Talzenna · 4.3 Contraindications · 1

HOS-098553 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The overall safety profile of Talzenna is based on pooled data from 1 088 patients, including 690 patients who received talazoparib monotherapy at 1 mg daily in clinical studies for solid tumours and 398 patients with mCRPC who received talazoparib 0.5 mg in combination with enzalutamide 160 mg in the TALAPRO-2 study. The most common (≥ 20%) adverse reactions in patients receiving talazoparib in these clinical studies were anaemia (55.6%), fatigue (52.5%), nausea (35.8%), neutropenia (30.3%), thrombocytopenia (25.2%) and decreased appetite (21.1%). The most common (≥ 10%) Grade ≥ 3 adverse reactions of talazoparib were anaemia (39.2%), neutropenia (16.5%) and thrombocytopenia (11.1%). 8 Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 58.7% of patients receiving Talzenna 1 mg monotherapy. The most common adverse reactions leading to dose modifications were anaemia (33.5%), neutropenia (11.7%) and thrombocytopenia (9.9%). Permanent discontinuation due to an adverse reaction occurred in 2.9% of patients receiving Talzenna; the most common was anaemia (0.6%). The median duration of exposure was 5.6 months (range 0.0 to 70.2). Dose interruptions of Talzenna due to adverse reactions occurred in 62.1% of patients with mCRPC receiving Talzenna in combination with enzalutamide; the most common was anaemia (44%). Dose reductions of Talzenna due to adverse reactions occurred in 52.8% of patients; the most common was anaemia (43.2%). Permanent discontinuation of Talzenna due to adverse reactions occurred in 18.8% of patients; the most common was anaemia (8.3%). The median duration of talazoparib exposure was 86 weeks (range 0.29 to 186.14). Tabulated list of adverse reactions Table 4 summarises adverse reactions based on pooled dataset listed by system organ class, and frequency category. Frequency categories are defined as: very common (≥ 1/10), common (≥ 1/100 to < 1/10) and uncommon (≥ 1/1 000 to < 1/100). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness. Table 4. Adverse reactions based on pooled dataset from 8 studies (N=1 088) System organ class All grades Grade 3 Grade 4 Frequency n (%) n (%) n (%) Preferred term Neoplasms

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HOS-098549 · has-contraindication-information · PDF-Seite 5

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. Breast-feeding (see section 4.6). 5

HOS-098548 · has-indication-information · PDF-Seite 3

Breast cancer Talzenna is indicated as monotherapy for the treatment of adult patients with germline BRCA1/2-mutations, who have HER2-negative locally advanced or metastatic breast cancer. Patients should have been previously treated with an anthracycline and/or a taxane in the (neo)adjuvant, locally advanced or metastatic setting unless patients were not suitable for these treatments (see section 5.1). Patients with hormone receptor (HR)-positive breast cancer should have been treated with a prior endocrine-based therapy, or be considered unsuitable for endocrine-based therapy. Prostate cancer Talzenna is indicated in combination with enzalutamide for the treatment of adult patients with metastatic castration-resistant prostate cancer (mCRPC) in whom chemotherapy is not clinically indicated.

HOS-098551 · has-interaction-information · PDF-Seite 6

Talazoparib is a substrate for drug transporters P-gp and breast cancer resistance protein (BCRP) and it is mainly eliminated by renal clearance as unchanged compound. 6 Agents that may affect talazoparib plasma concentrations P-gp inhibitors Effect of enzalutamide Co-administration with 160 mg enzalutamide increases talazoparib exposure approximately 2-fold. Administration of talazoparib 0.5 mg daily in combination with enzalutamide achieves approximately the same steady-state trough (Ctrough) concentration reported for talazoparib 1 mg daily (see section 5.2). When Talzenna is co-administered with enzalutamide, the Talzenna starting dose is 0.5 mg (see section 4.2). The interaction effect of doses other than 160 mg enzalutamide on talazoparib has not been quantified. The effect of co-administration of other P-gp inhibitors on talazoparib exposure when talazoparib is given in combination with enzalutamide has not been studied. If co-administration of P-gp inhibitors cannot be avoided, when Talzenna is given with enzalutamide, the patient should be monitored for potential increased adverse reactions. Effect of other P-gp inhibitors Data from a drug-drug interaction study in patients with advanced solid tumours indicated that co-administration of multiple daily doses of a P-gp inhibitor, itraconazole 100 mg twice daily with a single 0.5 mg talazoparib dose increased talazoparib total exposure (AUCinf) and peak concentration (Cmax) by approximately 56% and 40%, respectively, relative to a single 0.5 mg talazoparib dose administered alone. Population pharmacokinetic (PK) analysis has also shown that concomitant use of strong P-gp inhibitors increased talazoparib exposure by 45%, relative to talazoparib given alone. Concomitant use of strong P-gp inhibitors (including but not limited to amiodarone, carvedilol, clarithromycin, cobicistat, darunavir, dronedarone, erythromycin, indinavir, itraconazole, ketoconazole, lapatinib, lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, telaprevir, tipranavir, and verapamil) should be avoided. If co-administration with a strong P-gp inhibitor is unavoidable, the Talzenna dose should be reduced (see section 4.2). P-gp inducers Data from a drug-drug interaction study in patients with advanced solid tumours indicated that co-administration of single 1 mg talazoparib dose with multiple daily doses of a P-gp inducer, rifampin 600 mg, with rifampin

