Rubraca

HOS-098050 · has-adverse-reaction-information · PDF-Seite 8

Summary of the safety profile The overall safety profile of rucaparib is based on data from 1 594 patients in clinical trials in ovarian cancer treated with rucaparib monotherapy. Patients were exposed to rucaparib for a median of 7.4 months. Adverse reactions occurring in ≥ 20% of patients receiving rucaparib were nausea, fatigue/asthenia, vomiting, anaemia, abdominal pain, dysgeusia, ALT elevations, AST elevations, decreased appetite, diarrhoea, neutropenia and thrombocytopenia. The majority of adverse reactions were mild to moderate (Grade 1 or 2). The ≥ Grade 3 adverse reactions occurring in > 5% of patients were anaemia (25%), ALT elevations (10%), neutropenia (10%), fatigue/asthenia (9%), and thrombocytopenia (7%). The only serious adverse reaction occurring in > 2% of patients was anaemia (5%). Adverse reactions that most commonly led to dose reduction or interruption were anaemia (23%), fatigue/asthenia (15%), nausea (14%), thrombocytopenia (14%), neutropenia (10%) and AST/ALT elevations (10%). Adverse reactions leading to permanent discontinuation occurred in 15% of patients; with the most frequently reported being thrombocytopenia, nausea, anaemia, and fatigue/asthenia. Tabulated list of adverse reactions The adverse reaction frequency is listed by MedDRA System Organ Class (SOC) at the preferred term level. Frequencies of occurrence of adverse reactions are defined as: very common (≥ 1/10); common (≥ 1/100 to < 1/10); uncommon (≥ 1/1 000 to < 1/100); rare (≥ 1/10 000 to < 1/1 000); very rare (< 1/10 000), not known (cannot be estimated from the available data). Table 3. Tabulated list of adverse reactions by MedDRA system organ class Adverse reactions MedDRA system organ Frequency of all CTCAE grades Frequency of CTCAE grade 3 class and above Neoplasms benign, Common Common malignant and Myelodysplastic syndrome / Myelodysplastic syndrome / unspecified (including Acute myeloid leukaemia a Acute myeloid leukaemia a cysts and polyps) Blood and lymphatic Very common Very common system disorders Anaemia b, Thrombocytopenia b, Anaemia b, Neutropenia b Neutropenia , Leukopenia b b

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HOS-098046 · has-contraindication-information · PDF-Seite 4

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

HOS-098045 · has-indication-information · PDF-Seite 2

Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with advanced (FIGO Stages III and IV) high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) following completion of first-line platinum-based chemotherapy. Rubraca is indicated as monotherapy for the maintenance treatment of adult patients with platinum- sensitive relapsed high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response (complete or partial) to platinum-based chemotherapy. 2

HOS-098048 · has-interaction-information · PDF-Seite 6

Effect of other medicinal products on rucaparib Enzymes responsible for rucaparib metabolism have not been identified. Based on in vitro data, CYP2D6, and to a lesser extent CYP1A2 and CYP3A4, were able to metabolize rucaparib. Although in vitro rucaparib metabolism mediated by CYP3A4 was slow, a significant contribution of CYP3A4 in vivo cannot be excluded. Caution should be used for concomitant use of strong CYP3A4 inhibitors or inducers. In vitro, rucaparib was shown to be a substrate of P-gp and BCRP. Effect of P-gp and BCRP inhibitors on rucaparib PK cannot be ruled out. Caution is recommended when rucaparib is co-administered with medicinal products that are strong inhibitors of P-gp. Effects of rucaparib on other medicinal products In medicinal product interaction studies in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, BCRP and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, rosuvastatin, and digoxin, respectively). The effect of rucaparib on the pharmacokinetics of the combined oral contraceptive (ethinylestradiol and levonorgestrel) was also evaluated. Data suggest that rucaparib is a moderate inhibitor of CYP1A2, and a mild inhibitor of CYP2C9, CYP2C19, and CYP3A. Rucaparib also marginally inhibits P-gp and weakly inhibits BCRP in the gut. CYP1A2 substrates Rucaparib showed no effect on Cmax of caffeine while moderately increasing AUCinf of caffeine by 2.55 fold (90% CI: 2.12, 3.08). When co-administering medicinal products metabolized by CYP1A2, particularly medicines which have a narrow therapeutic index (e.g., tizanidine, theophylline), dose adjustments may be considered based on appropriate clinical monitoring. CYP2C9 substrates Rucaparib increased S-warfarin Cmax by 1.05 fold (90% CI: 0.99 to 1.12) and AUC0-96 h by 1.49 fold (90% CI: 1.40 to 1.58), respectively. When co-administering medicinal products that are CYP2C9 substrates with a narrow therapeutic index (e.g., warfarin, phenytoin), dose adjustments may be considered, if clinically indicated. Caution should be exercised and additional International Normalised Ratio (INR) monitoring with co-administration of warfarin and therapeutic drug level monitoring of phenytoin should be considered, if used concomitantly with rucaparib. CYP2C19 substrates Rucaparib increased omeprazole Cmax by 1.09 fold (90% CI: 0.93 to 1.27) and AUCinf by 1.55 fold (90% CI: 1.32 t

