TALZENNA

TALZENNA (talazoparib) is indicated as: 
a monotherapy for the treatment of adult patients with a deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated human epidermal growth factor receptor 2 (HER2)-negative locally advanced (not amenable to curative radiation or surgery) or metastatic breast cancer, who have previously been treated with chemotherapy in the neoadjuvant, adjuvant or metastatic setting, unless patients were inappropriate for these treatments.

1.1 Pediatrics

Pediatrics (<18 years of age): The safety and efficacy of TALZENNA in children and adolescents <18 years of age have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

1.2 Geriatrics

Geriatrics (≥65 years of age): Of the 494 patients who received TALZENNA, 85 patients were ≥65 years of age. 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.

TALZENNA is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

4.1 Dosing Considerations

• Treatment with TALZENNA should be initiated and supervised by a physician experienced in the use of anticancer medicinal products.
• Detection of a deleterious or suspected deleterious mutation(s) in hereditary breast cancer-related BRCA1 and BRCA2 genes should be determined by an experienced laboratory using a validated test method prior to treatment initiation.

4.2 Recommended Dose and Dosage Adjustment

The recommended dose of TALZENNA is 1 mg capsule taken orally once daily.

The 0.25 mg capsule is available for dose reduction.

Patients should be treated until disease progression or unacceptable toxicity occurs.

Dose modifications

To manage adverse reactions, consider interruption of treatment or dose reduction based on severity and clinical presentation. Recommended dose reductions are indicated in Table 1.

Monitor complete blood counts monthly for the first 12 months of treatment and periodically thereafter and as clinically indicated (see 7 WARNINGS AND PRECAUTIONS).

During treatment with the 1 mg dose, switching from the 1 mg capsules to the 4 x 0.25 mg capsules is not recommended.

Concomitant treatment with inhibitors or inducers of P-glycoprotein (P-gp) 
Strong inhibitors of P-gp may lead to increased talazoparib exposure. Concomitant use of strong P-gp inhibitors during treatment with talazoparib should be avoided.

If coadministration with a strong P-gp inhibitor is unavoidable, the TALZENNA dose should be reduced to the next lower dose. When the strong P-gp inhibitor is discontinued, the TALZENNA dose should be increased (after 3 to 5 half-lives of the P-gp inhibitor) to the dose used prior to the initiation of the strong P-gp inhibitor (see Section 9.4 Drug-Drug Interactions).

Coadministration of rifampin, a strong P-gp inducer, had no significant impact on talazoparib exposure. No talazoparib dose adjustments are required when coadministered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied.

Concomitant treatment with inhibitors of Breast Cancer Resistance Protein (BCRP) 
The effect of coadministration of BCRP inhibitors with TALZENNA has not been studied. Therefore, concomitant use of strong BCRP inhibitors during treatment with talazoparib should be avoided (see Section 9.4 Drug-Drug Interactions).

Special populations

Hepatic impairment
No dose adjustment is required for patients with mild hepatic impairment (total bilirubin ≤1 × upper limit of normal [ULN] and aspartate aminotransferase (AST) > ULN, or total bilirubin >1.0 to 1.5 × ULN and any AST), moderate hepatic impairment (total bilirubin >1.5 to 3.0 × ULN and any AST), or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST) (see Section 10.3 Pharmacokinetics, Special Populations and Conditions, Hepatic Impairment).

Renal impairment 
No dose adjustment is required for patients with mild renal impairment (60 mL/min ≤ creatinine clearance [CrCl] < 90 mL/min). For patients with moderate renal impairment (30 mL/min ≤ CrCl < 60 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily. For patients with severe renal impairment (15 mL/min ≤ CrCL < 30 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily. TALZENNA has not been studied in patients requiring hemodialysis (see Section 10.3 Pharmacokinetics, Special Populations and Conditions, Renal Impairment).

Geriatric (≥65 years of age) 
No dose adjustment is necessary in elderly (≥65 years of age) patients (see Section 10.3 Pharmacokinetics, Special Populations and Conditions, Geriatrics).

Pediatric (<18 years) 
The safety and efficacy of TALZENNA in children and adolescents <18 years of age have not been established. Health Canada has not authorized an indication for pediatric use.

