Talzenna

1 INDICATIONS AND USAGE TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for: Breast Cancer • As a single agent, for the treatment of adult patients with deleterious or suspected deleterious germline BRCA -mutated (g BRCA m) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA. ( 1.1 ) HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) • In combination with enzalutamide for the treatment of adult patients with HRR gene-mutated metastatic castration-resistant prostate cancer (mCRPC). ( 1.2 ) 1.1 BRCA -mutated (g BRCA m) HER2-negative Locally Advanced or Metastatic Breast Cancer TALZENNA is indicated as a single agent for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene ( BRCA )-mutated (g BRCA m) human epidermal growth factor receptor 2 (HER2)-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA [see Dosage and Administration (2.1) ] . 1.2 HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer (mCRPC) TALZENNA is indicated in combination with enzalutamide for the treatment of adult patients with homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC) [see Dosage and Administration (2.3) ] .

2 DOSAGE AND ADMINISTRATION • Take TALZENNA with or without food. ( 2.4 ) Breast Cancer • The recommended dosage of TALZENNA is 1 mg taken orally once daily until disease progression or unacceptable toxicity. ( 2.2 ) • For adverse reactions, consider dosing interruption or dose reduction. ( 2.5 ) HRR Gene-Mutated mCRPC • The recommended dosage of TALZENNA is 0.5 mg taken orally once daily in combination with enzalutamide until disease progression or unacceptable toxicity. ( 2.3 ) • Patients should also receive a gonadotropic-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. ( 2.3 ) 2.1 Patient Selection Information on the FDA-approved tests for the detection of genetic mutations is available at http://www.fda.gov/companiondiagnostics . g BRCA m HER2-negative Locally Advanced or Metastatic Breast Cancer Select patients for the treatment of advanced breast cancer with TALZENNA based on the presence of germline BRCA mutations [see Indications and Usage (1.1) , Clinical Studies (14.1) ] . HRR Gene-mutated Metastatic Castration-Resistant Prostate Cancer Select patients for the treatment of HRR gene-mutated mCRPC with TALZENNA based on the presence of alterations in genes directly or indirectly involved in HRR (ATM, ATR, BRCA1, BRCA2, CDK12, CHEK2, FANCA, MLH1, MRE11A, NBN, PALB2, or RAD51C) [see Indications and Usage (1.2) , Clinical Studies (14.2) ] . An FDA-approved test for the detection of HRR gene mutations for use with TALZENNA is not currently available. 2.2 Recommended Dosage for g BRCA m HER2-negative Locally Advanced or Metastatic Breast Cancer The recommended dosage of TALZENNA is 1 mg taken orally once daily, until disease progression or unacceptable toxicity. 2.3 Recommended Dosage for HRR Gene-mutated mCRPC The recommended dosage of TALZENNA is 0.5 mg taken orally once daily in combination with enzalutamide until disease progression or unacceptable toxicity. Refer to the enzalutamide prescribing information for recommended enzalutamide dosing information. Patients receiving TALZENNA and enzalutamide should also receive a gonadotropin-releasing hormone (GnRH) analog concurrently or should have had bilateral orchiectomy. 2.4 Administration Take TALZENNA with or without food. Swallow TALZENNA capsules whole. Do not open or dissolve. If a patient vomits or misses a dose of TALZENNA, instruct them to take the next prescribed dose at the usual time. 2.5 Dosage 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 1 and Table 2. Treatment with TALZENNA should be discontinued if more than three dose reductions are required. g BRCA m HER2-negative Locally Advanced or Metastatic Breast Cancer Table 1. Dose Reduction Levels for Adverse Reactions—Breast Cancer Dose Reductions Dose Level Recommended starting dose 1 mg once daily First dose reduction 0.75 mg once daily Second dose reduction 0.5 mg once daily Third dose reduction 0.25 mg once daily HRR Gene-mutated mCRPC Table 2. Dose Reduction Levels for Adverse Reactions—mCRPC Dose Reductions Dose Level Recommended starting dose 0.5 mg once daily First dose reduction 0.35 mg once daily Second dose reduction 0.25 mg once daily Third dose reduction 0.1 mg once daily Refer to the enzalutamide prescribing information for dose modifications for adverse reactions associated with enzalutamide. g BRCA m HER2-negative Locally Advanced or Metastatic Breast Cancer and HRR Gene-mutated mCRPC Monitor complete blood counts monthly and as clinically indicated [see Warnings and Precautions (5.2) ] . Table 3. Dose Modification and Management for Adverse Reactions Adverse Reactions Withhold TALZENNA Until Levels Resolve to Resume TALZENNA Hemoglobin <8 g/dL ≥9 g/dL Resume TALZENNA at a reduced dose Platelet count <50,000/μL ≥75,000/μL Neutrophil count <1,000/μL ≥1500/μL Non-hematologic Grade …

