Talazoparib Capsules

Name: Talazoparib Capsules

Indications

TALZENNA is indicated for the treatment of adult patients with deleterious or suspected deleterious germline breast cancer susceptibility gene (BRCA)-mutated (gBRCAm) 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].

How supplied

Dosage Forms And Strengths

Capsules
  • 0.25 mg capsule with an ivory cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 0.25” in black)
  • 1 mg capsule with a light red cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 1” in black)

Storage And Handling

TALZENNA is supplied in strengths and package configurations as described in Table 6:

Table 6. TALZENNA Capsules

Package Configuration Capsule Strength (mg) NDC Print
Bottles of 30 capsules 0.25 NDC: 0069-0296-30 Ivory cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 0.25” in black).
Bottles of 30 capsules 1 NDC: 0069-1195-30 Light red cap (printed with “Pfizer” in black) and a white body (printed with “TLZ 1” in black).

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).

Distributed by: Pfizer Labs Division of Pfizer Inc, NY 10017. Revised: Oct 2018

Clinical pharmacology

Mechanism Of Action

Talazoparib is an inhibitor of poly (ADP-ribose) polymerase (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 BRCA 1 and 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 that expressed mutated or wild-type BRCA 1 and 2.

Pharmacodynamics

Cardiac Electrophysiology

The 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.

Pharmacokinetics

After oral administration of 1 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 2 mg (2 times the recommended dose). The median accumulation ratio of talazoparib following repeated oral administration of 1 mg once daily was in the range of 2.3 to 5.2. Talazoparib plasma concentrations reached steady-state within 2 to 3 weeks.

Absorption

Following oral administration of talazoparib, the median time to Cmax (Tmax) was generally between 1 to 2 hours after dosing.

Food Effect

Following a 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 1 to 4 hours, and AUCinf was not affected.

Distribution

The mean apparent volume of distribution of talazoparib is 420 L. In vitro, protein binding of talazoparib is 74% and is independent of talazoparib concentration.

Elimination

The 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.

Metabolism

Talazoparib 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.

Excretion

Excretion 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 Populations

Age (18 to 88 years), sex, race (361 White, 41 Asian, 16 Black, 9 Others, and 63 Not Reported), and body weight (36 to 162 kg) had no clinically relevant effect on the PK of talazoparib.

Pediatric Patients

The pharmacokinetics of talazoparib have not been evaluated in patients <18 years of age.

Patients With Renal Impairment

Talazoparib CL/F was decreased by 14.4% in patients with mild renal impairment (CLcr 60 -89 mL/min) and 37.1% in patients with moderate renal impairment (CLcr 30 -59 mL/min), when compared to patients with normal renal function (CLcr ≥ 90 mL/min). The PK of talazoparib have not been studied in patients with severe renal impairment (CLcr < 30 mL/min) or in patients requiring hemodialysis.

Patients With Hepatic Impairment

Mild hepatic impairment (total bilirubin ≤1.0 x ULN and AST > ULN, or total bilirubin >1.0 to 1.5 x ULN and any AST) had no effect on the PK of talazoparib. The PK of talazoparib have not been studied in patients with moderate (total bilirubin >1.5 to 3.0 x ULN and any AST) or severe hepatic impairment (total bilirubin >3.0 x ULN and any AST).

Drug Interaction Studies

Effect Of Other Drugs On Talazoparib

Effect of P-gp inhibitors:

Coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil in clinical studies increased talazoparib exposure by 45% [see DOSAGE AND ADMINISTRATION , DRUG INTERACTIONS].

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 , DRUG INTERACTIONS].

Effect of P-gp inducers:

The effect of P-gp inducers on PK of talazoparib has not been studied.

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].

Effect of acid-reducing agents on talazoparib:

Coadministration of acid-reducing agents including proton pump inhibitors (PPI), histamine receptor 2 antagonists (H2RA), or other acid reducing agents has no effect on the absorption of talazoparib.

In Vitro Studies

Talazoparib is a substrate of P-gp and BCRP transporters.

Talazoparib is not a 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

EMBRACA Study (NCT01945775)

Deleterious or Suspected Deleterious Germline BRCA-mutated (gBRCAm) HER2-negative Locally Advanced or Metastatic Breast Cancer

EMBRACA (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 1 mg or healthcare provider's choice of chemotherapy (capecitabine, eribulin, gemcitabine, or vinorelbine) until disease progression or unacceptable toxicity. Randomization was 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 history of central nervous system (CNS) metastasis (yes versus no).

