Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and microbial flora. Therefore, no pharmacokinetic interaction is expected with rucaparib.

Coadministration has not been studied but should be approached with caution. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Rucaparib is an inhibitor of CYPs 1A2 (moderate), 2C9 (weak) and 2C19 (weak), and may increase concentrations of agomelatine. Coadministration of caffeine, a CYP1A2 substrate, with rucaparib increased caffeine exposure by 2.55-fold. A similar effect may occur with agomelatine. If coadministration is unavoidable, monitor closely for agomelatine toxicity. A dose reduction of agomelatine may be necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Rucaparib is an in vitro inhibitor of P-gp. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with aliskiren.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ambrisentan is metabolised by glucuronidation via UGTs 1A3, 1A9 and 2B7 and to a lesser extent by CYP3A4 and CYP2C19. Ambrisentan is also a substrate of P-gp. Rucaparib is an inhibitor of CYP3A4 (weak), CYP2C19 (weak) and P-gp (in vitro), and may increase ambrisentan concentrations. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with ambrisentan. Furthermore, both CYP3A4 and CYP2C19 are minor metabolic pathway. No clinically relevant effect on ambrisentan exposure is expected.

Coadministration has not been studied but care should be taken. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. In vitro, rucaparib has shown weak inhibition of OCT2 at clinical relevant concentrations and may increase amiloride concentrations. As the clinical relevance of this interaction is unknown, monitoring of blood pressure and amiloride toxicity may be required.

Coadministration has not been studied but is not recommended. Amiodarone is metabolised by CYP3A4 and CYP2C8. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of amiodarone. Monitoring for amiodarone toxicity may be required. Furthermore, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong) and 2B6 (moderate) and P-gp (strong). In vitro, rucaparib is metabolised by CYP3A4 and CYP2D6, and is also an in vitro substrate of P-gp and concentrations may increase due to inhibition by desethylamiodarone. As the clinical relevance of these interactions is unknown, care should be taken and monitoring for rucaparib toxicity may be required. Monitoring of rucaparib concentrations should be considered, if available. Furthermore, rucaparib and amiodarone may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised but is eliminated to a large extent in the bile. Rucaparib does not interfere with this elimination pathway. However, the European SPC for amphotericin B states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension. Monitoring may be required.

Coadministration has not been studied but care should be taken. Apixaban is a substrate of P-gp and BCRP, and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Rucaparib is a weak inhibitor of CYPs 3A4, 2C9 and 2C19, a moderate inhibitor of CYP1A2 and an in vitro inhibitor of BCRP and P-gp. Therefore, concentrations of apixaban may increase. Monitoring for apixaban toxicity and anti-Xa activity may be required.

Coadministration has not been studied but is not recommended. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Rucaparib is an in vitro inhibitor of P-gp. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with azithromycin. No clinically relevant on azithromycin exposure is expected. Furthermore, azithromycin is an inhibitor of P-gp. In vitro, rucaparib is a substrate of P-gp and concentrations may increase due to coadministration with azithromycin. As the clinical relevance of this interaction is unknown, monitoring for rucaparib toxicity may be required. Rucaparib and azithromycin may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but care should be taken. Bosentan is a substrate of CYP3A4 and CYP2C9. Rucaparib is a weak inhibitor of CYP3A4 and CYP2C9, and may increase bosentan concentrations. Monitoring of blood pressure and bosentan toxicity may be required. Furthermore, bosentan is a weak inducer of CYP3A4 and CYP2C9. In vitro, rucaparib is metabolised by CYP3A4 and exposure may decrease due to induction by bosentan. As the clinical relevance of this interaction is unknown, monitoring of rucaparib efficacy and, if available, rucaparib plasma concentrations may be required.

Coadministration has not been studied but care should be taken. Bupropion is primarily metabolised by CYP2B6. Rucaparib does not inhibit or induce CYP2B6. However, bupropion is a strong inhibitor of CYP2D6. In vitro, rucaparib is metabolised by CYP2D6 and concentrations may increase due to inhibition by bupropion. As the clinical relevance of this interaction is unknown, care should be taken and monitoring for rucaparib toxicity may be required.

Coadministration has not been studied but care should be taken. Buspirone is metabolised by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of buspirone. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with buspirone. Monitoring for buspirone toxicity may be required.

