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Talzenna

Generic Name: Talazoparib Tosylate
Class: Antineoplastic Agents
- PARP Inhibitors
- Poly(ADP-ribose) Polymerase Inhibitors
Chemical Name: (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
Molecular Formula: C19H14F2N6OC19H14F2N6O•C7H8O3S
CAS Number: 1207456-01-6

Medically reviewed by Drugs.com. Last updated on Jul 22, 2019.

Introduction

Antineoplastic agent; a potent and selective inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).1 5 6

Uses for Talzenna

Breast Cancer

Single-agent therapy for the treatment of confirmed or suspected deleterious germline BRCA-mutated (gBRCA-mutated) (as detected by an FDA-approved companion diagnostic test [BRACAnalysis CDx]), human epidermal growth factor receptor type 2 (HER2)-negative locally advanced or metastatic breast cancer.1 2

Talzenna Dosage and Administration

General

  • Confirm presence of deleterious germline BRCA mutation prior to initiation of therapy.1

  • Obtain CBC prior to initiation of therapy and monthly during therapy.1 (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

Restricted Distribution

  • Obtain talazoparib through specialty pharmacies.3

  • Contact manufacturer at 877-744-5675 or consult the Pfizer Oncology together website (https://www.pfizeroncologytogether.com/hcp) for specific availability information.3

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Swallow capsules whole; do not dissolve or open.1

Dosage

Available as talazoparib tosylate; dosage expressed in terms of talazoparib.1

Adults

Breast Cancer
Oral

1 mg once daily.1 Continue therapy until disease progression or unacceptable toxicity occurs.1

Avoid concomitant use of potent inhibitors of P-gp; if concomitant use cannot be avoided, reduce talazoparib dosage from 1 mg once daily to 0.75 mg once daily.1

General Dosage Modification
Oral

If adverse reactions occur, consider interruption of therapy or dosage reduction.1

If dosage reduction is necessary, reduce dosage to 0.75 mg once daily.1

If dosage reduction from 0.75 mg once daily is necessary, reduce dosage to 0.5 mg once daily.1

If further reduction is necessary, reduce dosage to 0.25 mg once daily.1

Permanently discontinue drug if 0.25 mg once daily is not tolerated.1

Dosage Modification for Hematologic Toxicity
Oral

For anemia (hemoglobin concentrations <8 g/dL), interrupt talazoparib therapy until hemoglobin concentrations ≥9 g/dL, and then resume at a reduced dosage.1 (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

For thrombocytopenia (platelet count <50,000/mm3), interrupt talazoparib therapy until platelet count ≥75,000/mm3, and then resume at a reduced dosage.1

For neutropenia (ANC <1000/mm3), interrupt talazoparib therapy until ANC ≥1500/mm3, and then resume at a reduced dosage.1

If MDS or AML is confirmed, discontinue talazoparib therapy.1

Dosage Modification for Nonhematologic Effects
Oral

If grade 3 or 4 nonhematologic toxicity occurs, interrupt talazoparib therapy until the toxicity resolves to grade 1 or less, and then consider dosage reduction or discontinuance of therapy.1

Prescribing Limits

Adults

Breast Cancer
Oral

Dosage <0.25 mg once daily not recommended.1

Special Populations

Hepatic Impairment

Mild hepatic impairment (total bilirubin concentration not exceeding ULN with AST concentration exceeding ULN or total bilirubin concentration exceeding ULN, but not >1.5 times the ULN, with any AST concentration): Dosage adjustment not necessary.1

Moderate to severe hepatic impairment (total bilirubin concentration >1.5 times the ULN, with any AST concentration): No specific dosage recommendations at this time.1 (See Hepatic Impairment under Cautions.)

Renal Impairment

Mild renal impairment (Clcr 60–89 mL/minute): Dosage adjustment not necessary.1

Moderate renal impairment (Clcr 30–59 mL/minute): Reduce initial dosage to 0.75 mg once daily.1

Severe renal impairment (Clcr <30 mL/minute) or dialysis: No specific dosage recommendations at this time.1 (See Renal Impairment under Cautions.)

Geriatric Patients

No specific dosage recommendations at this time.1 (See Geriatric Use under Cautions.)

Cautions for Talzenna

Contraindications

  • Manufacturer states none known.1

Warnings/Precautions

Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)

MDS and AML reported rarely in patients receiving talazoparib.1 All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents.1 The duration of talazoparib therapy in patients who developed MDS/AML ranged from 4–24 months.1

Monitor CBC counts at baseline and monthly thereafter.1 Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved.1

If prolonged hematologic toxicity occurs, interrupt therapy and monitor CBC counts weekly until recovery.1 If hematologic toxicity persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 If MDS/AML is confirmed, discontinue talazoparib.1

Hematologic Effects

Adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) may occur.1

Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved.1 Monitor CBC counts at baseline and monthly thereafter.1 If hematologic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of talazoparib may be necessary.1 (See Dosage Modification under Dosage and Administration.)