4.4 Administration

The capsule(s) should be swallowed whole, and must not be opened, crushed, chewed or dissolved.

The capsules should be taken at approximately the same time every day and can be taken with or without food.

4.5 Missed Dose

If the patient vomits or misses a dose, an additional dose should not be taken. The next prescribed dose should be taken at the usual time.

There is no specific treatment in the event of TALZENNA overdose, and symptoms of overdose are not established. In the event of overdose, treatment with TALZENNA should be stopped, and physicians should consider gastric decontamination, follow general supportive measures and treat symptomatically.

TALZENNA 0.25 mg capsules  
Opaque, size #4 hard hypromellose (HPMC) capsule with an ivory cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 0.25” in black).

TALZENNA 1 mg capsules  
Opaque, size #4 hard hypromellose (HPMC) capsule with a light red cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 1” in black).

General  
In order to receive TALZENNA, patients must have a deleterious or suspected deleterious germline mutation in a BRCA gene, as confirmed by an experienced laboratory using a validated BRCA assay. In the EMBRACA study, a majority of patient samples were sent to a centralized lab (Myriad Genetics) to confirm BRCA mutation status (BRACAnalysis).

Carcinogenesis and Mutagenesis 
Secondary primary malignancies have been reported in patients that received TALZENNA.

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.

Complete blood counts should be obtained at baseline and monitored monthly for signs of hematologic toxicity during treatment. If MDS/AML is confirmed, TALZENNA should be discontinued.

Driving and Operating Machinery

Due caution should be exercised when driving or operating a vehicle or potentially dangerous machinery. No studies have been conducted on the effects of talazoparib on the ability to drive or operate machinery. However, patients experiencing fatigue/asthenia or dizziness while taking talazoparib should exercise caution when driving or operating machinery.

Hematologic  
Myelosuppression consisting of anemia, neutropenia, and/or thrombocytopenia, have been reported in patients treated with TALZENNA. The frequency of Grade ≥ 3 for each event in patients who received TALZENNA at 1 mg daily in clinical studies was 35.2%, 17.4%, and 16.8%, respectively. The frequency of dose modifications for anemia, neutropenia, and thrombocytopenia was 33.0%, 15.8%, and 13.4%, respectively. Discontinuations due to these events were 0.6%, 0.2%, and 0.2%, respectively (see Section 8.1 Adverse Reaction Overview).

Do not start TALZENNA until patients have recovered from hematological toxicity caused by previous therapy (≤ Grade 1).

Precautions should be taken to monitor monthly for the first 12 months of treatment and periodically thereafter for hematology parameters (complete blood counts) and signs and symptoms associated with anemia, leukopenia/neutropenia, and/or thrombocytopenia in patients receiving TALZENNA. If such events occur, dose modifications (reduction or interruption) are recommended (see Section 8.1 Adverse Reaction Overview).

Supportive care with or without blood and/or platelet transfusions and/or administration of colony stimulating factors may be used as appropriate.

Sexual Health 
Reproduction 
Based on the mechanism of action and animal studies, talazoparib has demonstrated genotoxicity, reproductive organ toxicity, and embryofetal toxicity at subtherapeutic thresholds (see Fertility, section 7.1 Special Populations, Pregnant Women and Section 16 Non-Clinical-Toxicology). Therefore, talazoparib should not be given to pregnant patients or those who plan to become pregnant during treatment. Advise pregnant women of the potential risk to the fetus as TALZENNA can cause fetal harm when administered to a pregnant woman.

Women of childbearing potential should be advised to avoid becoming pregnant while receiving TALZENNA. A highly effective method of contraception is required for female patients of childbearing potential during treatment with TALZENNA, and for at least 7 months after completing therapy.

Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception (even after vasectomy), during treatment with TALZENNA and for at least 4 months after the final dose.

Male and female patients should not donate sperm or eggs during treatment and for 4 and 7 months after the last dose of TALZENNA, respectively.

Fertility 
There is no information on fertility in patients. Based on non-clinical findings in the testes and ovary, male and female fertility may be compromised by treatment with TALZENNA (see Section 16 Non-Clinical Toxicology).

Monitoring and Laboratory Tests

BRCA Testing 
Prior to treatment initiation, detection of a deleterious or suspected deleterious germline mutation(s) in a BRCA gene must be confirmed by an experienced laboratory using a validated test method.

