (2.2)Patients should be treated until disease progression or unacceptable toxicity occurs. (2.2)For adverse reactions, consider dosing interruption or dose reduction. (2.3)For patients with moderate renal impairment (CLcr 30 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily. (2.4)For patients with severe renal impairment (Clcr 15 29 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily. (2.4). The recommended dose of TALZENNA is mg taken as single oral daily dose, with or without food. (2.2). Patients should be treated until disease progression or unacceptable toxicity occurs. (2.2). For adverse reactions, consider dosing interruption or dose reduction. (2.3). For patients with moderate renal impairment (CLcr 30 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily. (2.4). For patients with severe renal impairment (Clcr 15 29 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily. (2.4). 2.1Patient Selection. Select patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA mutations [see Indications and Usage (1), Clinical Studies (14)]. Information on the FDA-approved test for the detection of BRCA mutations is available at http://www.fda.gov/companiondiagnostics.. 2.2Recommended Dosing. The recommended dose of TALZENNA is mg taken orally once daily, with or without food.The 0.25 mg, 0.5 mg, and 0.75 mg capsules are available for dose reduction.Patients should be treated until disease progression or unacceptable toxicity occurs.The hard capsules should be swallowed whole and must not be opened or dissolved. If the patient vomits or misses dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.. 2.3Dose Modifications for Adverse Reactions. To manage adverse reactions, consider interruption of treatment with or without dose reduction based on severity and clinical presentation. Recommended dose reductions are indicated in Table and Table 2. Treatment with TALZENNA should be discontinued if more than three dose reductions are required.Table 1.Dose Reduction Levels for Adverse ReactionsDose LevelDoseRecommended starting dose1 mg once dailyFirst dose reduction0.75 mg once dailySecond dose reduction0.5 mg once dailyThird dose reduction0.25 mg once dailyTable 2.Dose Modification and ManagementMonitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5.2)].Adverse ReactionsWithhold TALZENNA until levels resolve toResume TALZENNAHemoglobin <8 g/dL>=9 g/dLResume TALZENNA at reduced dosePlatelet count <50,000/uL>=75,000/uLNeutrophil count <1,000/uL>=1500/uLNon-hematologic Grade or Grade 4<=Grade 1Consider resuming TALZENNA at reduced dose or discontinue. 2.4Dose Modifications for Patients with Renal Impairment. For patients with moderate renal impairment (CLcr 30 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily. For patients with severe renal impairment (CLcr 15 29 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily [see Use in Specific Populations (8.6), Clinical Pharmacology (12.3)].. 2.5Dose Modifications for Use with P-glycoprotein (P-gp) Inhibitors. Reduce the TALZENNA dose to 0.75 mg once daily when coadministered with certain P-gp inhibitors. For additional information on interacting P-gp inhibitors, see Drug Interactions (7.1) and Clinical Pharmacology (12.3).When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3-5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the P-gp inhibitor [see Drug Interactions (7.1), Clinical Pharmacology (12.3)].

DRUG INTERACTIONS SECTION.

7 DRUG INTERACTIONS. P-gp Inhibitors: Reduce TALZENNA dose for certain P-gp inhibitors, and monitor for potential increased adverse reactions as appropriate. (2.5, 7.1, 12.3) BCRP Inhibitors: Monitor for potential increased adverse reactions. (7.1). P-gp Inhibitors: Reduce TALZENNA dose for certain P-gp inhibitors, and monitor for potential increased adverse reactions as appropriate. (2.5, 7.1, 12.3). BCRP Inhibitors: Monitor for potential increased adverse reactions. (7.1). 7.1Effect of Other Drugs on TALZENNA. Effect of P-gp InhibitorsCoadministration with P-gp inhibitors may increase talazoparib exposure.In patients with advanced solid tumors, coadministration of P-gp inhibitor (itraconazole) increased talazoparib plasma exposure by 56%. In the clinical studies, coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil resulted in an approximate 45% increase in talazoparib exposure and an increase in the rate of TALZENNA dose reduction. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the TALZENNA dose [see Dosage and Administration (2.5)]. When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3-5 half-lives of the inhibitor) to the dose used prior to the initiation of the P-gp inhibitor [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].When coadministering TALZENNA with P-gp inhibitors not listed above, monitor patients for potential increased adverse reactions [see Dosage and Administration (2.5), Clinical Pharmacology (12.3)].. Effect of BCRP inhibitorsCoadministration with BCRP inhibitors may increase talazoparib exposure. If coadministration cannot be avoided, monitor patients for potential increased adverse reactions when coadministering [see Clinical Pharmacology (12.3)].