Patients received no more than 3 prior cytotoxic chemotherapy regimens for their metastatic or locally advanced disease. Patients were required to have received treatment with an anthracycline and/or a 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 1 of the 4 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 a PARP inhibitor was permitted. Of the 431 patients randomized in the EMBRACA study, 408 (95%) were centrally confirmed to have a deleterious or suspected deleterious gBRCAm using a clinical trial assay; out of which 354 (82%) were confirmed using the BRACAnalysis CDx®. BRCA mutation status (breast cancer susceptibility gene 1 [BRCA1] positive or breast cancer susceptibility gene 2 [BRCA2] positive) was similar across both treatment arms.

The median age of patients treated with TALZENNA was 45 years (range 27 to 84) and 50 years (range 24 to 88) 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 0 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 a 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). A statistically significant improvement in PFS was demonstrated for TALZENNA compared with chemotherapy. A 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 (line of therapy, TNBC status, and history of CNS metastases). The overall survival (OS) data were not mature at the time of the final PFS analysis (38% of patients had died). Efficacy data from the EMBRACA study are summarized in Table 5, and the Kaplan-Meier curves for PFS are shown in Figure 1.

Table 5. Summary of Efficacy Results - EMBRACA Study

  TALZENNA Chemotherapy
Progression-Free Survival by BICR N=287 N=144
  Events, number (%) 186 (65) 83 (58)
  Median months (95% CI) 8.6 (7.2, 9.3) 5.6 (4.2, 6.7)
  Hazard Ratio (95% CI)a 0.54 (0.41, 0.71)
  p-valueb p<0.0001
Patients with Measurable Disease by Investigatorc N=219 N=114
  Objective Response Rate, % (95% CI)d 50.2 (43.4, 57.0) 18.4 (11.8, 26.8)
  Duration of Response Mediane months (95% CI) 6.4 (5.4, 9.5) 3.9 (3.0, 7.6)
Abbreviations: BICR=blinded independent central review; CI=confidence interval.
a. Hazard ratio is estimated from a 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).
b. P-values from stratified log-rank test (2-sided).
c. Conducted in intent-to-treat (ITT) population with measurable disease at baseline.
d. Response rate based on confirmed responses.
e. Median estimated from Kaplan-Meier probabilities.

Figure 1. Kaplan-Meier Curves of PFS - EMBRACA Study

Patient information

TALZENNA™
(Tal-ZEN-ah)
(talazoparib) capsules

What is the most important information I should know about TALZENNA?

TALZENNA 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 a sign of serious problems, including MDS or AML. Tell your healthcare provider if you have any of the following symptoms during treatment with TALZENNA:

  • weakness
  • weight loss
  • fever
  • frequent infections
  • blood in urine or stool
  • shortness of breath
  • feeling very tired
  • bruising or bleeding more easily

Your healthcare provider will do blood tests to check your blood cell counts:

  • before treatment with TALZENNA
  • every month during treatment with TALZENNA
  • weekly if you have low blood cell counts that last a 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 TALZENNA?

TALZENNA is a prescription medicine used to treat adults with:

  • a certain type of breast cancer (human epidermal growth factor receptor 2 [HER2]-negative), and
  • an abnormal inherited BRCA gene, and
  • whose cancer has spread to other parts of the body (locally advanced or metastatic).

Your healthcare provider will perform a 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 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 a 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 7 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 4 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 1 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 a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine.

How should I take TALZENNA?

  • 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 1 time a 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 a dose of TALZENNA or vomit, take your next dose at your regular time. Do not take an extra dose to make up for a 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 TALZENNA?

TALZENNA may cause serious side effects, including:

See “What is the most important information I should know about TALZENNA?”

The most common side effects of TALZENNA include:

  • tiredness or weakness
  • low number of red or white blood cells
  • nausea
  • low number of platelets
  • headache
  • loss of appetite
  • diarrhea
  • vomiting
  • hair loss

TALZENNA may cause fertility problems in males. This may affect your ability to father a child. Talk to your healthcare provider if this is a 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 I store TALZENNA?

Store TALZENNA at 68°F to 77°F (20°C to 25°C ).

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 a Patient Information leaflet. Do not use TALZENNA for a 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 TALZENNA?

Active ingredient: talazoparib tosylate

Inactive ingredients: silicified microcrystalline cellulose (sMCC). The white and ivory and white and light red opaque 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.

This Patient Information has been approved by the U.S. Food and Drug Administration.