3 DOSAGE FORMS AND STRENGTHS Capsules: Each capsule is a liquid-filled soft-gelatin capsule with the following description. Table 4. Dosage Forms and Strengths Strength Description 0.1 mg Red oval capsule (printed with “TLZ” and “010”) 0.25 mg Yellow oblong capsule (printed with “TLZ” and “025”) 0.35 mg Pink oblong capsule (printed with “TLZ” and “035”) 0.5 mg Pale orange oblong capsule (printed with “TLZ” and “050”) 0.75 mg Red oblong capsule (printed with “TLZ” and “075”) 1 mg Reddish brown oblong capsule (printed with “TLZ” and “1”) Capsules: 0.1 mg, 0.25 mg, 0.35 mg, 0.5 mg, 0.75 mg, and 1 mg ( 3 )

4 CONTRAINDICATIONS None. None. ( 4 )

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 adverse reactions (≥20%) as a single agent, including laboratory abnormalities, are: • Hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite. ( 6.1 ) Most common adverse reactions (≥10%) in combination with enzalutamide, including laboratory abnormalities, are: • Hemoglobin decreased, neutrophils decreased, lymphocytes decreased, fatigue, platelets decreased, calcium decreased, nausea, decreased appetite, sodium decreased, phosphate decreased, fractures, magnesium decreased, dizziness, bilirubin increased, potassium decreased, and dysgeusia. ( 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. The data described in the WARNINGS AND PRECAUTIONS section reflect exposure to single agent TALZENNA in solid tumor clinical studies, including 286 patients enrolled in EMBRACA trial and to TALZENNA 0.5 mg daily in combination with enzalutamide in 511 patients enrolled in the TALAPRO-2 trial that included 197 patients with HRR gene-mutated mCRPC. g BRCA m HER2-negative Locally Advanced or Metastatic Breast Cancer EMBRACA The safety of TALZENNA as a single agent was evaluated in g BRCA m 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 [see Clinical Studies (14.1) ] . 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. Serious adverse reactions of TALZENNA occurred in 32% of patients. Serious adverse reactions reported in >2% of patients included anemia (6%) and pyrexia (2%). Fatal adverse reactions occurred in 1% of patients, including cerebral hemorrhage, liver disorder, veno-occlusive liver disease, and worsening neurological symptoms (1 patient each). Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA; dose reductions due to any cause occurred in 53% of TALZENNA patients. The most common (≥20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased, neutrophils decreased, lymphocytes decreased, platelets decreased, fatigue, glucose increased, aspartate aminotransferase increased, alkaline phosphatase increased, alanine aminotransferase increased, calcium decreased, nausea, headache, vomiting, alopecia, diarrhea, and decreased appetite. Table 5 and Table 6 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study. Table 5. Adverse Reactions Graded according to NCI CTCAE 4.03. (≥20%) in Patients Receiving TALZENNA in EMBRACA Abbreviation: N=number of …

7 DRUG INTERACTIONS • P-gp Inhibitors : Reduce the dose when coadministered with certain P-gp inhibitors. Monitor for increased adverse reactions. ( 2.7 , 7.1 ) • BCRP Inhibitors : Monitor for potential increased adverse reactions. ( 7.1 ) 7.1 Effect of Other Drugs on TALZENNA Effect of P-gp Inhibitors Breast Cancer Avoid coadministration of TALZENNA with the following P-gp inhibitors: itraconazole, amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the dose of TALZENNA [see Dosage and Administration (2.7) ] . When the P-gp inhibitor is discontinued, increase the dose of TALZENNA [see Dosage and Administration (2.7) ] . Coadministration of TALZENNA with these P-gp inhibitors increased talazoparib concentrations [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions. Monitor for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with other P-gp inhibitors [see Dosage and Administration (2.5) ] . HRR Gene-mutated mCRPC The effect of coadministration of P-gp inhibitors on talazoparib exposure when TALZENNA is taken with enzalutamide has not been studied. Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a P-gp inhibitor [see Dosage and Administration (2.5) ] . Effect of Breast Cancer Resistance Protein (BCRP) Inhibitors Monitor patients for increased adverse reactions and modify the dosage as recommended for adverse reactions when TALZENNA is coadministered with a BCRP inhibitor [see Dosage and Administration (2.5) ] . Coadministration of TALZENNA with BCRP inhibitors may increase talazoparib exposure [see Clinical Pharmacology (12.3) ] , which may increase the risk of adverse reactions.

