Rucaparib

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.

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.

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. No dose adjustment is considered necessary for co-administered medicinal products that are CYP2C19 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.

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.

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.

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.

There are no clinical data in patients with severe renal impairment (CLcr less than 30 mL/min), therefore rucaparib is not recommended for use in patients with severe renal impairment. Rucaparib may only be used in patients with severe renal impairment if the potential benefit outweighs the risk. Patients with moderate or severe renal impairment should be carefully monitored for renal function and adverse reactions.

Patients with moderate hepatic impairment should be carefully monitored for hepatic function and adverse reactions.

There are no clinical data in patients with severe hepatic impairment (i.e., total bilirubin >3 times ULN), therefore rucaparib is not recommended for use in patients with severe hepatic impairment.

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. Moreover, according to its mechanism of action, rucaparib may impact human fertility.

There are no or limited data from the use of rucaparib in pregnant women. Studies in animals have shown reproductive toxicity. Based on its mechanism of action and preclinical data, rucaparib may cause fetal harm when administered to a pregnant woman. Rucaparib 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.

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. Rucaparib 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 rucaparib and for 2 weeks after the final dose.

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.

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. Moreover, according to its mechanism of action, rucaparib may impact human fertility.

Rucaparib 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 rucaparib.

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).

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).

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.

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.

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.

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. 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. 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.