Hematological testing  
Complete blood counts should be obtained at baseline and monitored monthly for the first 12 months of treatment and periodically thereafter for signs of hematologic toxicity during treatment. 

Pregnancy Testing  
A pregnancy test is recommended for females of reproductive potential prior to initiating TALZENNA treatment.

7.1 Special Populations

7.1.1 Pregnant Women

There are no clinical data from the use of TALZENNA in pregnant women. However, studies in animals have demonstrated genotoxicity and embryo-fetal toxicity including fetal malformations, decreased fetal weight, structural variations in bones and embryo-fetal death at sub therapeutic thresholds (see Section 16 Non-Clinical Toxicology). Therefore, TALZENNA can cause fetal harm when administered to a pregnant woman. TALZENNA should not be used during pregnancy or for women of childbearing potential not using contraception.

Advise male patients with female partners of reproductive potential and pregnant partners to use effective contraception (even after vasectomy), during treatment with TALZENNA and for at least 4 months after the final dose. If a female partner of a male patient receiving TALZENNA becomes pregnant, she should be apprised of the potential hazard to the fetus and the potential loss of the pregnancy.

7.1.2 Breast-feeding

It is unknown whether TALZENNA is excreted in human breast milk. A serious risk to newborns/infants cannot be excluded. Therefore, breastfeeding is not recommended during treatment with TALZENNA and for at least 1 month after the final dose.

7.1.3 Pediatrics

Pediatrics (<18 years of age): The safety and efficacy of TALZENNA in children and adolescents <18 years of age have not been established. Therefore, Health Canada has not authorized an indication for pediatric use.

7.1.4 Geriatrics

Geriatrics (≥65 years of age): Of the 494 patients who received TALZENNA, 85 patients were ≥65 years of age. 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.

8.1 Adverse Reaction Overview

The overall safety profile of TALZENNA is based on pooled data from 494 patients with a median duration of exposure of 5.4 months (range 0.03-61.1) who received TALZENNA at 1 mg daily in clinical studies for solid tumors, including 286 patients from a randomized Phase 3 study (EMBRACA) with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer and 83 patients from a nonrandomized Phase 2 study (ABRAZO) in patients with germline BRCA-mutated locally advanced or metastatic breast cancer.

Very common (≥10%) adverse reactions in patients receiving TALZENNA in these clinical studies were fatigue (57%), anemia (50%), nausea (44%), neutropenia (30%), thrombocytopenia (30%), headache (27%), diarrhea (23%), vomiting (22%), alopecia (22%), abdominal pain (21%), decreased appetite (20%), leukopenia (16%) and dizziness (14%).

The overall frequency of grade 3 and 4 AEs is 66%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (35%), neutropenia (17%), and thrombocytopenia (17%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (5%), dyspnea (2%), and pleural effusion (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving TALZENNA. Very common adverse reactions (≥ 10%) leading to dose modifications were anemia (33%), neutropenia (16%), and thrombocytopenia (13%).

Permanent discontinuation due to an adverse reaction occurred in 4% of patients receiving TALZENNA. The most common adverse event that led to treatment discontinuation is anemia (0.6%). Adverse events associated with death occurred in 4% of patients receiving TALZENNA. The events leading to death reported in more than 1 patient were breast cancer, dyspnea, general physical health deterioration, neoplasm progression, and ovarian cancer.

8.2 Clinical Trial Adverse Reactions

Because clinical trials are conducted under very specific conditions, the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The EMBRACA study, a randomized Phase 3 study with germline BRCA-mutated, HER2-negative locally advanced or metastatic breast cancer includes 286 patients treated with TALZENNA and 126 patients treated with chemotherapy. Chemotherapy included capecitabine (55 patients), eribulin (50), gemcitabine (12), and vinorelbine (9). The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy.

The overall frequency of grade ≥ 3 adverse events is 68%. The most common (≥ 10%) adverse reactions of CTCAE grade ≥ 3 are anemia (39%), neutropenia (21%), and thrombocytopenia (15%).

