Chemical formula: C₁₉H₁₈FN₃O Molecular mass: 323.371 g/mol PubChem compound: 9931954
Rucaparib interacts in the following cases:
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 increase metformin renal elimination and decrease liver uptake of metformin, caution is advised when metformin is co-administered with rucaparib. In addition, rucaparib is an inhibitor of the BCRP with IC50 value suggesting potential BCRP inhibition and increased exposures of medicinal products that are BCRP substrates (e.g., rosuvastatin). 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.
In a medicinal product interaction study in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, respectively). 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 in the gut.
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.
In a medicinal product interaction study in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, respectively). 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 in the gut.
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 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.
In a medicinal product interaction study in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, respectively). 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 in the gut.
Rucaparib increased S-warfarin Cmax by 1.05 fold (90% CI: 0.99 to 1.12) and AUC0-96h 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.
In a medicinal product interaction study in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, respectively). 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 in the gut.
Rucaparib increased midazolam Cmax by 1.13 fold (90% CI: 0.95 to 1.36) and AUCinf 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. Interactions between rucaparib and oral contraceptives have not been studied.
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.
In a medicinal product interaction study in cancer patients, the effects of steady-state rucaparib at 600 mg twice daily on CYP1A2, CYP2C9, CYP2C19, CYP3A, and P-gp were evaluated with single oral doses of sensitive probes (caffeine, S-warfarin, omeprazole, midazolam, and digoxin, respectively). 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 in the gut.
Rucaparib showed no effect on Cmax of digoxin while marginally increasing AUC0-72h 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.
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.
There are limited clinical data in patients with moderate or severe hepatic impairment (ie, any total bilirubin greater than 1.5 times ULN), therefore rucaparib is not recommended for use in patients with moderate or severe hepatic impairment.
Liver transaminase elevations (aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT)) occur early in treatment and are generally transient. Grade 1-3 elevations in AST/ALT can be managed without change to the rucaparib dose, or with treatment modification (interruption and/or dose reduction). Grade 4 reactions require treatment modification (see Table).
Other moderate to severe non-haematological adverse reactions such as nausea and vomiting, can be managed through dose interruption and/or reductions, if not adequately controlled by appropriate symptomatic management.
Management of Treatment-emergent AST/ALT Elevations:
| Grade of AST/ALT Elevation | Management |
|---|---|
| Grade 3 without other signs of liver dysfunction | Monitor LFTs weekly until resolution to Grade ≤2. Continue rucaparib provided bilirubin is < ULN and alkaline phosphatase is <3 x ULN. Interrupt treatment if AST/ALT levels do not decline within 2 weeks until Grade ≤2, then resume rucaparib at the same or at a reduced dose. |
| Grade 4 | Interrupt rucaparib until values return to Grade ≤2; then resume rucaparib with a dose reduction and monitor LFTs weekly for 3 weeks. |
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.
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 less than 1 month to approximately 28 months.
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, rucaparib should be discontinued.
During treatment with rucaparib, events of myelosuppression (anaemia, neutropenia, thrombocytopenia) may be observed and are typically first observed after 8-10 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 rucaparib, and monthly thereafter, is advised. Patients should not start rucaparib 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. Rucaparib should be interrupted or dose reduced according to the table below 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.
Adverse reactions may be managed through dose interruptions and/or dose reductions for moderate to severe reactions (i.e. CTCAE Grade 3 or 4) such as neutropenia, anaemia and thrombocytopenia.
Other moderate to severe non-haematological adverse reactions such as nausea and vomiting, can be managed through dose interruption and/or reductions, if not adequately controlled by appropriate symptomatic management.
Recommended dose adjustments:
| Dose reduction | Dose |
|---|---|
| Starting dose | 600 mg twice daily |
| First dose reduction | 500 mg twice daily |
| Second dose reduction | 400 mg twice daily |
| Third dose reduction | 300 mg twice daily |
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 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 rucaparib. 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.
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.
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 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.
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.
The overall safety profile of rucaparib is based on data from 937 patients in clinical trials in ovarian cancer treated with rucaparib monotherapy.
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, thrombocytopenia and creatinine elevations. 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 (23%), ALT elevations (10%), fatigue/asthenia (10%), neutropenia (8%), thrombocytopenia (6%), and nausea (5%). 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 (20%), fatigue/asthenia (18%), nausea (16%), thrombocytopenia (15%), and AST/ALT elevations (10%). Adverse reactions leading to permanent discontinuation occurred in 10% of patients, with thrombocytopenia, nausea, anaemia, and fatigue/asthenia being the most frequent adverse reactions leading to permanent discontinuation.
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 <1/1000); very rare (<1/10,000), not known (cannot be estimated from the available data).