Side effects

The following clinically significant adverse reactions are described elsewhere in the labeling:

  • Myelodysplastic Syndrome/Acute Myeloid Leukemia [see WARNINGS AND PRECAUTIONS]
  • Myelosuppression [see WARNINGS AND PRECAUTIONS]

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Treatment Of GBRCAm HER2-Negative Locally Advanced Or Metastatic Breast Cancer

EMBRACA

The safety of TALZENNA as monotherapy was evaluated in gBRCAm patients with HER2-negative locally advanced or metastatic breast cancer who had previously received no more than 3 lines of chemotherapy for the treatment of locally advanced/metastatic disease. EMBRACA was a randomized, open-label, multi-center study in which 412 patients received either TALZENNA 1 mg once daily (n=286) or a chemotherapy agent (capecitabine, eribulin, gemcitabine, or vinorelbine) of the healthcare provider's choice (n=126) until disease progression or unacceptable toxicity. The median duration of study treatment was 6.1 months in patients who received TALZENNA and 3.9 months in patients who received chemotherapy. Dosing interruptions due to an adverse reaction of any grade occurred in 65% of patients receiving TALZENNA and 50% of those receiving chemotherapy; dose reductions due to any cause occurred in 53% of TALZENNA patients and 40% of chemotherapy patients. Permanent discontinuation due to adverse reactions occurred in 5% of TALZENNA patients and 6% chemotherapy patients.

Table 2 and Table 3 summarize the most common adverse reactions and laboratory abnormalities, respectively, in patients treated with TALZENNA or chemotherapy in the EMBRACA study.

Table 3. Adverse Reactionsa (in ≥20% of Patients Receiving TALZENNA) in EMBRACA

Adverse Reactions TALZENNA
N=286 (%)
Chemotherapy
N=126 (%)
Grades
1-4
Grade 3 Grade 4 Grades
1-4
Grade 3 Grade 4
Blood and lymphatic system disorders
Anemiab 53 38 1 18 4 1
Neutropeniac 35 18 3 43 20 16
Thrombocytopeniad 27 11 4 7 2 0
Metabolism and nutrition disorders
Decreased appetite 21 <1 0 22 1 0
Nervous system disorders
Headache 33 2 0 22 1 0
Gastrointestinal disorders
Nausea 49 <1 0 47 2 0
Vomiting 25 2 0 23 2 0
Diarrhea 22 1 0 26 6 0
Skin and subcutaneous tissue disorders
Alopeciae 25 0 0 28 0 0
General disorders and administration site conditions
Fatiguef 62 3 0 50 5 0
Abbreviations: AR=adverse reaction; CTCAE=Common Terminology Criteria for Adverse Events; NCI=National Cancer Institute;
N=number of patients.
a. Graded according to NCI CTCAE 4.03.
b. Includes anemia, hematocrit decreased, hemoglobin decreased, and red blood cell count decreased.
c. Includes febrile neutropenia, neutropenia and neutrophil count decreased.
d. Includes thrombocytopenia and platelet count decreased.
e. For TALZENNA, Grade 1 in 23%, and Grade 2 in 2%. For the chemotherapy arm, Grade 1 in 20%, and Grade 2 in 8%.
f. Includes fatigue and asthenia.

The following adverse reactions have been identified in <20% of the 286 patients receiving TALZENNA, and thus were not included in Table 3: abdominal pain (19%), dizziness (17%), leukopenia (17%), dysgeusia (10%), dyspepsia (10%), stomatitis (8%), and lymphopenia (7%).

Table 4 Laboratory Abnormalities Reported in ≥25% of Patients in EMBRACA

  EMBRACA Study
TALZENNA
Na=286 (%)
Chemotherapy
Na=126 (%)
Parameter Grades 1-4 Grade 3 Grade 4 Grades 1-4 Grade 3 Grade 4
Decrease in hemoglobin 90 39 0 77 6 0
Decrease in leukocytes 84 14 0.3 73 22 2
Decrease in neutrophils 68 17 3 70 21 17
Decrease in lymphocytes 76 17 0.7 53 8 0.8
Decrease in platelets 55 11 4 29 2 0
Increase in glucoseb 54 2 0 51 2 0
Increase in aspartate aminotransferase 37 2 0 48 3 0
Increase in alkaline phosphatase 36 2 0 34 2 0
Increase in alanine aminotransferase 33 1 0 37 2 0
Decrease in calcium 28 1 0 16 0 0
Abbreviation: N=number of patients.
a. This number represents the safety population. The derived values in the table are based on the total number of evaluable patients for each laboratory parameter.
b. This number represents non-fasting glucose.

Read the entire FDA prescribing information for Talzenna (Talazoparib Capsules)

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