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HOS-098049 · has-pregnancy-information · PDF-Seite 7

Women of childbearing potential/contraception in females Women of childbearing potential should be advised to avoid becoming pregnant while receiving rucaparib. Patients should be advised to use effective contraception during treatment and for 6 months following the last dose of rucaparib (see section 4.5). Pregnancy There are no or limited data from the use of rucaparib in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). Based on its mechanism of action and preclinical data, rucaparib may cause foetal harm when administered to a pregnant woman. Rubraca should not be used during pregnancy unless the clinical condition of the woman requires treatment with rucaparib. A pregnancy test before initiating treatment is recommended in women of reproductive potential. Breast-feeding There are no animal studies on the excretion of rucaparib in breast milk. It is unknown whether rucaparib/or its metabolites are excreted in human milk. A risk to the newborns/infants cannot be excluded. Rubraca must not be used during breast-feeding. Because of the potential for serious adverse reactions in breast-fed infants from rucaparib, 7 breast-feeding is contraindicated during treatment with Rubraca and for 2 weeks after the final dose (see section 4.3). Fertility There are no data on the effect of rucaparib on human fertility. Based on the animal studies, impact on fertility associated with the use of rucaparib cannot be ruled out (see section 5.3). Moreover, according to its mechanism of action, rucaparib may impact human fertility.

HOS-098047 · has-warning-information · PDF-Seite 4

Haematological toxicity During treatment with rucaparib, events of myelosuppression (anaemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8 to 10 weeks of treatment with rucaparib. These reactions are manageable with routine medical treatment and/or dose adjustment 4 for more severe cases. Complete blood count testing prior to starting treatment with Rubraca, and monthly thereafter, is advised. Patients should not start Rubraca treatment until they have recovered from haematological toxicities caused by previous chemotherapy (≤ CTCAE Grade 1). Supportive care and institutional guidelines should be implemented for the management of low blood counts for the treatment of anaemia and neutropenia. Rubraca should be interrupted or dose reduced according to Table 1 (see section 4.2) and blood counts monitored weekly until recovery. If the levels have not recovered to CTCAE Grade 1 or better after 4 weeks, the patient should be referred to a haematologist for further investigations. Myelodysplastic syndrome/acute myeloid leukaemia Myelodysplastic syndrome/acute myeloid leukaemia (MDS/AML), including cases with fatal outcome, have been reported in patients who received rucaparib. The duration of therapy with rucaparib in patients who developed MDS/AML varied from < 2 months to approximately 6 years. If MDS/AML is suspected, the patient should be referred to a haematologist for further investigations, including bone marrow analysis and blood sampling for cytogenetics. If, following investigation for prolonged haematological toxicity, MDS/AML is confirmed, Rubraca should be discontinued. Photosensitivity Photosensitivity has been observed in patients treated with rucaparib. Patients should avoid spending time in direct sunlight because they may burn more easily during rucaparib treatment; when outdoors, patients should wear a hat and protective clothing, and use sunscreen and lip balm with sun protection factor (SPF) of 50 or greater. Gastrointestinal toxicities Gastrointestinal toxicities (nausea and vomiting) are frequently reported with rucaparib, are generally low grade (CTCAE Grade 1 or 2) and may be managed with dose reduction (refer to Table 1) or interruption. Antiemetics, such as 5-HT3 antagonists, dexamethasone, aprepitant and fosaprepitant, can be used as treatment for nausea/vomiting and may also be considered for prophylactic (i.e., preventative) use

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