The overall frequency of serious adverse events (SAEs) is 32%. The most common SAEs are anemia (6%), and pyrexia (2%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 66% of patients receiving TALZENNA. Common adverse reactions (≥ 5%) leading to dose modifications were anemia (38%), neutropenia (19%), thrombocytopenia (11%), and decreased platelet count (7%).

In the EMBRACA study, 13 (5%) patients in the TALZENNA arm and 7 (6%) patients in the chemotherapy arm had an adverse reaction that was the primary reason for permanent study drug discontinuation. Anemia was the only AE reported in more than 1 patient that led to discontinuation on the TALZENNA arm. AEs leading to death occurred in 2% of receiving TALZENNA. AEs leading to death included general physical health deterioration (2 patients), cerebral hemorrhage, liver disorder, neurological symptom, and veno-occlusive liver disease (1 patient each).

Table 4 summarizes the adverse reactions from the EMBRACA study.

8.3 Less Common Clinical Trial Adverse Reactions

All ADVERSE REACTIONS occurred at > 1% and are presented in Table 4, ADVERSE REACTIONS, Clinical Trial Adverse Reactions

8.4 Abnormal Laboratory Findings: Hematologic, Clinical Chemistry and Other Quantitative Data

Tables 5 and 6 summarize the hematologic and chemistry laboratory parameters by grade in patients treated with TALZENNA or chemotherapy from the EMBRACA study.

9.2 Overview

Talazoparib is a substrate for drug transporters P-gp and BCRP and mainly eliminated by renal clearance as unchanged compound.

9.4 Drug-Drug Interactions

Agents that may affect talazoparib plasma concentrations

Effect of P-gp inhibitors  
Data from a drug-drug interaction study in patients with advanced solid tumors indicated that coadministration of multiple daily doses of a P-gp inhibitor, itraconazole 100 mg twice daily, with a single 0.5 mg talazoparib dose increased talazoparib total exposure (AUC_inf) and peak concentration (C_max) by approximately 56% and 40%, respectively, relative to a single 0.5 mg talazoparib dose administered alone. Population pharmacokinetic (PK) analysis has shown that concomitant use of strong P-gp inhibitors with TALZENNA increased talazoparib exposure by 44.7%, relative to TALZENNA given alone. Concomitant use of strong P-gp inhibitors should be avoided. If patients must be coadministered a strong P-gp inhibitor, those that result in ≥2-fold increase in the exposure of an in vivo probe P-gp substrate (including but not limited to amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, valspodar, and verapamil), the TALZENNA dose should be reduced (see Section 4.2 Recommended Dose and Dosage Adjustment).

Population PK analysis has shown that coadministration with relatively weak P-gp inhibitors (including azithromycin, atorvastatin, diltiazem, felodipine, fluvoxamine, and quercetin) in clinical studies had no significant effect on talazoparib exposure.

Effect of P-gp inducers 
Data from a drug-drug interaction study in patients with advanced solid tumors indicated that coadministration of single 1 mg talazoparib dose with multiple daily doses of a P-gp inducer, rifampin 600 mg, with rifampin co-administered 30 minutes before talazoparib on the day of talazoparib dosing, increased talazoparib C_max by 37% whereas AUC_inf was not affected relative to a single 1 mg talazoparib dose administered alone. This is probably the net effect of both P-gp induction and inhibition by rifampin under the tested conditions in the drug-drug interaction study. No talazoparib dose adjustments are required when coadministered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited to carbamazepine, phenytoin, and St. John’s wort) may decrease talazoparib exposure.

Effect of BCRP inhibitors  
The effect of BCRP inhibitors on PK of talazoparib has not been studied. Concomitant use of strong BCRP inhibitors (including but not limited to curcumin, cyclosporine, and elacridar [GF120918]) should be avoided (see Section 4.2 Recommended Dose and Dosage Adjustment).

Effect of acid-reducing agents 
Population PK analysis indicates that coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor 2 antagonists (H2RA), or other acid-reducing agents had no significant impact on the absorption of talazoparib.

The drugs listed in this table are based on either drug interaction case reports or studies, or potential interactions due to the expected magnitude and seriousness of the interaction (i.e., those identified as contraindicated).

9.5 Drug-Food Interactions

Food intake decreased the rate but not the extent of talazoparib absorption. Based on these results, TALZENNA can be administered with or without food (see Section 10.3 Pharmacokinetics, Absorption, the effect of food).