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent CYP2C9 and CYP1A2. Rucaparib is an inhibitor of CYP2C9 (weak), CYP1A2 (moderate) and UGT1A1 (in vitro) and may increase concentrations of carvedilol. As the clinical relevance of this interaction is unknown, monitoring for carvedilol toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Caspofungin undergoes spontaneous chemical degradation and metabolism via a non CYP-mediated pathway. Rucaparib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but care should be taken. Chloramphenicol is predominantly glucuronidated. Rucaparib is an in vitro inhibitor of UGT1A1 and may increase concentrations of chloramphenicol. Furthermore, in vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). In vitro, rucaparib is metabolised by CYP2D6 and CYP3A4 and concentrations may increase due to inhibition by chloramphenicol. As the clinical relevance of this interaction is unknown, monitoring for rucaparib and chloramphenicol toxicity may be required. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically relevant interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Rucaparib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but care should be taken. Ciclosporin is a substrate of CYP3A4 and P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro), and may increase concentrations of ciclosporin. Monitoring for ciclosporin toxicity and, if available, plasma concentrations should be considered. Furthermore, ciclosporin is an inhibitor of CYP3A4 and OATP1B1. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by ciclosporin. The clinical relevance of this interaction is unknown but a significant effect on rucaparib exposure is not expected.

Coadministration has not been studied but care should be taken. Cimetidine is metabolised by CYP450 enzymes. Rucaparib is a weak inhibitor of CYPs 3A4, 2C9 and 2C19 and a moderate inhibitor of CYP1A2. Concentrations of cimetidine may increase due to inhibition by rucaparib. As the clinical relevance of this interaction is unknown, monitoring for cimetidine toxicity may be required. Furthermore, in vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. In vitro, rucaparib is metabolised by CYPs 2D6, 3A4 and 1A2, and concentrations may increase due to inhibition by cimetidine. The clinical relevance of this interaction is unknown. Care should be taken and monitoring for rucaparib toxicity may be required. Additionally, rucaparib has a pH independent solubility between pH 3 and 7, and no clinically relevant effect on the absorption of rucaparib is expected.

Coadministration has not been studied but is not recommended. Clarithromycin is metabolised by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of clarithromycin. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with clarithromycin. Furthermore, clarithromycin is an inhibitor of CYP3A4 (strong) and P-gp. In vitro, rucaparib is a substrate of CYP3A4 and P-gp and concentrations may increase due to inhibition by clarithromycin. As the clinical relevance of this interaction is unknown, monitoring for rucaparib toxicity may be required. Rucaparib and clarithromycin may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces. Rucaparib is unlikely to interfere with this elimination pathway. Furthermore, in vitro data suggest that clofazimine is a CYP3A4 inhibitor. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by clofazimine. The clinical relevance of this interaction is unknown, but a significant effect on rucaparib exposure is not expected. Rucaparib and clofazimine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but care should be taken. Clopidogrel is a prodrug and is converted to its active metabolite mainly by CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Rucaparib is an inhibitor of CYPs 2C19 (weak), 3A4 (weak) and 1A2 (moderate), and may increase concentrations of clopidogrel. Coadministration of omeprazole, a CYP2C19 substrate, with rucaparib increased omeprazole exposure by 1.55-fold. A similar effect may occur with clopidogrel. Thrombocyte aggregation tests and monitoring for clopidogrel toxicity may be required. Furthermore, clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. The clinical relevance of CYP2C9 inhibition by clopidogrel is unknown. Rucaparib is not metabolised by these CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dabigatran is transported via P-gp and is renally excreted. Rucaparib is an in vitro inhibitor of P-gp. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with dabigatran.

Coadministration has not been studied but care should be taken. Dexamethasone is a substrate of CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of dexamethasone. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with dexamethasone. Monitoring for dexamethasone toxicity may be required. Futhermore, dexamethasone has been described as a weak inducer of CYP3A4. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may decrease. However, the clinical relevance of this interaction is not known as the induction of CYP3A4 by dexamethasone has not yet been established. Monitoring of rucaparib efficacy and, if available, rucaparib concentrations may be required.

Coadministration has not been studied but care should be taken. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Rucaparib is a weak inhibitor of CYP2C9 and may increase concentrations of diclofenac. Monitoring for diclofenac toxicity may be required.

