Talazoparib
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
Brands: Talzenna
Introduction
Antineoplastic agent; a potent and selective inhibitor of poly(adenosine diphosphate [ADP]-ribose) polymerase (PARP).
Uses for Talazoparib
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.
Talazoparib Dosage and Administration
General
-
Confirm presence of deleterious germline BRCA mutation prior to initiation of therapy.
-
Obtain CBC prior to initiation of therapy and monthly during therapy. (See Myelodysplastic Syndrome [MDS]/Acute Myeloid Leukemia [AML] under Cautions.)
Restricted Distribution
-
Obtain talazoparib through specialty pharmacies.
-
Contact manufacturer at 877-744-5675 or consult the Pfizer Oncology together website ([Web]/hcp) for specific availability information.
Administration
Oral Administration
Administer orally once daily without regard to meals.
Swallow capsules whole; do not dissolve or open.
Dosage
Available as talazoparib tosylate; dosage expressed in terms of talazoparib.
Adults
Breast Cancer
Oral
1 mg once daily. Continue therapy until disease progression or unacceptable toxicity occurs.
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.
General Dosage Modification
OralIf adverse reactions occur, consider interruption of therapy or dosage reduction.
If dosage reduction is necessary, reduce dosage to 0.75 mg once daily.
If dosage reduction from 0.75 mg once daily is necessary, reduce dosage to 0.5 mg once daily.
If further reduction is necessary, reduce dosage to 0.25 mg once daily.
Permanently discontinue drug if 0.25 mg once daily is not tolerated.
Dosage Modification for Hematologic Toxicity
OralFor anemia (hemoglobin concentrations <8 g/dL), interrupt talazoparib therapy until hemoglobin concentrations ≥9 g/dL, and then resume at a reduced dosage. (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.
For neutropenia (ANC <1000/mm3), interrupt talazoparib therapy until ANC ≥1500/mm3, and then resume at a reduced dosage.
If MDS or AML is confirmed, discontinue talazoparib therapy.
Dosage Modification for Nonhematologic Effects
OralIf 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.
Prescribing Limits
Adults
Breast Cancer
Oral
Dosage <0.25 mg once daily not recommended.
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.
Moderate to severe hepatic impairment (total bilirubin concentration >1.5 times the ULN, with any AST concentration): No specific dosage recommendations at this time. (See Hepatic Impairment under Cautions.)
Renal Impairment
Mild renal impairment (Clcr 60–89 mL/minute): Dosage adjustment not necessary.
Moderate renal impairment (Clcr 30–59 mL/minute): Reduce initial dosage to 0.75 mg once daily.
Severe renal impairment (Clcr <30 mL/minute) or dialysis: No specific dosage recommendations at this time. (See Renal Impairment under Cautions.)
Geriatric Patients
No specific dosage recommendations at this time. (See Geriatric Use under Cautions.)
Cautions for Talazoparib
Contraindications
-
Manufacturer states none known.
Warnings/Precautions
Myelodysplastic Syndrome (MDS)/Acute Myeloid Leukemia (AML)
MDS and AML reported rarely in patients receiving talazoparib. All patients with MDS/AML had received previous chemotherapy with platinum-containing agents and/or other DNA-damaging antineoplastic agents. The duration of talazoparib therapy in patients who developed MDS/AML ranged from 4–24 months.
Monitor CBC counts at baseline and monthly thereafter. Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved.
If prolonged hematologic toxicity occurs, interrupt therapy and monitor CBC counts weekly until recovery. 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. If MDS/AML is confirmed, discontinue talazoparib.
Hematologic Effects
Adverse hematologic effects (e.g., anemia, neutropenia, thrombocytopenia) may occur.
Delay initiation of talazoparib until hematologic toxicity caused by previous chemotherapy has adequately resolved. Monitor CBC counts at baseline and monthly thereafter. If hematologic toxicity occurs, temporary interruption, dosage reduction, or discontinuance of talazoparib may be necessary. (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. (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.
