RUBRACA Film-coated tablet Ref.[7613] Active ingredients: Rucaparib

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 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 prior to starting Rubraca. It is important to proactively manage these events to avoid prolonged or more severe events of nausea/vomiting which have the potential to lead to complications such as dehydration or hospitalisation.

Intestinal obstruction

Cases of intestinal obstruction have been observed in ovarian cancer patients treated with rucaparib in clinical trials; 3.5% of patients treated with rucaparib experienced a serious event of intestinal obstruction, with a fatal outcome in 1 rucaparib treated patient (less than 0.1%). The underlying disease may play a role in the development of intestinal obstruction in patients with ovarian cancer. In the event of suspected intestinal obstruction, a prompt diagnostic evaluation should be conducted and the patient should be treated appropriately.

Embryofoetal toxicity

Rubraca can cause foetal harm when administered to a pregnant woman based on its mechanism of action and findings from animal studies. In an animal reproduction study, administration of rucaparib to pregnant rats during the period of organogenesis resulted in embryo-foetal toxicity at exposures below those in patients receiving the recommended human dose of 600 mg twice daily (see section 5.3).

Pregnancy/contraception

Pregnant women should be informed of the potential risk to a foetus. Women of reproductive potential should be advised to use effective contraception during treatment and for 6 months following the last dose of Rubraca (see section 4.6). A pregnancy test before initiating treatment is recommended in women of reproductive potential.

Excipients

This medicine contains less than 1 mmol sodium (23 mg) per tablet, that is to say essentially 'sodium-free'.

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 C_max of caffeine while moderately increasing AUC_inf 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 C_max by 1.05 fold (90% CI: 0.99 to 1.12) and AUC_0-96h 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 C_max by 1.09 fold (90% CI: 0.93 to 1.27) and AUC_inf by 1.55 fold (90% CI: 1.32 to 1.83). The risk for a clinically relevant effect of concomitant administration of proton pump inhibitors (PPIs) is likely small (see section 5.2). No dose adjustment is considered necessary for co-administered medicinal products that are CYP2C19 substrates.

CYP3A substrates

Rucaparib increased midazolam C_max by 1.13 fold (90% CI: 0.95 to 1.36) and AUC_inf by 1.38 fold (90% CI: 1.13 to 1.69). Caution is advised when co-administering medicinal products that are CYP3A substrates with a narrow therapeutic index (e.g., alfentanil, astemizole, cisapride, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, terfenadine). Dose adjustments may be considered, if clinically indicated based on observed adverse reactions.

Oral contraceptives

Rucaparib increased ethinylestradiol C_max by 1.09 fold (90% CI: 0.94 to 1.27) and AUC_last by 1.43 fold (90% CI: 1.15 to 1.77). Rucaparib increased levonorgestrel C_max by 1.19 fold (90% CI: 1.00 to 1.42) and AUC_last by 1.56 fold (90% CI: 1.33 to 1.83). No dose adjustment is recommended for co-administered oral contraceptives.

BCRP substrates

Rucaparib increased rosuvastatin C_max by 1.29 fold (90% CI: 1.07 to 1.55) and AUC_inf by 1.35 fold (90% CI: 1.17 to 1.57). No dose adjustment is recommended for co-administered medicinal products that are BCRP substrates.

P-gp substrates

Rucaparib showed no effect on C_max of digoxin while marginally increasing AUC_0-72h by 1.20 fold (90% CI: 1.12 to 1.29). No dose adjustment is recommended for co-administered medicinal products that are P-gp substrates.

Interaction of rucaparib with other enzymes and transporter was evaluated in vitro. Rucaparib is a weak inhibitor of CYP2C8, CYP2D6, and UGT1A1. Rucaparib down regulated CYP2B6 in human hepatocytes at clinically relevant exposures. Rucaparib is a potent inhibitor of MATE1 and MATE2-K, a moderate inhibitor of OCT1, and a weak inhibitor of OCT2. As inhibition of these transporters could decrease metformin renal elimination and decrease liver uptake of metformin, caution is advised when metformin is co-administered with rucaparib. The clinical relevance of UGT1A1 inhibition by rucaparib is not clear. Caution should be used when rucaparib is co-administered with UGT1A1 substrates (i.e. irinotecan) to patients with UGT1A1*28 (poor metabolizer) due to a possible increase in the exposure of SN-38 (the active metabolite of irinotecan) and associated toxicities.

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, 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.

Rubraca has minor influence on the ability to drive and use machines. Caution when driving or using machines is advised for patients who report fatigue, nausea, or dizziness during treatment with Rubraca (see section 4.8).