INFORMATION FOR PATIENTS SECTION.

17 PATIENT COUNSELING INFORMATION. Advise the patient to read the FDA-approved patient labeling (Patient Information).MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or need for blood transfusions. This may be sign of hematological toxicity or more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors [see Warnings and Precautions (5.1)].Myelosuppression: Advise patients that TALZENNA may affect hematopoiesis and can cause anemia, leukopenia/neutropenia, and/or thrombocytopenia [see Warnings and Precautions (5.2)].Administration Instructions: Advise patients that TALZENNA can be taken once daily with or without food. Instruct patients that if they miss dose of TALZENNA, they should take their next normal dose at the usual time. Also advise patients to swallow each capsule whole, and that capsules must not be opened or dissolved [see Dosage and Administration (2.2)].Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TALZENNA and for at least months after the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for at least months after receiving the last dose of TALZENNA [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].Lactation: Advise patients not to breastfeed while taking TALZENNA and for at least month after receiving the last dose [see Use in Specific Populations (8.2)].. MDS/AML: Advise patients to contact their healthcare provider if they experience weakness, feeling tired, fever, weight loss, frequent infections, bruising, bleeding easily, breathlessness, blood in urine or stool, and/or laboratory findings of low blood cell counts, or need for blood transfusions. This may be sign of hematological toxicity or more serious uncommon bone marrow problem called MDS or AML, which have been reported in patients who received PARP inhibitors [see Warnings and Precautions (5.1)].. Myelosuppression: Advise patients that TALZENNA may affect hematopoiesis and can cause anemia, leukopenia/neutropenia, and/or thrombocytopenia [see Warnings and Precautions (5.2)].. Administration Instructions: Advise patients that TALZENNA can be taken once daily with or without food. Instruct patients that if they miss dose of TALZENNA, they should take their next normal dose at the usual time. Also advise patients to swallow each capsule whole, and that capsules must not be opened or dissolved [see Dosage and Administration (2.2)].. Embryo-Fetal Toxicity: Advise females to inform their healthcare provider if they are pregnant or become pregnant. Inform female patients of the risk to fetus and potential loss of the pregnancy [see Use in Specific Populations (8.1)]. Advise females of reproductive potential to use effective contraception during treatment with TALZENNA and for at least months after the last dose. Advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for at least months after receiving the last dose of TALZENNA [see Warnings and Precautions (5.3), Use in Specific Populations (8.1, 8.3)].. Lactation: Advise patients not to breastfeed while taking TALZENNA and for at least month after receiving the last dose [see Use in Specific Populations (8.2)].

PHARMACOKINETICS SECTION.