Confirmation of pregnancy status recommended prior to initiating talazoparib therapy. Avoid pregnancy during therapy. Women of reproductive potential should use effective contraceptive methods while receiving talazoparib and for ≥7 months after the drug is discontinued. 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. Apprise patients of potential fetal hazard if the drug is used during pregnancy.
Impairment of Fertility
Results of animal studies suggest that talazoparib may impair male fertility. Effect on fertility in humans not known.
Specific Populations
Pregnancy
May cause fetal harm. (See Fetal/Neonatal Morbidity and Mortality under Cautions.)
Confirmation of pregnancy status prior to initiation of therapy recommended.
Lactation
Not known whether talazoparib is distributed into milk. Discontinue nursing during therapy and for ≥1 month after drug discontinuance.
Pediatric Use
Safety and efficacy not established.
Pharmacokinetic profile not established in patients <18 years of age.
Geriatric Use
No overall differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.
Hepatic Impairment
Pharmacokinetics not altered by mild hepatic impairment; dosage adjustment not necessary in such patients. (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.
Renal Impairment
Decreased clearance in patients with mild or moderate renal impairment; dosage reduction recommended in patients with moderate renal impairment. (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.
Common Adverse Effects
Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, alopecia, vomiting, diarrhea, decreased appetite, decreased hemoglobin concentrations, decreased WBC count, decreased ANC, decreased lymphocyte concentrations, elevated glucose concentrations, elevated AST/ALT concentrations, elevated alkaline phosphatase concentrations, decreased calcium concentrations.
Interactions for Talazoparib
In vitro, does not inhibit CYP isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5 or induce CYP isoenzymes 1A2, 2B6, or 3A4.
In vitro, talazoparib is not an inhibitor of UGT 1A1, 1A4, 1A6, 1A9, 2B7, and 2B15.
In vitro, talazoparib is a substrate, but not an inhibitor, of P-gp and breast cancer resistance protein (BCRP). 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.
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.
Drugs Affecting Efflux Transport Systems
Potent P-gp inhibitors: Potential increased systemic exposure of talazoparib. Avoid concomitant use. If concomitant therapy cannot be avoided, reduce talazoparib dosage from 1 mg once daily to 0.75 mg once daily. (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.
Moderate or weak P-gp inhibitors: No clinically meaningful effect on systemic exposure of talazoparib. Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur. (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.
Specific Drugs
Drug |
Interaction |
Comments |
---|---|---|
Amiodarone |
Potent P-gp inhibitors (e.g., amiodarone): Increased systemic exposure of talazoparib by approximately 45% |
Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If amiodarone discontinued, resume talazoparib (after 3–5 terminal half-lives of amiodarone) at dosage used prior to initiation of amiodarone |
Antacids |
No clinically meaningful effect on talazoparib absorption |
|
Atorvastatin |
Moderate/weak P-gp inhibitors (e.g., atorvastatin): No clinically meaningful effect on systemic exposure of talazoparib |
Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur |
Calcium-channel blocking agents (e.g., diltiazem, felodipine, verapamil) |
Potent P-gp inhibitors (e.g., verapamil): Increased systemic exposure of talazoparib by approximately 45% Moderate/weak P-gp inhibitors (e.g., diltiazem, felodipine): No clinically meaningful effect on systemic exposure of talazoparib |
Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage 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 inhibitor Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur |
Carvedilol |
Potent P-gp inhibitors (e.g., carvedilol): Increased systemic exposure of talazoparib by approximately 45% |
Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If carvedilol discontinued, resume talazoparib (after 3–5 terminal half-lives of carvedilol) at dosage used prior to initiation of carvedilol |
Fluvoxamine |
Moderate/weak P-gp inhibitors (e.g., fluvoxamine): No clinically meaningful effect on systemic exposure of talazoparib |
Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur |
Histamine H2-receptor antagonists |
No clinically meaningful effect on talazoparib absorption |
|
Itraconazole |
Potent P-gp inhibitors (e.g., itraconazole): Increased systemic exposure of talazoparib by approximately 45% |
Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage If itraconazole discontinued, resume talazoparib (after 3–5 terminal half-lives of itraconazole) at dosage used prior to initiation of itraconazole |
Macrolides (azithromycin, clarithromycin) |
Potent P-gp inhibitors (e.g., clarithromycin): Increased systemic exposure of talazoparib by approximately 45% Moderate/weak P-gp inhibitors (e.g., azithromycin): No clinically meaningful effect on systemic exposure of talazoparib |
Potent P-gp inhibitors: Avoid concomitant use; if concomitant use cannot be avoided, reduce talazoparib dosage 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 inhibitor Moderate/weak P-gp inhibitors: Monitor for signs of toxicity; may need to interrupt therapy and reduce dosage if adverse effects occur |
Proton-pump inhibitors |
No clinically meaningful effect on talazoparib absorption |
Talazoparib Pharmacokinetics
Absorption
Bioavailability
Pharmacokinetics are linear over a dosage range of 0.025–2 mg; median accumulation ratio is 2.3–5.2 following repeated administration of talazoparib 1 mg daily.