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HOS-098552 · has-pregnancy-information · PDF-Seite 8

Women of childbearing potential/Contraception in males and females Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior to treatment (see section 4.4). Women of childbearing potential must use highly effective forms of contraception (see section 4.4) prior to starting treatment with talazoparib, during treatment, and for 7 months after stopping treatment with talazoparib. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used. Male patients with female partners of reproductive potential or pregnant partners should be advised to use effective contraception (even after vasectomy) during treatment with Talzenna, and for at least 4 months after the final dose (see section 4.4). Pregnancy There are no data from the use of Talzenna in pregnant women. Studies in animals have shown embryo-foetal toxicity (see section 5.3). Talzenna may cause foetal harm when administered to a pregnant woman. Talzenna is not recommended during pregnancy or for women of childbearing potential not using contraception (see section 4.4). Breast-feeding It is unknown whether talazoparib is excreted in human breast milk. A risk to breast-fed children cannot be excluded and therefore breast-feeding is contraindicated (see section 4.3) during treatment with Talzenna and for at least 1 month after the final dose. Fertility There is no information on fertility in patients. Based on non-clinical findings in testes (partially reversible) and ovary (reversible), Talzenna may impair fertility in males of reproductive potential (see section 5.3).

HOS-098550 · has-warning-information · PDF-Seite 6

Myelosuppression Myelosuppression consisting of anaemia, leukopenia/neutropenia, and/or thrombocytopenia, have been reported in patients treated with talazoparib (see section 4.8). Talazoparib should not be started until patients have recovered from haematological toxicity caused by previous therapy (≤ Grade 1). Precautions should be taken to routinely monitor haematology parameters and signs and symptoms associated with anaemia, leukopenia/neutropenia, and/or thrombocytopenia in patients receiving talazoparib. If such events occur, dose modifications (reduction or interruption) are recommended (see section 4.2). Supportive care with or without blood and/or platelet transfusions and/or administration of colony stimulating factors may be used as appropriate. Myelodysplastic syndrome/Acute myeloid leukaemia Myelodysplastic syndrome/Acute Myeloid Leukaemia (MDS/AML) have been reported in patients who received poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitors, including talazoparib. Overall, MDS/AML has been reported in < 1% of solid tumour patients treated with talazoparib in clinical studies (see section 4.8). Potential contributing factors for the development of MDS/AML include previous platinum-containing chemotherapy, other DNA damaging agents or radiotherapy. Complete blood counts should be obtained at baseline and monitored monthly for signs of haematologic toxicity during treatment. If MDS/AML is confirmed, talazoparib should be discontinued. Venous thromboembolic events In patients with mCRPC a higher incidence of venous thromboembolic events was observed with Talzenna in combination with enzalutamide compared with enzalutamide alone. Patients should be monitored for clinical signs and symptoms of deep venous thrombosis and pulmonary embolism and treated as medically appropriate (see section 4.8). Contraception in women of childbearing potential Talazoparib was clastogenic in an in vitro chromosomal aberration assay in human peripheral blood lymphocytes and in an in vivo bone marrow micronucleus assay in rats but not mutagenic in Ames assay (see section 5.3), and may cause foetal harm when administered to a pregnant woman. Pregnant women should be advised of the potential risk to the foetus (see section 4.6). Women of childbearing potential should not become pregnant while receiving Talzenna and should not be pregnant at the beginning of treatment. A pregnancy test should be performed on all women of childbearing potential prior

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