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 by the microbial flora. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolized by glucuronidation (by several UGTs, major UGT1A6). Regorafenib does not inhibit or induce CYPs or UGT1A6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Alendronate is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, alendronate should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfentanil undergoes extensive CYP3A4 metabolism. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfuzosin is metabolized by CYP3A. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aliskiren is minimally metabolized and is mainly excreted unchanged in faeces. However, P-glycoprotein is a major determinant of aliskiren bioavailability. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on aliskiren is expected in vivo.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Allopurinol is also an inhibitor of xanthine oxidase. Regorafenib not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that alosetron is metabolized by CYPs 2C9, 3A4 and 1A2. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Alprazolam is mainly metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Regorafenib is unlikely to interfere with this metabolic pathway. Furthermore, decreased absorption of regorafenib is not expected in combination with antacids as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied. 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. Although regorafenib is an inhibitor of P-gp in vitro, no clinically relevant effect on ambrisentan is expected in vivo. Regorafenib is an in vitro inhibitor of UGT1A9 and may increase concentrations of ambrisentan. The clinical relevance of this interaction is unknown. Caution should be taken and monitoring for ambrisentan toxicity and blood pressure is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amikacin is eliminated by glomerular filtration therefore no pharmacokinetic interaction is expected with regorafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Regorafenib is unlikely to significantly inhibit amiloride renal elimination.

Coadministration has not been studied. Amiodarone is metabolised by CYP3A4 and CYP2C8. Regorafenib does not inhibit or induce CYPs. However, 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). Concentrations of regorafenib may increase due to weak inhibition of CYP3A4. The clinical relevance of this interaction is unknown. Monitoring for regorafenib toxicity and, if available, regorafenib plasma concentrations may be required. 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 clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally (possibly via OCT). Regorafenib is unlikely to significantly impair amisulpride elimination. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amlodipine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Regorafenib is unlikely to interfere with amoxicillin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amphotericin is not appreciably metabolized and is eliminated to a large extent in the bile. Regorafenib does not interfere with amphotericin B elimination pathway. However, the European SPC for amphotericin 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 based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20 to 40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60 to 80% is excreted in the urine within 6 hours. Regorafenib is unlikely to significantly inhibit ampicillin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperature. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Regorafenib is unlikely to interfere with this metabolic pathway. Furthermore, decreased absorption of regorafenib is not expected in combination with antacids as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Apixaban is metabolized by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but should be approached with caution. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Regorafenib does not inhibit or induce CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of regorafenib during the three days of coadministration. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Therefore, coadministration is not recommended. If coadministration is unavoidable, monitor closely for regorafenib toxicity. Reduce the regorafenib dose to 50% of the original dose during the few days of coadministration. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of regorafenib may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Asenapine is metabolized by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). Regorafenib does not inhibit or induce CYPs or UGT1A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Astemizole is metabolized by CYPs 2D6, 2J2 and 3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on atorvastatin is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Azathioprine is converted to 6-mercaptopurine which is metabolized analogously to natural purines by xanthine oxidase. Regorafenib does not interfere with this metabolic pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on azithromycin is expected in vivo. Azithromycin is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition is unknown. No effect on regorafenib concentrations is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Beclometasone is a pro-drug which is not metabolised by CYP450, but is hydrolysed via esterase enzymes to the highly active metabolite beclometasone -17-monopropionate. Regorafenib does not interact with beclomethasone metabolism. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bedaquiline is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically significant interaction is unlikely in the range of observed clinical concentrations. In addition, there is no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes and therefore is unlikely to impact regorafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bepridil is metabolized by CYP2D6 (major) and CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Betamethasone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as half of bezafibrate dose is eliminated unchanged in the urine. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1. Regorafenib does not interact with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisacodyl is converted to an active metabolite by intestinal and bacterial enzymes. Absorption from the gastrointestinal tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6, partly eliminated unchanged in the urine and is a substrate for P-gp. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on bisoprolol is expected in vivo.

Coadministration has not been studied. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Regorafenib does not inhibit or induce CYPs. However, concentrations of regorafenib may decrease due to weak induction of CYP3A4. The clinical relevance of this interaction is unknown. Monitoring of regorafenib efficacy and, if available, regorafenib plasma concentrations should be considered.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Bromazepam undergoes oxidative biotransformation. Drug-drug interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may play a role. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Budesonide is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Regorafenib is an inhibitor of UGT1A1 in vitro. However, a clinically relevant interaction is unlikely since glucuronidation via UGT1A1 is not a major pathway involved in buprenorphine elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolised by CYP2B6 and is a strong inhibitor of CYP2D6. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Buspirone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Co-administration has not been studied but a clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine and sweat. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Candesartan is mainly eliminated unchanged via urine and bile. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Regorafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Captopril is largely excreted in the urine by OAT1. Regorafenib does not interfere with captopril elimination.