9.6 Drug-Herb Interactions

Interactions with herbal products have not been established.

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

10.1 Mechanism of Action

TALZENNA is an inhibitor of poly(adenosine diphosphate [ADP] ribose) polymerase (PARP) enzymes, PARP1, and PARP2. PARP enzymes are involved in cellular DNA damage response signaling pathways such as DNA repair, gene transcription, cell cycle regulation, and cell death. PARP inhibitors (PARPi) exert cytotoxic effects on cancer cells by 2 mechanisms, inhibition of PARP catalytic activity and by PARP trapping, whereby PARP protein bound to a PARPi does not readily dissociate from a DNA lesion, thus preventing DNA repair, replication, and transcription and ultimately leading to apoptosis and/or cell death. Treatment of cancer cell lines that are harboring defects in DNA repair genes with talazoparib single agent leads to double strand DNA breaks, resulting in decreased cell proliferation and increased apoptosis. The cytotoxicity observed with talazoparib against multiple tumor cell lines harboring mutations in the DNA damage response pathways, can be attributed to its inhibition of PARP catalytic activity and PARP trapping. Talazoparib anti-tumor activity was also observed in the patient-derived xenograft BRCA1 or BRCA2-mutant breast cancer models.

10.2 Pharmacodynamics

Cardiac electrophysiology 
The effect of talazoparib on cardiac repolarization was evaluated using time-matched electrocardiograms (ECGs) in assessing the relationship between the change of the QT interval corrected for heart rate (QTc) from baseline and the corresponding plasma talazoparib concentrations in 37 patients with advanced solid tumors. Talazoparib did not have a clinically relevant effect on QTc prolongation at the maximum clinically recommended dose of 1 mg once daily.

10.3 Pharmacokinetics

Talazoparib exposure generally increased proportionally with dose across the range of 0.025 mg to 2 mg after daily administration of multiple doses. Following repeated daily dosing of 1 mg talazoparib to patients, the geometric mean area under the plasma concentration-time curve (AUC) and maximum observed plasma concentration (C_max) of talazoparib at steady-state was in the range of 126 ng•hr/mL to 208 ng•hr/mL and 11.4 ng/mL to 19.1 ng/mL, respectively. Following repeated daily dosing, talazoparib plasma concentrations reached steady-state within 2 to 3 weeks. The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.33 to 5.15.

Absorption: Following oral administration of talazoparib, the median time to C_max (T_max) was generally between 1 to 2 hours after dosing under fasting conditions. An absolute bioavailability study has not been conducted in humans. However, based on urinary excretion data the absolute bioavailability is at least 54.6% with fraction absorbed of at least 68.7% (see Elimination).

The effect of food 
Food intake decreased the rate but not the extent of talazoparib absorption. Following a single oral dose of talazoparib with high-fat, high-calorie food (approximately 827 calories, 57% fat), the mean C_max of talazoparib was decreased by approximately 46%, the median T_max was delayed from 1 to 4 hours, while the AUC_inf was not affected. Based on these results, TALZENNA can be administered with or without food.

Distribution: The population mean apparent volume of distribution (V_ss/F) of talazoparib was 420 L. In vitro, talazoparib is approximately 74% bound to plasma proteins with no concentration dependence over the concentration range of 0.01 µM to 1 µM. Renal or hepatic impairment does not appear to impact talazoparib protein binding as there was no obvious trend in the mean talazoparib fraction of unbound drug (f_u) in human plasma in vivo with worsening renal or hepatic function.

Metabolism: Talazoparib undergoes minimal hepatic metabolism in humans. Following oral administration of a single 1 mg dose of [¹⁴C]talazoparib to humans, no major circulating metabolites were identified in plasma, and talazoparib was the only circulating drug-derived entity identified. No metabolites that individually represented more than 10% of the administered dose were recovered in the urine or feces. The identified metabolic pathways of talazoparib in humans include: 1) mono-oxidation; 2) dehydrogenation; 3) cysteine conjugation of mono-desfluoro-talazoparib; and 4) glucuronide conjugation.