Coadministration has not been studied but is not recommended. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Rucaparib is an inhibitor of CYPs 1A2 (moderate), 2C9 (weak) and 2C19 (weak), and may increase diphenhydramine concentrations. Since these are minor pathways, no clinically relevant effect on diphenhydramine exposure is expected. However, diphenhydramine is a weak inhibitor of CYP2D6. In vitro, rucaparib is metabolised by CYP2D6 and concentrations may increase due to inhibition by diphenhydramine. As the clinical relevance of this interaction is unknown, monitoring for rucaparib toxicity may be required. Rucaparib and diphenhydramine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but is not recommended. Erythromycin is a substrate of CYP3A4 and P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro) and may increase concentrations of erythromycin. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). Similar effects may occur with erythromycin. Furthermore, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. In vitro, rucaparib is a substrate of CYP3A4 and P-gp and concentrations may increase due to inhibition by erythromycin. As the clinical relevance of this interaction is unknown, monitoring for rucaparib and erythromycin toxicity may be required. Rucaparib and erythromycin may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but care should be taken. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Rucaparib is an inhibitor of CYP3A4 (weak), CYP2C9 (weak) and UGT1A1 (in vitro), and may increase concentrations of ethinylestradiol. Monitoring for ethinylestradiol toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. In vitro data suggest that fenofibric acid inhibits OAT3. Rucaparib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also renally eliminated unchanged (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Rucaparib is an in vitro inhibitor of UGT1A1 and may increase furosemide concentrations. However, since UGT1A1 is a minor pathway, no clinically relevant effect on furosemide exposure is expected. Furthermore, in vitro data indicate that furosemide is an inhibitor of OAT1/OAT3. Rucaparib is not transported by OATs.

Coadministration has not been studied but care should be taken. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Rucaparib is a weak inhibitor of CYP3A4 and CYP2C9, and may increase concentrations of glibenclamide. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with glibenclamide. Monitoring of blood glucose levels and glibenclamide toxicity may be required.

Coadministration has not been studied but care should be taken. Gliclazide is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C19. Rucaparib is a weak inhibitor of CYP2C9 and CYP2C19, and may increase concentrations of gliclazide. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with gliclazide. Monitoring of blood glucose levels and gliclazide toxicity and may be required.

Coadministration has not been studied but care should be taken. Glimepiride is mainly metabolised by CYP2C9. Rucaparib is a weak inhibitor of CYP2C9 and may increase concentrations of glimepiride. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with glimepiride. Monitoring of blood glucose levels and glimepiride toxicity may be required.

Coadministration has not been studied but care should be taken. Glipizide is mainly metabolised by CYP2C9. Rucaparib is a weak inhibitor of CYP2C9 and may increase concentrations of glipizide. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with glipizide. Monitoring of blood glucose levels and glipizide toxicity may be required.

Coadministration has not been studied but should be approached with caution. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Rucaparib is unlikely to interfere with this elimination pathway. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolised by CYPs, such as rucaparib. In vitro, rucaparib is metabolised by CYPs 2D6, 3A4 and 1A2, and concentrations may decrease due to induction by griseofulvin. As the clinical relevance of this interaction is unknown, monitoring of rucaparib efficacy is recommended. Monitoring rucaparib plasma concentrations should be considered, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Heparin is thought to be eliminated via the reticuloendothelial system. Rucaparib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised but is cleared by the kidneys via OAT1. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Rucaparib does not inhibit or induce OATs.

Coadministration has not been studied but is not recommended. Indapamide is extensively metabolised by CYP450s. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Rucaparib is a moderate inhibitor of CYP1A2 and a weak inhibitor of CYPs 2C9, 2C19 and 3A4, Concentrations of indapamide may increase. As the clinical relevance of this interaction is unknown, monitoring of blood pressure and indapamide toxicity may be required. Rucaparib and indapamide may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but care should be taken. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Rucaparib is an inhibitor of CYP2C9 (weak) and UGT1A1 (in vitro), and may increase concentrations of irbesartan. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with irbesartan. Monitoring for irbesartan toxicity and blood pressure may be required.

Coadministration has not been studied but care should be taken. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of isosorbide dinitrate. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with isosorbide dinitrate. Monitoring of blood pressure and isosorbide dinitrate toxicity may be required.

Coadministration has not been studied but care should be taken. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Rucaparib is an in vitro inhibitor of UGT1A1 and may increase labetalol exposure. The clinical relevance of this interaction is unknown. Care should be taken. Monitoring of blood pressure and labetalol toxicity may be required.