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Regorafenib does not inhibit or induce CYPs. However, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Coadministration of rifampicin and a single dose of regorafenib decreased regorafenib AUC by ~50%, increased the mean exposure of the active metabolite M-5 by 3-4-fold, but had no effect on the exposure of active metabolite M-2. A similar effect may occur with carbamazepine. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7 and metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Carvedilol is also a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on carvedilol is expected in vivo. Regorafenib is also an in vitro inhibitor of UGT1A1 and may increase concentrations of carvedilol. The clinical relevance of this interaction is unknown. Caution should be taken and monitoring for carvedilol toxicity and blood pressure is recommended.

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. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged renally by glomerular filtration and tubular secretion via OAT1 and MATE1. Regorafenib does not interfere with cefalexin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Regorafenib does not interfere with cefazolin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cefixime is renally excreted predominantly by glomerular filtration. Regorafenib does not interfere with cefixime renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolized by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates in the renal elimination of cefotaxime. Regorafenib does not interfere with cefotaxime renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as ceftazidime is excreted predominantly by renal glomerular filtration. Regorafenib does not interfere with ceftazidime renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine predominantly by glomerular filtration and the remainder via the biliary and intestinal tracts. Regorafenib does not interfere with ceftriaxone renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolized by CYP2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine inhibits OCT2. Regorafenib is unlikely to interact with cetirizine renal elimination.

Coadministration has not been studied. Chloramphenicol is predominantly glucuronidated. Regorafenib is an in vitro inhibitor of UGT1A1 and UGT1A9 and may increase plasma concentrations of chloramphenicol. As the clinical relevance of this interaction is unknown, close monitoring for chloramphenicol toxicity is recommended. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of regorafenib may increase due to CYP3A4 inhibition, increasing the risk of adverse events. The clinical relevance of this interaction is unknown. Monitoring for regorafenib toxicity and plasma concentrations may be required, if available. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlordiazepoxide is extensively metabolised by CYP3A4, but does not inhibit or induce CYPs. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorphenamine is predominantly metabolized in the liver via CYP2D6. Regorafenib is unlikely to interact with chlorphenamine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Regorafenib does not interact with this metabolic pathway. 

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. Regorafenib does not interact with this pathway.

Coadministration has not been studied but should be avoided. Ciclosporin is metabolised mainly by CYP3A4. Regorafenib does not inhibit or induce CYP3A4. However, ciclosporin is an inhibitor of CYP3A4 and OATP1B1 and may increase regorafenib concentrations. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cilazapril is mainly eliminated unchanged by the kidneys. 

Coadministration has not been studied. Cimetidine is metabolised by CYP enzymes. Regorafenib does not inhibit or induce CYPs. Cimetidine is also a weak inhibitor of several CYP enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Concentrations of regorafenib may increase due to weak inhibition of CYP3A4. The clinical relevance of this interaction is unknown. Monitoring for regorafenib toxicity and, if available, regorafenib plasma concentrations may be required. Furthermore, cimetidine may decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine also inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Regorafenib does not interact with this pathway. Cimetidine is unlikely to alter regorafenib absorption.

Coadministration has not been studied but should be avoided. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. Ciprofloxacin is also metabolised and partially cleared through the bile and intestine. Regorafenib does not interfere with this elimination pathway. However, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of regorafenib may increase due to CYP3A4 inhibition. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cisapride is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but should be avoided. Clarithromycin is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs. However, clarithromycin is an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of regorafenib may increase due to CYP3A4 inhibition. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, and regorafenib increased regorafenib AUC by ~33%, and decreased the mean exposure of the active metabolites, M-2 and M-5 by ~90%. A similar effect may occur after coadministration with clarithromycin. Therefore, coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolized (likely non CYP mediated pathway) and excreted in the urine by glomerular filtration. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clemastine is predominantly metabolized in the liver via CYP2D6. Regorafenib is unlikely to interact with clemastine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. However, in vitro data suggest that clindamycin is a CYP3A4 inhibitor and may increase concentrations of regorafenib. The clinical relevance of this interaction is unknown. Monitoring for regorafenib toxicity and, if available, regorafenib plasma concentrations may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with the topical use of clobetasol.