Frequency of all CTCAE grades:
Common: Myelodysplastic syndrome/Acute myeloid leukaemiaa
Frequency of CTCAE grade 3 and above:
Common: Myelodysplastic syndrome/Acute myeloid leukaemiaa
Frequency of all CTCAE grades:
Very common: Anaemiab, Thrombocytopeniab, Neutropeniab
Common: Leukopeniab, Lymphopeniab, Febrile neutropenia
Frequency of CTCAE grade 3 and above:
Very common: Anaemiab
Common: Thrombocytopeniab, Neutropeniab, Febrile neutropenia, Leukopeniab
Uncommon: Lymphopeniab
Frequency of all CTCAE grades:
Very common: Decreased appetite, Increased blood creatinineb
Common: Hypercholesterolaemiab, Dehydration
Frequency of CTCAE grade 3 and above:
Common: Decreased appetite, Dehydration
Uncommon: Increased blood creatinine, Hypercholesterolaemiab
Frequency of all CTCAE grades:
Very common: Dysgeusia, Dizziness
Frequency of CTCAE grade 3 and above:
Uncommon: Dysgeusia, Dizziness
Frequency of all CTCAE grades:
Common: Dyspnoea
Frequency of CTCAE grade 3 and above:
Uncommon: Dyspnoea
Frequency of all CTCAE grades:
Very common: Nausea, Vomiting, Diarrhoea, Dyspepsia, Abdominal pain
Frequency of CTCAE grade 3 and above:
Common: Nausea, Vomiting, Diarrhoea, Abdominal pain
Uncommon: Dyspepsia
Frequency of all CTCAE grades:
Very common: Increased alanine aminotransferase, Increased aspartate aminotransferase
Common: Increased transaminasesb
Frequency of CTCAE grade 3 and above:
Common: Increased alanine aminotransferase, Increased aspartate aminotransferase
Uncommon: Increased transaminases
Frequency of all CTCAE grades:
Very common: Photosensitivity reaction, Rash
Common: Rash maculo-papular, Palmarplantar erythrodysaesthesia syndrome, Erythema
Frequency of CTCAE grade 3 and above:
Uncommon: Photosensitivity reaction, Rash, Rash maculo-papular, Palmarplantar erythrodysaesthesia syndrome
Frequency of all CTCAE grades:
Very common: Fatiguec, Pyrexia
Frequency of CTCAE grade 3 and above:
Common: Fatiguec
Uncommon: Pyrexia
a MDS/AML rate is based on overall total patient population of 1321 who have received one dose of oral rucaparib.
b Includes laboratory findings.
c Includes fatigue, asthenia and lethargy.
Haematological adverse reactions of all CTCAE Grades of anaemia, thrombocytopenia and neutropenia were reported in 42%, 26% and 16% of patients respectively. Thrombocytopenia and anaemia led to discontinuation in 1.8% and 2.1% of patients. Adverse reactions CTCAE Grade 3 or higher occurred in 23% (anaemia), 8% (neutropenia) and 6% (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).
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 (1.3%) for all patients including during the long term safety follow up (rate is calculated based on overall safety population of 1321 patients exposed to at least one dose of oral rucaparib in all clinical studies). In the pivotal Phase 3 study (ARIEL3), the incidence of MDS/AML during therapy in patients who received rucaparib was 0.8%. Although no cases were reported during therapy in patients who received placebo, one case has been reported in a placebo-treated patient 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.
Vomiting and nausea were reported in 42% and 77% of patients, respectively and were generally low grade (CTCAE Grade 1 to 3). Abdominal pain (combined terms abdominal pain, abdominal pain lower, abdominal pain upper) was reported in 40.1% of rucaparib treated patients, but was also very common (33%) in placebo patients, most likely associated with underlying disease.
Photosensitivity was reported in 13% of patients as low grade skin reactions (CTCAE Grade 1 or 2), and by 2 (0.2%) patients as ≥ CTCAE Grade 3 reaction.
Events related to increases in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were observed in 38% (all grades) and 11% (≥ 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 34.8% (all grades) and 9.9% (≥ CTCAE Grade 3) of patients, increased AST in 31.4% (all grades) and 2.8% (≥ CTCAE Grade 3) of patients and increased ALT and AST in 28.6% (all grades) and 2.1% (≥ 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.
Increases in serum creatinine, predominantly mild to moderate (CTCAE Grade 1 or 2), were observed in 20% of patients within the first few weeks of treatment with rucaparib. Four (0.4%) 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.
In patients ≥75 years old, frequencies of some adverse reactions increased: increased blood creatinine (32%), dizziness (20%), pruritus (15%), and memory impairment (4%) were higher than in patients <75 years old (18%, 15%, 9% and 1% respectively).
In patients with moderate renal impairment (CLcr of 30-59 mL/min), frequencies of some adverse reactions increased: Grade 3 or 4 anaemia (31%), Grade 3 or 4 thrombocytopenia (12%), and Grade 3 fatigue/asthenia (15%) were higher than in patients with mild renal impairment (CLcr >59-80 mL/min) or normal renal function (CLcr >80 mL/min) (21%, 5%, and 8%).
No studies have been conducted to investigate the pharmacokinetics of rucaparib in paediatric patients.
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