Coadministration has not been studied but care should be taken. Lacidipine is metabolised by CYP3A4. Rucaparib is a weak inhibitor fo CYP3A4 and may increase concentrations of lacidipine. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with lacidipine. Monitoring of blood pressure and lacidipine toxicity may be required.

Coadministration has not been studied but care should be taken. Lercanidipine is mainly metabolised by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of lercanidipine. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with lercanidipine. Monitoring of blood pressure and lercanidipine toxicity may be required.

Coadministration has not been studied but should be approached with caution. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Rucaparib is an inhibitor of CYP1A2 (moderate) and CYP3A4 (weak), and may increase concentrations of lidocaine. Coadministration of caffeine, a CYP1A2 substrate, with rucaparib increased caffeine exposure by 2.55-fold. A similar effect may occur with lidocaine. If coadministration is unavoidable, monitor closely for lidocaine toxicity. A dose reduction of lidocaine may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro), and may increase concentrations of linagliptin. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with linagliptin. Furthermore, since CYP3A4 is only a minor metabolic pathway, no clinically relevant effect on linagliptin exposure is expected. Linagliptin is also a weak inhibitor of CYP3A4. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by linagliptin. The clinical relevance of this interaction is unknown but a significant effect on rucaparib exposure is not expected.

Coadministration has not been studied but care should be taken. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Rucaparib is a weak inhibitor of CYP2C9 and may increase concentrations of losartan and thus decrease concentrations of the active metabolite. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with losartan. Monitoring of losartan efficacy and blood pressure may be required.

Coadministration has not been studied but care should be taken. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Rucaparib is a weak inhibitor of CYPs 3A4, 2C19 and 2C9, and may increase macitentan concentrations. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with macitentan. Monitoring of blood pressure and macitentan toxicity may be required.

Coadministration has not been studied but care should be taken. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Rucaparib has shown in vitro inhibition of OCT1 (moderate), OCT2 (weak), MATE1 and MATE2 at clinical relevant concentrations, and may increase concentrations of metformin. No a priori dose adjustment is necessary. However, monitoring for metformin toxicity should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolised by the CYP450 system (mainly CYP2D6). Rucaparib does not inhibit or induce CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Miconazole is extensively metabolised by the liver. Rucaparib is not expected to interact with this unspecified pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by miconazole. The clinical relevance of this interaction is unknown but a significant effect on rucaparib exposure is not expected.

Midazolam is metabolised by CYP3A4. Coadministration of midazolam with rucaparib increased midazolam exposure by 1.38-fold. Monitoring for midazolam toxicity may be required.

Coadministration has not been studied but should be approached with caution. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Rucaparib is an inhibitor of CYP1A2 (moderate) and CYP3A4 (weak), and may increase concentrations of mirtazapine. If coadministration is unavoidable, monitor closely for mirtazapine toxicity. A dose reduction of mirtazapine may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Rucaparib is an in vitro inhibitor of P-gp and UGT1A1. However, after coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with morphine. Furthermore, UGT1A1 is only a minor metabolic pathway. No clinically relevant effect on morphine exposure is expected.

Coadministration has not been studied but should be approached with caution. Moxifloxacin is predominantly glucuronidated by UGT1A1. Rucaparib is an in vitro inhibitor of UGT1A1 and may increase concentrations of moxifloxacin. As the clinical relevance of this interaction is unknown, monitoring for moxifloxacin toxicity may be required. The product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as rucaparib. If coadministration is unavoidable, use with extreme caution, including ECG monitoring.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nandrolone is metabolised in the liver by alpha-reductase. Rucaparib does not interact with this metabolic pathway.

Coadministration has not been studied but care should be taken. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Rucaparib is a weak inhibitor of CYP3A4 and CYP2C9, and may increase concentrations of nateglinide. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with nateglinide. Monitoring of blood glucose levels and nateglinide toxicity may be required.

Coadministration has not been studied but care should be taken. Nefazodone is metabolised mainly by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of nefazodone. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with nefazodone. Monitoring for nefazodone toxicity may be necessary. Furthermore, nefazodone is a strong inhibitor of CYP3A4. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by nefazodone. The clinical relevance of this interaction is unknown, but a significant effect on rucaparib exposure is not expected.

