TALZENNA® (talazoparib) capsules

TALZENNA® (talazoparib) capsules

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TALZENNA® (talazoparib) capsules

Talazoparib is an inhibitor of mammalian polyadenosine 5’-diphosphoribose polymerase (PARP) enzyme. The chemical name of talazoparib tosylate is (8S,9R)-5-Fluoro-8-(4-fluorophenyl)-9-(1-methyl-1H-1,2,4-triazol5-yl)-2,7,8,9-tetrahydro-3H-pyrido[4,3,2-de]phthalazin-3-one 4-methylbenzenesulfonate (1:1). The chemical formula of talazoparib tosylate is C26H22F2N6O4S, and the relative molecular mass is 552.56 Daltons.

Talazoparib tosylate is a white to yellow solid. TALZENNA capsules for oral use are available as a 0.25 mg hard hypromellose (HPMC) capsule that contains 0.363 mg talazoparib tosylate equivalent to 0.25 mg talazoparib free base or as a 1 mg HPMC capsule that contains 1.453 mg talazoparib tosylate equivalent to 1 mg talazoparib free base.

Inactive ingredients: silicified microcrystalline cellulose (sMCC). The white/ivory and white/light red opaque capsule shells contain HPMC, yellow iron oxide, red iron oxide and titanium dioxide; and the printing ink contains shellac, black iron oxide, potassium hydroxide, ammonium hydroxide, and propylene glycol.

Indications and usage

TALZENNA is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for the treatment of adult patients with deleterious or suspected deleterious germline BRCA-mutated (gBRCAm) HER2-negative locally advanced or metastatic breast cancer. Select patients for therapy based on an FDA-approved companion diagnostic for TALZENNA

Dosage and administration

  • The recommended dose of TALZENNA is 1 mg taken as a single oral daily dose, with or without food.
  • Patients should be treated until disease progression or unacceptable toxicity occurs.
  • For adverse reactions, consider dosing interruption or dose reduction.
  • For patients with moderate renal impairment (CLcr 30 – 59 mL/min), the recommended dose of TALZENNA is 0.75 mg once daily.
  • For patients with severe renal impairment (Clcr 15 – 29 mL/min), the recommended dose of TALZENNA is 0.5 mg once daily.

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 BRCA 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 bearing mutated BRCA 1 or mutated BRCA 2 or wild-type BRCA 1 and BRCA 2.

Contraindications

None

Adverse reactions

  • Most common (≥20%) adverse reactions of any grade were: Fatigue, anemia, nausea, neutropenia, headache, thrombocytopenia, vomiting, alopecia, diarrhea, decreased appetite.
  • Most common laboratory abnormalities (≥25%) were: Decreases in hemoglobin, platelets, neutrophils, lymphocytes, leukocytes, and calcium. Increases in glucose, alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase.

Warnings and precautions

Myelodysplastic Syndrome/Acute Myeloid Leukemia: 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.

Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous chemotherapy. Monitor complete blood counts for cytopenia at baseline and monthly thereafter. For prolonged hematological toxicities, interrupt TALZENNA and monitor blood counts weekly until recovery. If the levels have not recovered after 4 weeks, refer the patient to a hematologist for further investigations, including bone marrow analysis and blood sample for cytogenetics. If MDS/AML is confirmed, discontinue TALZENNA.

Myelosuppression: Myelosuppression consisting of anemia, leukopenia/neutropenia, and/or thrombocytopenia, have been reported in patients treated with TALZENNA [see Adverse Reactions (6)]. Grade ≥3 anemia, neutropenia, and thrombocytopenia were reported, respectively, in 39%, 21%, and 15% of patients receiving TALZENNA. Discontinuation due to anemia, neutropenia, and thrombocytopenia occurred, respectively, in 0.7%, 0.3%, and 0.3% of patients.

