Dosage Forms
Excipient information presented when available (limited, particularly for generics); consult specific product labeling.
Capsule, Oral, as tosylate:
Talzenna: 0.25 mg, 1 mg
Pharmacology
Mechanism of Action
Talazoparib is a poly (ADP-ribose) polymerase (PARP) enzyme inhibitor, including PARP1 and PARP2. PARP enzymes are involved in DNA transcription, cell cycle regulation, and DNA repair. Talazoparib is a potent PARP inhibitor, with both strong catalytic inhibition and a PARP-trapping potential that is significantly greater than other PARP inhibitors (Litton 2018). Catalytic inhibition causes cell death due to accumulation of irreparable DNA damage; talazoparib also traps PARP-DNA complexes, which may be more effective in cell death than enzymatic inhibition alone (Litton 2018).
Pharmacokinetics/Pharmacodynamics
Distribution
Vd: 420 L
Metabolism
Minimal hepatic metabolism; metabolic pathways include mono-oxidation, dehydrogenation, cysteine conjugation of mono-desfluoro-talazoparib, and glucuronide conjugation
Excretion
Urine: ~69% (54.6% as unchanged drug); Feces: ~20% (13.6% as unchanged drug)
Time to Peak
1 to 2 hours
Half-Life Elimination
90 (±58) hours
Protein Binding
74%
Use in Specific Populations
Special Populations: Renal Function Impairment
Talazoparib clearance (CL/F) was decreased by ~14% and ~37% in patients with mild (CrCl 60 to 89 mL/minute) and moderate (CrCl 30 to 59 mL/minute) renal impairment, respectively, as compared to patients with normal renal function (CrCl ≥90 mL/minute).
Use: Labeled Indications
Breast cancer, locally advanced or metastatic (BRCA-mutated, HER2-negative): Treatment of 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 in adults (as detected by an approved test).
Contraindications
There are no contraindications listed in the manufacturer's labeling.
Dosage and Administration
Dosing: Adult
Note: Administer only to patients with germline BRCA mutation (as detected by an approved test).
Breast cancer, locally advanced or metastatic, BRCA-mutated, HER2-negative: Oral: 1 mg once daily until disease progression or unacceptable toxicity (Litton 2018)
Missed doses: If a dose is missed or vomited, an additional dose should not be administered; administer the next dose at the usual scheduled time.
Dosage adjustment for concomitant therapy:
P-gp inhibitors: Reduce the talazoparib dose to 0.75 mg once daily when coadministered with certain P-gp inhibitors (amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil). When the P-gp inhibitor is discontinued and 3 to 5 half-lives of the P-gp inhibitor have elapsed, increase the talazoparib dose back to the dose used prior to the initiation of the P-gp inhibitor.
Dosing: Geriatric
Refer to adult dosing.
Dosing: Adjustment for Toxicity
Consider therapy interruption with or without dose reduction for adverse reactions, depending on the severity and clinical presentation. Talazoparib should be discontinued if more than 3 dose reductions are necessary.
Recommended talazoparib dose reductions for toxicity:
Initial/usual starting dose: 1 mg once daily
First dose reduction: 0.75 mg once daily
Second dose reduction: 0.5 mg once daily
Third dose reduction: 0.25 mg once daily
Hematologic toxicity:
Hemoglobin <8 g/dL: Withhold talazoparib until hemoglobin is ≥9 g/dL, then resume therapy at a reduced dose.
Neutrophils <1,000/mm3: Withhold talazoparib until neutrophils are ≥1,500/mm3, then resume therapy at a reduced dose.
Platelets <50,000/mm3: Withhold talazoparib until platelets are ≥75,000/mm3, then resume therapy at a reduced dose.
MDS/AML (confirmed): Discontinue therapy
Nonhematologic toxicity: Grade 3 or 4 toxicity: Withhold talazoparib until toxicity is ≤ grade 1, then consider resuming therapy at a reduced dose or discontinuing talazoparib (depending on the severity of the toxicity).
Administration
Oral: Administer with or without food. Swallow capsules whole; do not open or dissolve capsule.
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).