Coadministration has not been studied but care should be taken. Nifedipine is metabolised mainly by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of nifedipine. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with nifedipine. Monitoring for nifedipine toxicity may be required.

Coadministration has not been studied but care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of nitrendipine. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with nitrendipine. Monitoring for nitrendipine toxicity may be required.

Coadministration has not been studied but care should be taken. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Rucaparib is an in vitro inhibitor of UGT1A1 and may increase norethisterone exposure. As the clinical relevance of this interaction is unknown, monitoring for norethisterone toxicity may be required.

Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Coadministration of omeprazole with rucaparib increased omeprazole exposure by 1.55-fold. Monitoring for omeprazole toxicity may be required. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. In vitro, rucaparib is metabolised by CYP1A2 and exposure of rucaparib may decrease due to induction by omeprazole. As the clinical relevance of this interaction is unknown, monitoring of rucaparib efficacy and, if available, rucaparib plasma concentrations may be required. Additionally, rucaparib has a pH independent solubility between pH 3 and 7, and no clinically relevant effect of gastric acid reducing agents on the absorption of rucaparib is expected.

Coadministration has not been studied but care should be taken. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Rucaparib does not interact with this pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. In vitro, rucaparib is metabolised by CYP3A4 and exposure of rucaparib may decrease due to CYP3A4 induction by oxcarbazepine. As the clinical relevance of this interaction is unknown, monitoring of rucaparib efficacy and, if available, rucaparib plasma concentrations may be required.

Coadministration has not been studied but care should be taken. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of both oxycodone and oxymorphone. Monitoring for oxycodone toxicity may be required.

Coadministration has not been studied but care should be taken. Paliperidone is primarily renally eliminated (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Rucaparib is an inhibitor of CYP3A4 (weak) and an in vitro inhibitor of OCT1 (moderate) and OCT2 (weak) at clinically relevant concentrations. Concentrations of paliperidone may increase. No a priori dose adjustment is necessary. However, monitoring for paliperidone toxicity should be considered.

Coadministration has not been studied but care should be taken. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Rucaparib is a weak inhibitor of CYP2C9 and CYP3A4, and may increase concentrations of phenprocoumon. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. Furthermore, coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. Similar effects may occur after coadministration with phenprocoumon. Monitoring of INR/PT and phenprocoumon toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Rucaparib is an inhibitor of CYPs 3A4 (weak), 1A2 (moderate) and 2C9 (weak). However, since these are minor pathways, no clinically relevant effect on pioglitazone exposure is expected.

Coadministration has not been studied but care should be taken. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. Rucaparib is a weak inhibitor of CYPs 3A4, 2C9 and 2C19 and may increase prasugrel concentrations. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with prasugrel. Thrombocyte aggregation tests and monitoring for prasugrel toxicity may be required.

Coadministration has not been studied but care should be taken. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Rucaparib is an in vitro inhibitor of UGT1A1 and may increase ramipril and ramiprilat exposure. As the clinical relevance of this interaction is unknown, monitoring of blood pressure and ramipril toxicity may be required.

Coadministration has not been studied but is not recommended. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro), and may increase concentrations of ranolazine. After coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with ranolazine and therefore, no clinically relevant effect on ranolazine exposure is expected due to P-gp inhibition. However, coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with ranolazine. Monitoring of blood pressure and ranolazine toxicity may be required. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. In vitro, rucaparib is a substrate of CYP2D6, CYP3A4, and concentrations may increase due to inhibition by ranolazine. As the clinical relevance of this interaction is unknown, monitoring for rucaparib toxicity may be required. Rucaparib and ranolazine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but care should be taken. Reboxetine is metabolised by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of reboxetine. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with reboxetine. Monitoring for reboxetine toxicity may be required. Furthermore, in vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. Although rucaparib is metabolised by CYP3A4 in vitro, no clinically relevant effect on rucaparib exposure is expected.

Coadministration has not been studied but care should be taken. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of OATP1B1. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of repaglinide. Monitoring of blood glucose levels and repaglinide toxicity may be required.

Coadministration has not been studied but care should be taken. Rifampicin is metabolised via deacetylation. Rucaparib is unlikely to interfere with this metabolic pathway. However, rifampicin is a strong CYP3A4 and P-gp inducer. In vitro, rucaparib is a substrate of CYP3A4 and P-gp, and concentrations of rucaparib may decrease due to induction by rifampicin. As the clinical relevance of this interaction is unknown, monitoring of rucaparib efficacy and, if available, rucaparib plasma concentrations may be required.