In vitro, talazoparib was not an inhibitor of cytochrome (CYP)1A2, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2D6, or CYP3A4/5 or inducer of CYP1A2, CYP2B6, or CYP3A4 at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major intestinal, hepatic or renal membrane transporters (P-gp, BCRP, 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) at clinically relevant concentrations.

In vitro, talazoparib did not inhibit any of the major uridine-diphosphate glucuronosyltransferase (UGT) isoforms (1A1, 1A4, 1A6, 1A9, 2B7, and 2B15) at clinically relevant concentrations.

Elimination: The mean terminal plasma half-life of talazoparib was 89.8 hours and the population mean apparent oral clearance (CL/F) was 6.45 L/h in cancer patients. In 6 female patients with advanced solid tumors given a single oral dose of [¹⁴C]talazoparib, a mean of 68.7% and 19.7% of the total administered radioactive dose was recovered in urine and feces, respectively. Excretion of unchanged talazoparib in urine was the major route of elimination accounting for 54.6% of the administered dose, while unchanged talazoparib recovered in the feces accounted for 13.6%.

Special Populations and Conditions

Pediatrics: Pharmacokinetics of talazoparib have not been evaluated in patients < 18 years of age.

Age: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of age (ranging from 18 to 88 years) on the PK of talazoparib. The results have shown that age had no clinically relevant effect on the PK of talazoparib.

Sex: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of sex (53 males and 437 females) on the PK of talazoparib. The results have shown that sex had no clinically relevant effect on the PK of talazoparib.

Pregnancy and Breast-feeding: There are no data from the use of TALZENNA in pregnant women. Studies in animals have shown genotoxicity and embryo-fetal toxicity (see Section 16 Non-Clinical Toxicology). TALZENNA can cause fetal harm when administered to a pregnant woman. It is unknown whether TALZENNA is excreted in human breast milk. A risk to newborns/infants cannot be excluded and therefore breastfeeding is not recommended during treatment with TALZENNA and for at least 1 month after the final dose.

Race: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not reported) on the PK of talazoparib. The results have shown that ethnicity had no clinically relevant effect on the PK of talazoparib.

Hepatic Insufficiency: Based on a population PK analysis that included 490 patients, where 118 patients had mild hepatic impairment (total bilirubin ≤ 1.0 × ULN and AST > ULN, or total bilirubin > 1.0 to 1.5 × ULN and any AST), mild hepatic impairment had no effect on the PK of talazoparib. The PK of talazoparib in patients with normal hepatic function, mild hepatic impairment, moderate hepatic impairment (total bilirubin >1.5 to 3.0 × ULN and any AST), or severe hepatic impairment (total bilirubin >3.0 × ULN and any AST) was studied in a PK trial. Population PK analysis using data from this PK trial indicated that mild, moderate, or severe hepatic impairment had no significant impact on the PK of talazoparib.

Renal Insufficiency: Data from a PK trial in advanced cancer patients with varying degrees of renal impairment indicate that talazoparib total exposure (AUC_0-24) after multiple talazoparib once-daily doses did not change and increased by 85%, and 167% in patients with mild (60 mL/min ≤ CrCL <90 mL/min), moderate (30 mL/min ≤ CrCL <60 mL/min) and severe (15 mL/min ≤ CrCL < 30 mL/min) renal impairment, respectively, relative to patients with normal renal function (CrCL ≥90mL/min). Talazoparib C_max increased by 8%, 86%, and 93% in patients with mild, moderate, and severe renal impairment, respectively, relative to patients with normal renal function. Consistent with these findings, a population PK analysis that included 490 patients, where 132 patients had mild renal impairment, 33 patients had moderate renal impairment, and 1 patient had severe renal impairment, showed that talazoparib CL/F was decreased by 14.4% and 37.1% in patients with mild and moderate renal impairment, corresponding to 17% and 59% increase in AUC, respectively, when compared to patients with normal renal function. The PK of talazoparib has not been studied in patients requiring hemodialysis.

Obesity: A population PK analysis was conducted using data from 490 patients with cancer to evaluate the impact of body weight (ranging from 35.7 kg to 162 kg) on the PK of talazoparib. The results have shown that body weight had no clinically relevant effect on the PK of talazoparib.

Store between 15°C to 30°C. Maintain in original bottle to protect from light.

None

Control #: 250258 
February 2, 2022