TALZENNA Hard capsule Ref.[7615] Active ingredients: Talazoparib

Myelosuppression

Myelosuppression consisting of anaemia, leucopenia/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, leucopenia/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 2 out of 584 (0.3%) solid tumour patients treated with talazoparib in clinical studies. 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.

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 to treatment.

A highly effective method of contraception is required for female patients during treatment with Talzenna, and for at least 7 months after completing therapy. Since the use of hormonal contraception is not recommended in patients with breast cancer, two non-hormonal and complementary contraception methods should be used (see section 4.6).

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.

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.

Agents that may affect talazoparib plasma concentrations

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 (AUC_inf) and peak concentration (C_max) 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 co-administered 30 minutes before talazoparib on the day of talazoparib dosing, increased talazoparib C_max by approximately 37% whereas AUC_inf was not affected relative to a single 1 mg talazoparib dose administered alone. This is probably the net effect of both P-gp induction and inhibition by rifampin under the tested conditions in the drug-drug interaction study. No talazoparib dose adjustments are required when co-administered with rifampin. However, the effect of other P-gp inducers on talazoparib exposure has not been studied. Other P-gp inducers (including but not limited to carbamazepine, phenytoin, and St. John’s wort) may decrease talazoparib exposure.

BCRP inhibitors

The effect of BCRP inhibitors on PK of talazoparib has not been studied in vivo. Co-administration of talazoparib with BCRP inhibitors may increase talazoparib exposure. Concomitant use of strong BCRP inhibitors (including but not limited to curcumin and cyclosporine) should be avoided. If co-administration of strong BCRP inhibitors cannot be avoided, patient should be monitored for potential increased adverse reactions.

Effect of acid-reducing agents

Population PK analysis indicates that co-administration of acid-reducing agents including proton pump inhibitors and histamine receptor 2 antagonists (H₂RA), or other acid-reducing agents had no significant impact on the absorption of talazoparib.

Systemic hormonal contraception

Drug-drug interaction studies between talazoparib and oral contraceptives have not been conducted.

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 not recommended 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).

Talzenna may have a minor influence on the ability to drive and use machines. Fatigue/asthenia or dizziness may occur following administration of talazoparib.

Summary of the safety profile

The overall safety profile of Talzenna is based on pooled data from 494 patients who received talazoparib at 1 mg daily in clinical studies for solid tumours, including 286 patients from a randomised Phase 3 study with germline BRCA-mutated (gBRCAm), HER2-negative locally advanced or metastatic breast cancer and 83 patients from a nonrandomised Phase 2 study in patients with germline BRCA-mutated locally advanced or metastatic breast cancer.

The most common (≥25%) adverse reactions in patients receiving talazoparib in these clinical studies were fatigue (57.1%), anaemia (49.6%), nausea (44.3%), neutropenia (30.2%), thrombocytopenia (29.6%), and headache (26.5%). The most common (≥10%) Grade ≥3 adverse reactions of talazoparib were anaemia (35.2%), neutropenia (17.4%), and thrombocytopenia (16.8%).

Dose modifications (dose reductions or dose interruptions) due to any adverse reaction occurred in 62.3% of patients receiving Talzenna. The most common adverse reactions leading to dose modifications were anaemia (33.0%), neutropenia (15.8%), and thrombocytopenia (13.4%).

Permanent discontinuation due to an adverse reaction occurred in 3.6% of patients receiving Talzenna. The median duration of exposure was 5.4 months (range 0.03-61.1).

Tabulated list of adverse reactions

Table 3 summarises adverse reactions based on pooled dataset listed by system organ class, and frequency category. Frequency categories are defined as: very common (≥1/10) and common (≥1/100 to <1/10). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 3. Adverse reactions based on pooled dataset from 5 studies (N=494):

Abbreviations: n=number of patients; N/A=not applicable.
* There were no Grade 5 adverse drug reactions.
^a Includes preferred terms of thrombocytopenia and platelet count decreased. ^b Includes preferred terms of anaemia, haematocrit decreased and haemoglobin decreased.
^c Includes preferred terms of neutropenia and neutrophil count decreased.
^d Includes preferred terms of leucopenia and white blood cell count decreased. ^e Includes preferred terms of lymphocyte count decreased and lymphopenia.
^f Includes preferred terms of abdominal pain, abdominal pain upper, abdominal discomfort and abdominal pain
lower.
^g For talazoparib Grade 1 is 21% and Grade 2 is 2%.
^h Includes preferred terms of fatigue and asthenia.

Description of selected adverse reactions

Myelosuppression

Myelosuppression-related adverse reactions of anaemia, neutropenia, and thrombocytopenia were very commonly reported in patients treated with talazoparib 1 mg/day. Grade 3 and Grade 4 myelosuppression-related events were reported for anaemia 34.8% and 0.4%, neutropenia 15.6% and 1.8%, and thrombocytopenia 12.8% and 4.0%. No deaths were reported due to myelosuppression-related adverse reactions. Myelosuppression-related adverse events associated with dose modifications were reported for up to approximately 30% of patients in the talazoparib 1 mg/day population and those associated with permanent study drug discontinuation were reported for less than 1% of patients.

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Not applicable.