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro) and may increase concentrations of saxagliptin. After coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). A similar effect may occur with saxagliptin. However, coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with saxagliptin. Monitoring of saxagliptin exposure and blood glucose levels may be required.

Coadministration has not been studied but care should be taken. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Rucaparib is a weak inhibitor of CYP3A4 and CYP2C9, and may increase concentrations of sildenafil. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with sildenafil. Monitoring of blood pressure and sildenafil toxicity may be required.

Coadministration has not been studied but care should be taken. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro), and may increase concentrations of sirolimus. Monitoring for sirolimus toxicity and, if available, sirolimus plasma concentrations should be considered. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but care should be taken. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Rucaparib is a weak inhibitor of CYP3A4 and may increase tamsulosin concentrations. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with tamsulosin. Monitoring for tamsulosin toxicity may be required.

Coadministration has not been studied but care should be taken. Ticagrelor is a substrate of CYP3A4 and P-gp. Rucaparib is an inhibitor of CYP3A4 (weak) and P-gp (in vitro), and may increase concentrations of ticagrelor. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. After coadministration with digoxin, a P-gp substrate, no clinically relevant effect was observed (digoxin AUC increased by 1.2-fold). Similar effects may occur after coadministration with ticagrelor. Thrombocyte aggregation tests and monitoring for ticagrelor toxicity may be required. Furthermore, ticagrelor is a weak inhibitor of CYP3A4. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by ticagrelor. The clinical relevance of this interaction is unknown, but a significant effect on rucaparib exposure is not expected.

Coadministration has not been studied but care should be taken. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Rucaparib is a weak inhibitor of CYP2C9 and CYP2C19, and may increase concentrations of tolbutamide. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with tolbutamide. Monitoring of blood glucose levels and tolbutamide toxicity may be required.

Coadministration has not been studied but care should be taken. Torasemide is metabolised mainly by CYP2C9. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Rucaparib is a weak inhibitor of CYP2C9 and may increase torasemide concentrations. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with torasemide. Monitoring of blood pressure and torasemide toxicity may be required.

Coadministration has not been studied but care should be taken. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Rucaparib is an inhibitor of CYPs 1A2 (moderate), 3A4 (weak) and 2C9 (weak). However, since these are minor pathways, no clinically relevant effect on trimethoprim exposure is expected. Furthermore, sulfamethoxazole is metabolised by CYP2C9. Rucaparib is a weak inhibitor of CYP2C9 and may increase concentrations of sulfamethoxazole. Coadministration of warfarin, a CYP2C9 substrate, with rucaparib increased warfarin exposure by 1.49-fold. A similar effect may occur with sulfamethoxazole. Monitoring for sulfamethoxazole toxicity may be required. Trimethoprim is a weak CYP2C8 inhibitor and in vitro data suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is a weak inhibitor of CYP2C9. Rucaparib is not a substrate of these CYPs, OCTs or MATEs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Rucaparib is a weak inhibitor of CYPs 3A4, 2C19 and 2C9, and may increase venlafaxine concentrations. However, since these are minor pathways, no clinically relevant effect on venlafaxine exposure is expected.

Coadministration has not been studied but care should be taken. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Rucaparib is an inhibitor of CYPs 3A4 (weak), 1A2 (moderate) and 2C9 (weak), and may increase concentrations of verapamil. Coadministration of midazolam, a CYP3A4 substrate, with rucaparib increased midazolam exposure by 1.38-fold. A similar effect may occur with verapamil. Monitoring for verapamil toxicity may be required. Furthermore, verapamil is a moderate inhibitor of CYP3A4. In vitro, rucaparib is metabolised by CYP3A4 and concentrations may increase due to inhibition by verapamil. The clinical relevance of this interaction is unknown, but a significant effect on rucaparib exposure is not expected.

Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Rucaparib is an inhibitor of CYPs 1A2 (moderate), 3A4 (weak) and 2C9 (weak), and may increase concentrations of warfarin. Coadministration with warfarin increased warfarin exposure by 1.49-fold. Monitoring of INR/PT and warfarin toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. Rucaparib is a weak inhibitor of CYP3A4 and may increase concentrations of zaleplon. However, since CYP3A4 is a minor pathway, no clinically relevant effect on zaleplon exposure is expected.