Coadministration has not been studied. Clofazimine is largely excreted unchanged in the faeces. Regorafenib is unlikely to interfere with this elimination pathway. However, in vitro data suggest that clofazimine is a CYP3A4 inhibitor and may increase regorafenib concentrations. Concentrations of the active metabolites of regorafenib may decrease. The clinical relevance of this interactions is unknown. Monitoring for regorafenib toxicity and, if available, plasma concentrations may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolyzed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Regorafenib does not interfere with clofibrate elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clomipramine is metabolized by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 but is unlikely to interact with regorafenib elimination. In addition, regorafenib does not interfere with clonidine elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Regorafenib does not inhibit or induce CYPs. Clopidogrel is also an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clorazepate is rapidly converted to nordiazepam which is then metabolized to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Regorafenib is an in vitro inhibitor of UGT1A1 and UGT1A9. However, a clinically relevant interaction is unlikely since oxazepam has a broad therapeutic index.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clozapine is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2C19 and CYP2D6. Regorafenib does not inhibit or induce CYPs. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolised by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Morphine is also a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro but no clinically relevant effect on morphine is expected in vivo. Regorafenib is also an inhibitor of UGT1A1 and UGT1A9 in vitro, but a clinically relevant interaction is unlikely since glucuronidation via UGT1A1 is not a major pathway for morphine. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Colchicine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly excreted renally via glomerular filtration. Regorafenib does not interact with this metabolic pathway.

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. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on dabigatran is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys. Regorafenib does not interfere with the renal excretion of dalteparin. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as desipramine is metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Dexamethasone is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs. Dexamethasone has also been described as a weak inducer of CYP3A4 and could possibly decrease regorafenib plasma concentrations. However, the clinical relevance of CYP3A4 induction by dexamethasone has not been established yet. Monitoring of regorafenib efficacy and, if available, plasma concentrations may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dextropropoxyphene is mainly metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diamorphine is rapidly metabolized by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Regorafenib is an inhibitor of UGT1A1 in vitro but a clinically relevant interaction is unlikely since glucuronidation via UGT1A1 is not a major pathway for diamorphine. Morphine is also a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro, but no clinically significant effect on diamorphine is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolized to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Regorafenib is an in vitro inhibitor of UGT1A1 and UGT1A9. However, a clinically relevant interaction is unlikely since temazepam has a wide therapeutic index.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidized by CYP2C9. Regorafenib does not inhibit or induce CYPs or UGT2B7.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-glycoprotein. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on digoxin is expected in vivo. Clinical data indicate that regorafenib has no effect on digoxin pharmacokinetics and can be given concomitantly with P-gp such as digoxin, without a clinically meaningful drug interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but should be avoided. Diltiazem is metabolised by CYP3A4 and CYP2D6. Regorafenib does not inhibit or induce CYPs. However, diltiazem inhibits CYP3A4 and could potentially increase regorafenib concentrations. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is a weak inhibitor of CYP2D6. Regorafenib does not interact with this pathway.

Coadministration has not been studied. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Regorafenib is an inhibitor of UGT1A1 and UGT1A9 in vitro and may increase dipyridamole exposure. The clinical relevance of this interaction is unknown. Care should be taken when regorafenib is coadministered with substrates of UGT1A1 or UGT1A9 with a narrow therapeutic index and close monitoring for signs and symptoms of increased exposure to dipyridamole is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Disopyramide is metabolized by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Domperidone is mainly metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dopamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase to inactive compounds. About 25% of a dose of dopamine is metabolised to norepinephrine within the adrenergic nerve terminals. There is little potential for dopamine to affect disposition of regorafenib, or to be affected if co-administered with regorafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxazosin is metabolized mainly by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40%-60% of an administered dose can be accounted for in the urine. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolized to a minor extent via CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is degraded by endogenous endopeptidases. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since regorafenib efficacy is more likely to be correlated to trough plasma concentrations instead of maximum plasma concentrations of regorafenib, the clinical relevance of delayed absorption is considered to be limited.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Duloxetine is metabolized by CYP2D6 and CYP1A2. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dutasteride is mainly metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on edoxaban is expected in vivo.

Coadministration has not been studied. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Regorafenib is an inhibitor of UGT1A1 in vitro and may increase eltrombopag exposure. The clinical relevance of this interaction is unknown. Care should be taken when regorafenib is coadministered with substrates of UGT1A1 with a narrow therapeutic index and close monitoring for signs and symptoms of increased exposure to eltrombopag is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is eliminated renally (possibly via OATs). 