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:

^a MDS/AML rate is based on overall total patient population of 3 025 who have received one dose of oral rucaparib.
^b Includes laboratory findings
^c Most commonly observed events include hypersensitivity, drug hypersensitivity and swelling/oedema of the face and eyes.
^d Includes intestinal obstruction, large intestinal obstruction, and small intestinal obstruction
^e Includes fatigue, asthenia and lethargy

Description of selected adverse reactions

Haematological toxicity

Haematological adverse reactions of all CTCAE Grades of anaemia, thrombocytopenia and neutropenia were reported in 46%, 26% and 21% of patients, respectively. Anaemia and thrombocytopenia led to discontinuation in 2% and 1% of patients, respectively. Adverse reactions CTCAE Grade 3 or higher occurred in 25% (anaemia), 10% (neutropenia) and 7% (thrombocytopenia) of patients. The time of onset for adverse reactions of myelosuppression Grade 3 or higher was generally later in treatment (after 2 or more months). For risk mitigation and management, see section 4.4.

Myelodysplastic syndrome/Acute myeloid leukaemia

MDS/AML are serious adverse reactions that occur uncommonly (0.5%) in patients on treatment and during the 28 day safety follow up, and commonly (1.1%) for all patients including during the long term safety follow up (rate is calculated based on overall safety population of 3 025 patients exposed to at least one dose of oral rucaparib in all clinical studies). In the placebo-controlled Phase 3 studies, ARIEL3 and ATHENA-MONO, the incidence of MDS/AML during therapy in patients who received rucaparib was 1.6% and 0.5%, respectively. Although no cases were reported during therapy in patients who received placebo, six cases have been reported in placebo-treated patients during the long term safety follow up. All patients had potential contributing factors for the development of MDS/AML; in all cases, patients had received previous platinum-containing chemotherapy regimens and/or other DNA damaging agents. For risk mitigation and management, see section 4.4.

Gastrointestinal toxicities

Vomiting and nausea were reported in 37% and 68% of patients, respectively, and were generally low grade (CTCAE Grade 1 to 2). Abdominal pain (combined terms abdominal pain, abdominal pain lower, abdominal pain upper) was reported in 39% of rucaparib treated patients, but was also very common (34%) in placebo patients, most likely associated with underlying disease. For risk mitigation and management, see section 4.4.

Photosensitivity

Photosensitivity was reported in 10% of patients as low grade skin reactions (CTCAE Grade 1 or 2), and by 0.2% of patients as ≥ CTCAE Grade 3 reaction. For risk mitigation and management, see section 4.4.

Increases in serum aminotransferases (AST/ALT)

Events related to increases in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) were observed in 39% (all grades) and 10% (≥ CTCAE Grade 3) of patients. These events occurred within the first few weeks of treatment with rucaparib, were reversible, and were rarely associated with increases in bilirubin. Increased ALT was observed in 37% (all grades) and 10% (≥ CTCAE Grade 3) of patients; increased AST in 33% (all grades) and 3% (≥ CTCAE Grade 3) of patients and increased ALT and AST in 31% (all grades) and 3% (≥ CTCAE Grade 3) of patients. No events met Hy's Law criteria for drug-induced liver injury. AST/ALT elevations may need to be managed with treatment interruption and/or dose reduction as described in Table 2 (see section 4.2). Most patients could continue rucaparib with or without treatment modification without recurrence of Grade ≥ 3 LFT abnormalities.

Elevations in serum creatinine

Increases in serum creatinine, predominantly mild to moderate (CTCAE Grade 1 or 2), were observed in 17% of patients within the first few weeks of treatment with rucaparib; 0.6% of patients reported a CTCAE Grade 3 reaction. Elevations in creatinine with rucaparib treatment may be due to inhibition of the renal transporters MATE1 and MATE2-K (see section 4.5). These increases in serum creatinine were clinically asymptomatic.

Elderly

In patients ≥75 years old, frequencies of some adverse reactions increased: increased blood creatinine (33%), dizziness (19%), pruritus (16%), and memory impairment (4%) were higher than in patients <75 years old (16%, 14%, 11% and 1%, respectively).

Patients with Renal Impairment

In patients with moderate renal impairment (CLcr of 30-59 mL/min), frequencies of some adverse reactions of Grade 3 or above severity increased: anaemia (34%), neutropenia (13%), thrombocytopenia (12%), fatigue/asthenia (12%) and combined AST/ALT increased (12%) were higher than in patients with normal renal function (CLcr >90 mL/min) (23%, 8%, 5%, 7% and 7%, respectively).

Paediatric population

No studies have been conducted to investigate the pharmacokinetics of rucaparib in paediatric 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.