Monitor complete blood count for cytopenia at baseline and monthly thereafter. Do not start TALZENNA until patients have adequately recovered from hematological toxicity caused by previous therapy. If this occurs, dose modifications (dosing interruption with or without dose reduction) are recommended

Embryo-Fetal Toxicity: Based on its mechanism of action and findings from animal data, TALZENNA can cause fetal harm when administered to a pregnant woman. In an animal reproduction study, administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations, and embryo-fetal death at exposures that were 0.24 times the area under the concentration-time curve (AUC) in patients receiving the recommended human dose of 1 mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of TALZENNA.

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Based on findings from genetic toxicity and animal reproduction studies, advise male patients with female partners of reproductive potential or who are pregnant to use effective contraception during treatment and for at least 4 months following the last dose of TALZENNA

Drug interactions

Effect of P-gp Inhibitors: Coadministration with P-gp inhibitors may increase talazoparib exposure.

In patients with advanced solid tumors, coadministration of a P-gp inhibitor (itraconazole) increased talazoparib plasma exposure by 56%. In the clinical studies, coadministration with P-gp inhibitors including amiodarone, carvedilol, clarithromycin, itraconazole, and verapamil resulted in an approximate 45% increase in talazoparib exposure and an increase in the rate of TALZENNA dose reduction. If coadministration of TALZENNA with these P-gp inhibitors cannot be avoided, reduce the TALZENNA dose

When the P-gp inhibitor is discontinued, increase the TALZENNA dose (after 3–5 half-lives of the inhibitor) to the dose used prior to the initiation of the P-gp inhibitor

Effect of BCRP inhibitors: Coadministration with BCRP inhibitors may increase talazoparib exposure. If coadministration cannot be avoided, monitor patients for potential increased adverse reactions when coadministering

Use in specific populations

Pregnancy: Based on findings from animal studies and its mechanism of action, TALZENNA can cause embryo-fetal harm when administered to a pregnant woman. There are no available data on TALZENNA use in pregnant women to inform a drug-associated risk. In an animal reproduction study, the administration of talazoparib to pregnant rats during the period of organogenesis caused fetal malformations and structural skeletal variations and embryo-fetal death at maternal exposures that were 0.24 times the AUC in patients receiving the recommended dose of 1 mg daily. Apprise pregnant women and females of reproductive potential of the potential risk to a fetus.

Lactation: There are no data on the presence of talazoparib in human milk, the effects of the drug on milk production, or the effects of the drug on the breastfed child. Because of the potential for serious adverse reactions in a breastfed child from talazoparib, advise lactating women not to breastfeed during treatment with TALZENNA and for at least 1 month after the final dose.

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

Infertility: Based on animal studies, TALZENNA may impair fertility in males of reproductive potential

Pediatric Use: The safety and effectiveness of TALZENNA have not been established in pediatric patients.

Geriatric Use: In clinical trials of TALZENNA enrolling 494 patients with advanced solid tumors who received TALZENNA 1 mg daily as monotherapy, 85 (17%) patients were ≥65 years of age, and this included 19 (4%) patients who were ≥75 years old. There were 5 patients ≥85 years old. 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.

Renal Impairment: Patients with moderate or severe renal impairment have a higher exposure to TALZENNA than patients with normal renal function. Reduce the recommended dose of TALZENNA in patients with moderate (CLcr 30 – 59 mL/min) and severe (CLcr 15 – 29 mL/min) renal impairment. Monitor patients with severe renal impairment for potential increased adverse reactions and adjust dosing accordingly. No dose adjustment is required for patients with mild renal impairment (CLcr 60 – 89 mL/min). TALZENNA has not been studied in patients requiring hemodialysis

Hepatic Impairment: No dose modification is recommended for patients with mild, moderate, or severe hepatic impairment (based on NCI criteria)

Overdosage

There is no specific treatment in the event of TALZENNA overdose, and symptoms of overdose have not been established. In the event of overdose, discontinue treatment with TALZENNA, consider gastric decontamination, follow general supportive measures, and treat symptomatically

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