Median time to peak plasma concentrations is 1–2 hours following oral administration.
Steady-state concentrations are achieved within 2–3 weeks.
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.
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.
Moderate or severe hepatic impairment (total bilirubin concentration >1.5 times the ULN with any AST concentration): Pharmacokinetics not studied.
Severe renal impairment (Clcr <30 mL/minute) or dialysis: Pharmacokinetics not studied.
Age, body weight, gender, or race does not affect pharmacokinetics of talazoparib.
Distribution
Extent
Not known whether talazoparib is distributed into milk.
Plasma Protein Binding
74% (independent of talazoparib concentration).
Elimination
Metabolism
Minimal hepatic metabolism.
Mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluorotalazoparib, and glucuronide conjugation.
Elimination Route
Eliminated in urine (68.7%; 54.6% as unchanged drug) and feces (19.7%; 13.6% as unchanged drug).
Half-life
Mean terminal half-life: 90 hours.
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.
Stability
Storage
Oral
Capsules
20–25°C (may be exposed to 15–30°C).
Actions
-
Potent and selective inhibitor of mammalian PARP enzymes, including PARP-1 and PARP-2. PARP enzymes are involved in normal cellular homeostasis, including DNA transcription, cell cycle regulation, and DNA repair.
-
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.
-
PARP inhibitors, including talazoparib, appear to be selective for tumors cells harboring certain homologous recombination deficiencies (e.g., BRCA1 and BRCA2 mutations).
-
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.
-
Substantially more potent than rucaparib and olaparib in estrogen receptor-negative, progesterone receptor-negative, and HER2-negative breast tumor cell lines harboring BRCA1 mutation.
-
Exhibits antitumor activity of xenograft models of human cancer harboring either mutated or wild-type BRCA1/2.
Advice to Patients
-
Importance of reading the manufacturer's patient information.
-
Importance of advising patients to take talazoparib capsules once daily without regard to meals. Importance of advising patients to swallow talazoparib capsules whole and not to dissolve or open the capsules.
-
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.
-
Risk of MDS and AML. 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.
-
Risk of bone marrow suppression. Importance of hematologic monitoring during talazoparib therapy.
-
Risk of fetal harm and pregnancy loss. 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. 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. Importance of women informing clinicians immediately if they are pregnant or become pregnant during therapy. If pregnancy occurs, advise pregnant women of potential risk to the fetus.
-
Importance of advising women to avoid breast-feeding while receiving talazoparib and for ≥1 month following discontinuance of therapy.
-
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.
-
Importance of informing patients of other important precautionary information. (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. (See Restricted Distribution under Dosage and Administration.)
Routes |
Dosage Forms |
Strengths |
Brand Names |
Manufacturer |
---|---|---|---|---|
Oral |
Capsules |
0.25 mg (of talazoparib) |
Talzenna |
Pfizer |
AHFS DI Essentials™. © Copyright 2022, Selected Revisions July 22, 2019. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.
Frequently asked questions
More about talazoparib
- Side effects
- Drug interactions
- Dosage information
- During pregnancy or Breastfeeding
- En español
- Drug class: PARP inhibitors
Patient resources
Professional resources
- Other brands
- Talzenna