If hematologic toxicity develops and persists for >4 weeks following interruption of therapy, refer patient to a hematologist for further evaluation, including bone marrow analysis and cytogenetic testing of a blood sample.1 (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm based on mechanism of action and animal findings; embryotoxicity and teratogenicity demonstrated in animals.1

Confirmation of pregnancy status recommended prior to initiating talazoparib therapy.1 Avoid pregnancy during therapy.1 Women of reproductive potential should use effective contraceptive methods while receiving talazoparib and for ≥7 months after the drug is discontinued.1 Men who are partners with such women, including those who are pregnant, should use effective contraceptive methods while receiving the drug and for ≥4 months after the drug is discontinued.1 Apprise patients of potential fetal hazard if the drug is used during pregnancy.1

Impairment of Fertility

Results of animal studies suggest that talazoparib may impair male fertility.1 Effect on fertility in humans not known.1

Specific Populations

Pregnancy

May cause fetal harm.1 (See Fetal/Neonatal Morbidity and Mortality under Cautions.)

Confirmation of pregnancy status prior to initiation of therapy recommended.1

Lactation

Not known whether talazoparib is distributed into milk.1 Discontinue nursing during therapy and for ≥1 month after drug discontinuance.1

Pediatric Use

Safety and efficacy not established.1

Pharmacokinetic profile not established in patients <18 years of age.1

Geriatric Use

No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

Hepatic Impairment

Pharmacokinetics not altered by mild hepatic impairment; dosage adjustment not necessary in such patients.1 (See Hepatic Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics: Absorption.)

Not studied in patients with moderate or severe hepatic impairment.1

Renal Impairment

Decreased clearance in patients with mild or moderate renal impairment; dosage reduction recommended in patients with moderate renal impairment.1 (See Renal Impairment under Dosage and Administration and also see Special Populations under Pharmacokinetics: Elimination.)

Not studied in patients with severe renal impairment or in those receiving dialysis.1

Common Adverse Effects

Fatigue,1 anemia,1 nausea,1 neutropenia,1 headache,1 thrombocytopenia,1 alopecia,1 vomiting,1 diarrhea,1 decreased appetite,1 decreased hemoglobin concentrations,1 decreased WBC count,1 decreased ANC,1 decreased lymphocyte concentrations,1 elevated glucose concentrations,1 elevated AST/ALT concentrations,1 elevated alkaline phosphatase concentrations,1 decreased calcium concentrations.1

Interactions for Talzenna

In vitro, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or induce CYP isoenzymes 1A2, 2B6, or 3A4.1

In vitro, talazoparib is not an inhibitor of UGT 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15.1

In vitro, talazoparib is a substrate, but not an inhibitor, of P-gp and breast cancer resistance protein (BCRP).1 In vitro, talazoparib is not a substrate or inhibitor of organic anion transport protein (OATP) 1B1, OATP1B3, organic cation transporter (OCT) 1, OCT2, organic anion transporter (OAT) 1, OAT3, bile salt export pump (BSEP), and multidrug and toxic compound extrusion protein (MATE) 1 and MATE2K.1

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Because talazoparib undergoes minimal hepatic metabolism, pharmacokinetic interactions appear unlikely with inhibitors or inducers of CYP isoenzymes.1 4

Drugs Affecting Efflux Transport Systems

Potent P-gp inhibitors: Potential increased systemic exposure of talazoparib.1 Avoid concomitant use.1 If concomitant therapy cannot be avoided, reduce talazoparib dosage from 1 mg once daily to 0.75 mg once daily.1 (See Specific Drugs under Interactions.) If potent P-gp inhibitor is discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor.1

Moderate or weak P-gp inhibitors: No clinically meaningful effect on systemic exposure of talazoparib.1 4 Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur.1 4 (See Breast Cancer under Dosage and Administration and also see Specific Drugs under Interactions.)

BCRP inhibitors: Potential increased systemic exposure of talazoparib. Avoid concomitant use. If concomitant use cannot be avoided, monitor for signs of toxicity.1

Specific Drugs

Drug

Interaction

Comments

Amiodarone

Potent P-gp inhibitors (e.g., amiodarone): Increased systemic exposure of talazoparib by approximately 45%1 4

Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage1

If amiodarone discontinued, resume talazoparib (after 3–5 terminal half-lives of amiodarone) at dosage used prior to initiation of amiodarone1

Antacids

No clinically meaningful effect on talazoparib absorption1 4

Atorvastatin

Moderate/weak P-gp inhibitors (e.g., atorvastatin): No clinically meaningful effect on systemic exposure of talazoparib1 4

Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur1 4

Calcium-channel blocking agents (e.g., diltiazem, felodipine, verapamil)

Potent P-gp inhibitors (e.g., verapamil): Increased systemic exposure of talazoparib by approximately 45%1 4

Moderate/weak P-gp inhibitors (e.g., diltiazem, felodipine): No clinically meaningful effect on systemic exposure of talazoparib1 4

Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage1

If potent P-gp inhibitor discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor1

Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur1 4

Carvedilol

Potent P-gp inhibitors (e.g., carvedilol): Increased systemic exposure of talazoparib by approximately 45%1 4

Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage1

If carvedilol discontinued, resume talazoparib (after 3–5 terminal half-lives of carvedilol) at dosage used prior to initiation of carvedilol1

Fluvoxamine

Moderate/weak P-gp inhibitors (e.g., fluvoxamine): No clinically meaningful effect on systemic exposure of talazoparib1 4

Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur1 4

Histamine H2-receptor antagonists

No clinically meaningful effect on talazoparib absorption1 4

Itraconazole

Potent P-gp inhibitors (e.g., itraconazole): Increased systemic exposure of talazoparib by approximately 45%1 4

Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage1

If itraconazole discontinued, resume talazoparib (after 3–5 terminal half-lives of itraconazole) at dosage used prior to initiation of itraconazole1

Macrolides (azithromycin, clarithromycin)

Potent P-gp inhibitors (e.g., clarithromycin): Increased systemic exposure of talazoparib by approximately 45%1 4

Moderate/weak P-gp inhibitors (e.g., azithromycin): No clinically meaningful effect on systemic exposure of talazoparib1 4

Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage1

If potent P-gp inhibitor discontinued, resume talazoparib (after 3–5 terminal half-lives of the P-gp inhibitor) at dosage used prior to initiation of P-gp inhibitor1

Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur1 4

Proton-pump inhibitors

No clinically meaningful effect on talazoparib absorption1 4

Talzenna Pharmacokinetics

Absorption

Bioavailability

Pharmacokinetics are linear over a dosage range of 0.025–2 mg;1 8 median accumulation ratio is 2.3–5.2 following repeated administration of talazoparib 1 mg daily.1

Median time to peak plasma concentrations is 1–2 hours following oral administration.1

Steady-state concentrations are achieved within 2–3 weeks.1

Food

Administration with a high-fat, high-calorie meal (800–1000 calories with approximately 50–75% of calories from fat) delayed the time to peak concentrations by 3 hours and decreased mean peak plasma concentrations by 46%, but did not substantially affect the extent of absorption.1

Special Populations

Mild hepatic impairment (total bilirubin concentration not exceeding the ULN with AST concentration exceeding the ULN or total bilirubin concentration exceeding the ULN, but not >1.5 times the ULN, with any AST concentration) does not affect pharmacokinetics of talazoparib.1

Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Pharmacokinetics not studied.1

Severe renal impairment (Clcr <30 mL/minute) or dialysis: Pharmacokinetics not studied.1

Age, body weight, gender, or race does not affect pharmacokinetics of talazoparib.1

Distribution

Extent

Not known whether talazoparib is distributed into milk.1

Plasma Protein Binding

74% (independent of talazoparib concentration).1

Elimination

Metabolism

Minimal hepatic metabolism.1

Mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluorotalazoparib, and glucuronide conjugation.1

Elimination Route

Eliminated in urine (68.7%; 54.6% as unchanged drug) and feces (19.7%; 13.6% as unchanged drug).1

Half-life

Mean terminal half-life: 90 hours.1

Special Populations

In patients with mild (Clcr 60–89 mL/minute) or moderate (Clcr 30–59 mL/minute) renal impairment, clearance decreased by 14.4 or 37.1%, respectively, relative to individuals with normal renal function.1

Stability

Storage

Oral

Capsules

20–25°C (may be exposed to 15–30°C).1

Actions

  • Potent and selective inhibitor of mammalian PARP enzymes, including PARP-1 and PARP-2.1 5 6 PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.4 5

  • Talazoparib-induced cytotoxicity may involve inhibition of PARP enzymatic activity and increased formation of PARP-DNA complexes, which result in DNA damage, decreased cell proliferation, and apoptosis.1

  • PARP inhibitors, including talazoparib, appear to be selective for tumors cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).7

  • In vitro, ≥18-fold or 37-fold more potent than rucaparib and olaparib in BRCA-deficient or phosphatase and tensin homolog (PTEN)-deficient tumor cells lines, respectively.5 7

  • Substantially more potent than rucaparib and olaparib in estrogen receptor-negative, progesterone receptor-negative, and HER2-negative breast tumor cell lines harboring BRCA1 mutation.7

  • Exhibits antitumor activity of xenograft models of human cancer harboring either mutated or wild-type BRCA1/2.1