12.3 Pharmacokinetics. After oral administration of mg TALZENNA once daily in patients, the recommended dose, the geometric mean [% coefficient of variation (CV%)] of AUC and maximum observed plasma concentration (Cmax) of talazoparib at steady-state was 208 (37%) ng.hr/mL and 16.4 (32%) ng/mL, respectively. The pharmacokinetics (PK) of talazoparib is linear from 0.025 mg to mg (2 times the recommended dose). The median accumulation ratio of talazoparib following repeated oral administration of mg once daily was in the range of 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within to weeks.. AbsorptionFollowing oral administration of talazoparib, the median time to Cmax (Tmax) was generally between to hours after dosing.. Food Effect Following single oral dose of 0.5 mg TALZENNA with high-fat, high-calorie food (approximately 800 to 1000 calories with 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively), the mean Cmax of talazoparib was decreased by 46%, the median Tmax was delayed from to hours, and AUCinf was not affected.. DistributionThe mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.. EliminationThe mean terminal plasma half-life (+-standard deviation) of talazoparib is 90 (+-58) hours, and the mean apparent oral clearance (inter-subject variability) is 6.45 L/h (31.1%) in cancer patients.. MetabolismTalazoparib undergoes minimal hepatic metabolism. The identified metabolic pathways of talazoparib in humans include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation.. ExcretionExcretion of talazoparib in urine was the major route of elimination. Approximately 68.7% (54.6% unchanged) of the total administered radioactive dose [14C]talazoparib was recovered in urine, and 19.7% (13.6% unchanged) was recovered in feces.. Specific PopulationsAge (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, Others, and 63 Not Reported), body weight (36 to 162 kg), and mild to severe hepatic impairment based on NCI criteria had no clinically relevant effect on the PK of talazoparib.. Pediatric PatientsThe PK of talazoparib have not been evaluated in patients <18 years of age.. Patients with Renal Impairment Talazoparib steady-state total exposure (AUC0-24) increased by 12%, 43%, and 163% in patients with mild (eGFR 60 89 mL/min/1.73 m2), moderate (eGFR 30 59 mL/min/1.73 m2), and severe (eGFR 15 29 mL/min/1.73 m2) renal impairment, respectively, relative to patients with normal renal function (eGFR >= 90 mL/min/1.73 m2). Talazoparib steady-state peak concentration (Cmax) increased by 11%, 32%, and 89% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis. There was no evidence of relationship between the protein binding of talazoparib and renal function.. Drug Interaction Studies Effect of Other Drugs on TalazoparibEffect of P-gp inhibitors: In patients with advanced solid tumors, coadministration of P-gp inhibitor (multiple 100 mg twice-daily doses of itraconazole) with single 0.5 mg talazoparib dose increased talazoparib AUCinf and Cmax by approximately 56% and 40%, respectively. Population PK analysis showed that coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil in clinical studies increased talazoparib exposure by 45% [see Dosage and Administration (2.5), Drug Interactions (7.1)]. Coadministration with P-gp inhibitors including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin in clinical studies increased talazoparib exposure by 8% [see Dosage and Administration (2.5), Drug Interactions (7)].Effect of P-gp inducers: In patients with advanced solid tumors, coadministration of P-gp inducer (multiple 600 mg once-daily doses of rifampin) with single mg talazoparib dose increased talazoparib Cmax by 37% with no effect on talazoparib exposure.Effect of BCRP inhibitors: The effect of BCRP inhibitors on PK of talazoparib has not been studied. Coadministration with BCRP inhibitors may increase talazoparib exposure [see Drug Interactions (7)].Effect of acid-reducing agents on talazoparib: Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor antagonists (H2RA), or other acid reducing agents has no effect on the absorption of talazoparib.. In Vitro StudiesTalazoparib is substrate of P-gp and BCRP transporters. Talazoparib is not substrate of organic anion transporting polypeptide [OATP]1B1, OATP1B3, organic cationic transporter [OCT]1, OCT2, organic anion transporter [OAT]1, OAT3, bile salt export pump [BSEP], multidrug and toxin extrusion [MATE]1, and MATE2-K.Talazoparib is not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5, or inducer of CYP1A2, CYP2B6, or CYP3A4.Talazoparib is not an inhibitor of transporters including P-gp, BCRP, OATP1B1, OATP1B3, OCT1, OCT2, OAT1, OAT3, BSEP, MATE1, and MATE2-K.Talazoparib is not an inhibitor of uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15).

WARNINGS AND PRECAUTIONS SECTION.

5 WARNINGS AND PRECAUTIONS. Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML has been reported in <1% (3 out of 787, 0.4%) of 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). Myelodysplastic Syndrome/Acute Myeloid Leukemia (MDS/AML): MDS/AML has been reported in <1% (3 out of 787, 0.4%) of 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). 5.1Myelodysplastic 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 <1% (3 out of 787, 0.4%) of solid tumor patients treated with TALZENNA in clinical studies. The duration of TALZENNA treatment in these three patients prior to developing MDS/AML was months, 24 months, and 60 months respectively. These 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 weeks, refer the patient to hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.. 5.2Myelosuppression 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)].. 5.3Embryo-Fetal Toxicity Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to 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 mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 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 months following the last dose of TALZENNA [see Use in Specific Populations (8.1, 8.3), Nonclinical Toxicology (13.1)].