8 USE IN SPECIFIC POPULATIONS • Lactation : Advise women not to breastfeed. ( 8.2 ) • Renal Impairment : Reduce the dose and monitor for increased adverse reactions for patients with moderate or severe renal impairment. ( 2.6 , 8.7 ) 8.1 Pregnancy Risk Summary Based on findings from animal studies and its mechanism of action [see Clinical Pharmacology (12.1) ] , TALZENNA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on TALZENNA use in pregnant women to inform a 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 1 mg daily (see Data ) . Apprise pregnant women and females of reproductive potential of the potential risk to a 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 Data In 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 of 1 mg daily). A 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 Summary There 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 a breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for 1 month after the last dose. 8.3 Females and Males of Reproductive Potential TALZENNA can cause fetal harm when administered to pregnant women [see Use in Specific Populations (8.1) ] . Pregnancy Testing Verify pregnancy status in females of reproductive potential prior to initiating TALZENNA treatment. Contraception Females Advise females of reproductive potential to use effective contraception during treatment and for 7 months following the last dose of TALZENNA. Males Based 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 4 months following the last dose [see Use in Specific Populations (8.1) , Nonclinical Toxicology (13.1) ] . Infertility Males Based 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 1 mg daily as a single agent, 85 (17%) patients were ≥65 years of age, and this included 19 (4%) patients who were ≥75 years old. There were 5 patients ≥85 years old. In the TALAPRO-2 trial, of 197 patients who received TALZENNA, 77% were ≥65 years of age, while 30% were ≥75 years of age. No overall differences in safety or effectiveness of TALZENNA were observed between these patients and younger patients. 8.6 Hepatic Impairment No dosage modification is recommended for patients with hepatic impairment [see Clinical Pharmacology (12.3) ] . 8.7 Renal Impairment Reduce the r …

12.1 Mechanism of Action Talazoparib is an inhibitor of PARP enzymes, including PARP1 and PARP2, which play a role in DNA repair. In vitro studies with cancer cell lines that harbored defects in DNA repair genes, including BRCA1 and BRCA2 , 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 patient-derived xenograft breast cancer models bearing mutated BRCA1 or mutated BRCA2 or wild type BRCA1 and BRCA2 .

11 DESCRIPTION Talazoparib is an inhibitor of mammalian polyadenosine 5'-diphosphoribose (ADP-ribose) polymerase (PARP) enzymes. TALZENNA contains talazoparib tosylate. The chemical name of talazoparib tosylate is (8 S ,9 R )-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1 H -1,2,4-triazol-5-yl)-2,7,8,9-tetrahydro-3 H -pyrido[4,3,2- de ]phthalazin-3-one 4-methylbenzenesulfonate (1:1). The chemical formula of talazoparib tosylate is C 26 H 22 F 2 N 6 O 4 S, and the relative molecular mass is 552.56 Daltons. The chemical structure of talazoparib tosylate is shown below: Talazoparib tosylate is a white to yellow solid. TALZENNA capsules for oral use are available as liquid-filled soft gelatin capsules. Each capsule contains 0.1 mg, 0.25 mg, 0.35 mg, 0.5 mg, 0.75, or 1 mg of talazoparib equivalent to 0.145 mg, 0.363 mg, 0.509 mg, 0.727 mg, 1.09 mg, or 1.453 mg talazoparib tosylate, respectively. TALZENNA capsules contain the following inactive ingredients: gelatin, glycerol, iron oxide (red), iron oxide (yellow), polyethylene glycol 400, purified water, sorbitol, titanium dioxide, and tocopherol. Chemical Structure

10 OVERDOSAGE There is no specific treatment in the event of TALZENNA overdose, and symptoms of overdose have not been established. In the event of overdose, discontinue treatment with TALZENNA, consider gastric decontamination, follow general supportive measures, and treat symptomatically.

16 HOW SUPPLIED/STORAGE AND HANDLING TALZENNA is supplied in strengths and package configurations as described in Table 12: Table 12. TALZENNA Capsules Package Configuration Capsule Strength (mg) NDC Print Bottles of 30 capsules 0.1 0069-0252-30 Red oval liquid-filled soft gelatin capsule printed with “TLZ” and “010”. Bottles of 30 capsules 0.25 0069-0353-30 Yellow oblong liquid-filled soft gelatin capsule printed with “TLZ” and “025”. Bottles of 30 capsules 0.35 0069-0454-30 Pink oblong liquid-filled soft gelatin capsule printed with “TLZ” and “035”. Bottles of 30 capsules 0.5 0069-0546-30 Pale orange oblong liquid-filled soft gelatin capsule printed with “TLZ” and “050”. Bottles of 30 capsules 0.75 0069-0655-30 Red oblong liquid-filled soft gelatin capsule printed with “TLZ” and “075”. Bottles of 30 capsules 1 0069-0757-30 Reddish brown oblong liquid-filled soft gelatin capsule printed with “TLZ” and “1”. Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F). [See USP Controlled Room Temperature].