Advice to Patients

  • Importance of reading the manufacturer's patient information.1

  • Importance of advising patients to take talazoparib capsules once daily without regard to meals.1 Importance of advising patients to swallow talazoparib capsules whole and not to dissolve or open the capsules.1

  • If a dose is missed or vomited, importance of administering the next dose at the regularly scheduled time; an additional dose should not be administered to make up for a missed dose.1

  • Risk of MDS and AML.1 Importance of informing clinician if fatigue/asthenia, fever, weight loss, frequent infections, bruising, unusual bleeding (including hematuria or bloody stool), shortness of breath, abnormal CBC count, or requirement for blood product transfusion occurs.1

  • Risk of bone marrow suppression.1 Importance of hematologic monitoring during talazoparib therapy.1

  • Risk of fetal harm and pregnancy loss.1 Necessity of advising women of reproductive potential to use effective contraception during talazoparib therapy and for ≥7 months after the last dose of the drug.1 Necessity of advising men who are partners of such women, including those who are pregnant, that they should use effective contraception during talazoparib therapy and for ≥4 months after the last dose of the drug.1 Importance of women informing clinicians immediately if they are pregnant or become pregnant during therapy.1 If pregnancy occurs, advise pregnant women of potential risk to the fetus.1

  • Importance of advising women to avoid breast-feeding while receiving talazoparib and for ≥1 month following discontinuance of therapy.1

  • Importance of informing clinicians of existing or contemplated concomitant therapy, including prescription and OTC drugs and dietary or herbal supplements, as well as any concomitant illnesses.1

  • Importance of informing patients of other important precautionary information.1 (See Cautions.)

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

Distribution of talazoparib is restricted.3 (See Restricted Distribution under Dosage and Administration.)

Talazoparib Tosylate

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Capsules

0.25 mg (of talazoparib)

Talzenna

Pfizer

AHFS DI Essentials™. © Copyright 2020, Selected Revisions July 22, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

References

1. Pfizer. Talzenna (talazoparib tosylate) capsules prescribing information. New York, NY; 2018 Oct.

2. Litton JK, Rugo HS, Ettl J et al. Talazoparib in Patients with Advanced Breast Cancer and a Germline BRCA Mutation. N Engl J Med. 2018; 379:753-763. http://www.ncbi.nlm.nih.gov/pubmed/30110579?dopt=AbstractPlus

3. Pfizer. Specialty pharmacy distribution network. From the Pfizer Oncology together website. 2019 Jan. Accessed 2019 Mar 29. https://www.pfizeroncologytogether.com/sites/default/files/Specialty_Pharmacy_List.pdf

4. Food and Drug Administration. Center for Drug Evaluation and Research. Application number 211651Orig1s000: Multi-discipline review. From FDA website. https://www.accessdata.fda.gov/drugsatfda_docs/nda/2018/211651Orig1s000MultidisciplineR.pdf

5. Nur Husna SM, Tan HT, Mohamud R et al. Inhibitors targeting CDK4/6, PARP and PI3K in breast cancer: a review. Ther Adv Med Oncol. 2018; 10:1758835918808509. http://www.ncbi.nlm.nih.gov/pubmed/30542378?dopt=AbstractPlus

6. Guney Eskiler G, Cecener G, Egeli U et al. BMN 673 (talazoparib): A potent PARP inhibitor for triple negative breast cancer with different genetic profile. J Biochem Mol Toxicol. 2019; :e22286. http://www.ncbi.nlm.nih.gov/pubmed/30672063?dopt=AbstractPlus

7. Shen Y, Rehman FL, Feng Y et al. BMN 673, a novel and highly potent PARP1/2 inhibitor for the treatment of human cancers with DNA repair deficiency. Clin Cancer Res. 2013; 19:5003-15. http://www.ncbi.nlm.nih.gov/pubmed/23881923?dopt=AbstractPlus

8. de Bono J, Ramanathan RK, Mina L et al. Phase I, Dose-Escalation, Two-Part Trial of the PARP Inhibitor Talazoparib in Patients with Advanced Germline Mutations and Selected Sporadic Cancers. Cancer Discov. 2017; 7:620-629. http://www.ncbi.nlm.nih.gov/pubmed/28242752?dopt=AbstractPlus

9. Ettl J, Quek RGW, Lee KH et al. Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial. Ann Oncol. 2018; 29:1939-1947. http://www.ncbi.nlm.nih.gov/pubmed/30124753?dopt=AbstractPlus

10. Turner NC, Telli ML, Rugo HS et al. A Phase II Study of Talazoparib after Platinum or Cytotoxic Nonplatinum Regimens in Patients with Advanced Breast Cancer and Germline Mutations (ABRAZO). Clin Cancer Res. 2018; http://www.ncbi.nlm.nih.gov/pubmed/30563931?dopt=AbstractPlus

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