Drug Interactions
Amiodarone: May increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of amiodarone, increase the talazoparib dose to the dose used before initiation of amiodarone. Consider therapy modification
BCG (Intravesical): Myelosuppressive Agents may diminish the therapeutic effect of BCG (Intravesical). Avoid combination
BCRP/ABCG2 Inhibitors: May increase the serum concentration of Talazoparib. Monitor therapy
Carvedilol: May increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of carvedilol, increase the talazoparib dose to the dose used before initiation of carvedilol. Consider therapy modification
Chloramphenicol (Ophthalmic): May enhance the adverse/toxic effect of Myelosuppressive Agents. Monitor therapy
Cladribine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Avoid combination
Clarithromycin: May increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of clarithromycin, increase the talazoparib dose to the dose used before initiation of clarithromycin. Consider therapy modification
CloZAPine: Myelosuppressive Agents may enhance the adverse/toxic effect of CloZAPine. Specifically, the risk for neutropenia may be increased. Monitor therapy
Deferiprone: Myelosuppressive Agents may enhance the neutropenic effect of Deferiprone. Management: Avoid the concomitant use of deferiprone and myelosuppressive agents whenever possible. If this combination cannot be avoided, monitor the absolute neutrophil count more closely. Consider therapy modification
Dipyrone: May enhance the adverse/toxic effect of Myelosuppressive Agents. Specifically, the risk for agranulocytosis and pancytopenia may be increased Avoid combination
Itraconazole: May increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of itraconazole, increase the talazoparib dose to the dose used before initiation of itraconazole. Consider therapy modification
Mesalamine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
P-glycoprotein/ABCB1 Inhibitors: May increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Exceptions: Amiodarone; Carvedilol; Clarithromycin; Itraconazole; Verapamil. Monitor therapy
Promazine: May enhance the myelosuppressive effect of Myelosuppressive Agents. Monitor therapy
Verapamil: May increase the serum concentration of Talazoparib. Management: If concurrent use cannot be avoided, reduce talazoparib dose to 0.75 mg once daily. After a period of 3 to 5 times the half-life of verapamil, increase the talazoparib dose to the dose used before initiation of verapamil. Consider therapy modification
Adverse Reactions
>10%
Central nervous system: Fatigue (62%), headache (33%), dizziness (17%)
Dermatologic: Alopecia (25%)
Endocrine & metabolic: Increased serum glucose (54%), decreased serum calcium (28%)
Gastrointestinal: Nausea (49%), vomiting (25%), diarrhea (22%), decreased appetite (21%), abdominal pain (19%)
Hematologic & oncologic: Decreased hemoglobin (90%; grade 3: 39%), anemia (53%; grade 3: 38%; grade 4: 1%), neutropenia (35%; grade 3: 18%; grade 4: 3%), thrombocytopenia (27%; grade 3: 11%; grade 4: 4%), leukopenia (17%)
Hepatic: Increased serum aspartate aminotransferase (37%), increased serum alkaline phosphatase (36%), increased serum alanine aminotransferase (33%)
1% to 10%:
Gastrointestinal: Dysgeusia (10%), dyspepsia (10%), stomatitis (8%)
Hematologic & oncologic: Lymphocytopenia (7%)
Frequency not defined: Hematologic & oncologic: Bone marrow depression
<1%, postmarketing, and/or case reports: Acute myelocytic leukemia, myelodysplastic syndrome
Warnings/Precautions
Concerns related to adverse effects:
- Bone marrow suppression: Anemia, leukopenia/neutropenia, and/or thrombocytopenia have been reported, including ≥grade 3 events. Monitor complete blood counts at baseline and monthly thereafter (and as clinically indicated); do not initiate talazoparib until any hematologic toxicity caused by previous chemotherapy has adequately recovered. If prolonged hematologic toxicity occurs during therapy, interrupt treatment and monitor blood counts weekly until recovered; if counts do not recover to ≤ grade 1 after 4 weeks, further evaluation (including bone marrow and cytogenetic analyses) is necessary.
- GI toxicity: Nausea and vomiting (usually mild to moderate) may commonly occur; diarrhea may also occur.
- Secondary malignancy: Myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) have been reported (rarely) in clinical trials (for various solid tumors). The duration of talazoparib therapy prior to development of the secondary cancers ranged from 4 months to 2 years; patients had received prior chemotherapy with platinum agents and/or other DNA-damaging medications, including radiation. If prolonged hematologic toxicity occurs during talazoparib therapy and blood counts do not recover to ≤ grade 1 after 4 weeks, further evaluation (including bone marrow and cytogenetic analyses) is necessary. If MDS/AML is confirmed, discontinue therapy.
Disease-related concerns:
- Renal impairment: Talazoparib clearance is decreased in patients with mild or moderate renal impairment. Dosage adjustment is recommended in patients with moderate impairment.
Concurrent drug therapy issues:
- Drug-drug interactions: Potentially significant interactions may exist, requiring dose or frequency adjustment, additional monitoring, and/or selection of alternative therapy. Consult drug interactions database for more detailed information.
Dosage form specific issues:
- Propylene glycol: Some dosage forms may contain propylene glycol; large amounts are potentially toxic and have been associated with hyperosmolality, lactic acidosis, seizures, and respiratory depression; use caution (AAP 1997; Zar 2007).
Other warnings/precautions:
- BRCA-mutation status: Select patients for the treatment of HER2-negative locally advanced or metastatic breast cancer based on the presence of deleterious or suspected deleterious BRCA-mutations. Information on approved tests for the detection of BRCA-mutations may be found at http://www.fda.gov/companiondiagnostics.
Monitoring Parameters
BRCA-mutation status; complete blood count at baseline and monthly thereafter, or as clinically indicated (weekly until recovery for prolonged hematologic toxicity), renal function, pregnancy test (prior to treatment initiation in females of reproductive potential); monitor for signs/symptoms of acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). Monitor adherence.
Pregnancy
Pregnancy Considerations
Based on the mechanism of action and information from animal reproduction studies, talazoparib may cause fetal harm if administered during pregnancy.
Pregnancy testing is recommended prior to therapy in females of reproductive potential. Females of reproductive potential should use effective contraception during therapy and for at least 7 months after the last talazoparib dose. Males with female partners of reproductive potential or female partners who are pregnant should also use effective contraception during therapy and for at least 4 months after the last talazoparib dose.
Patient Education
- Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
- Patient may experience hair loss, headache, abdominal pain, dizziness, change in taste, mouth irritation, mouth sores, diarrhea, vomiting, nausea, or lack of appetite. Have patient report immediately to prescriber signs of infection, signs of bleeding (vomiting blood or vomit that looks like coffee grounds; coughing up blood; blood in the urine; black, red, or tarry stools; bleeding from the gums; abnormal vaginal bleeding; bruises without a reason or that get bigger; or any severe or persistent bleeding), severe loss of strength and energy, weight loss, or shortness of breath (HCAHPS).
- Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.
Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.