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Enoxaparin does not undergo cytochrome metabolism but is desulphated and depolymerised in the liver, and is excreted predominantly renally. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as eprosartan is largely excreted in bile and urine as unchanged drug. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor component. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but should be avoided. Erythromycin is a substrate of CYP3A4 and P-gp. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on erythromycin is expected in vivo. However, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Concentrations of regorafenib may increase due to CYP3A4 inhibition. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Regorafenib does not inhibit or induce CYPs. Esomeprazole inhibits CYP2C19, but regorafenib does not interact with this pathway. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Estazolam is metabolized to its major metabolite 4-hydroxyestazolam via CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%). Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Regorafenib does not inhibit or induce CYPs, but is an inhibitor of UGT1A1 in vitro and may increase ethinylestradiol exposure. The clinical relevance of this interaction is unknown. However, since ethinylestradiol has a wide therapeutic index, no clinically relevant effect on ethinylestradiol exposure is expected.

Coadministration has not been studied but based on the metabolism/elimination a clinically relevant interaction is unlikely. Ethionamide is extensively metabolized in the liver, animal studies suggest involvement of flavin-containing monooxygenases. Regorafenib does not interfere with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro, but no clinically relevant effect on everolimus is expected in vivo. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as exenatide is cleared mainly by glomerular filtration. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since regorafenib efficacy is more likely to be correlated to trough plasma concentrations instead of maximum plasma concentrations of regorafenib, the clinical relevance of delayed absorption is considered to be limited.

Coadministration has not been studied. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Regorafenib is an inhibitor of UGT1A1 in vitro and may increase ezetimibe exposure. The clinical relevance of this interaction is unknown. Therefore, it is recommended to monitor patients for signs and symptoms of increased exposure to ezetimibe.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Regorafenib does not inhibit or induce OATs. Furthermore, decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Felodipine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl undergoes extensive CYP3A4 metabolism. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fexofenadine undergoes negligible metabolism and is mainly eliminated unchanged in the faeces. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Finasteride is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flecainide is metabolized mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Regorafenib does not interact with this elimination pathway. However, flucloxacillin has been described as a CYP3A4 inducer and may decrease regorafenib exposure. As the clinical relevance of this interaction is unknown, monitoring of regorafenib efficacy and, if available, plasma concentrations may be required.

Coadministration has not been studied but should be avoided. Fluconazole is renally excreted. Regorafenib is unlikely to interfere with this elimination pathway. However, fluconazole is an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of regorafenib may increase due to CYP3A4 inhibition. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase to an inactive metabolite. Regorafenib does not interfere with this metabolic pathway. However, 5-FU binds to the enzyme thymidylate synthase resulting in DNA damage. This mechanism occurs in all fast dividing cells including bone marrow cells, resulting in haematological toxicity. Regorafenib also induces haematological toxicity which could be enhanced by the use of flucytosine. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludrocortisone is metabolized in the liver to inactive metabolites, possibly by CYP3A. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Flunitrazepam is metabolized mainly via CYP3A4 and 2C19. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Regorafenib does not inhibit or induce CYPs. Furthermore, fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. The metabolism of flurazepam is most likely CYP-mediated. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Regorafenib does not inhibit or induce CYPs. Fluvastatin also potentially inhibits CYP2C9, but the clinical relevance of CYP2C9 inhibition is unknown. Regorafenib does not interact with this pathway.

Coadministration has not been studied but should be avoided. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Regorafenib does not inhibit or induce CYPs. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of regorafenib may increase due to CYP3A4 inhibition. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is eliminated predominantly renally. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation being another pathway. As multiple CYP and UGT enzymes catalyze the transformation the potential for a pharmacokinetic interaction is low.

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Regorafenib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Regorafenib does not inhibit or induce CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of regorafenib during the three days of coadministration. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Therefore, coadministration is not recommended. If coadministration is unavoidable, monitor closely for regorafenib toxicity. Reduce the regorafenib dose to 50% of the original dose during the few days of coadministration. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of regorafenib may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied but should be avoided. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Regorafenib does not inhibit or induce CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Coadministration of rifampicin and a single dose of regorafenib decreased regorafenib AUC by ~50%, increased the mean exposure of the active metabolite M-5 by 3-4-fold, but had no effect on the exposure of active metabolite M-2. A similar effect may occur with fosphenytoin. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied. 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. In vitro data indicate that furosemide is also an inhibitor of OAT1/OAT3. Regorafenib is an in vitro inhibitor of UGT1A1 and UGT1A9 and may increase furosemide exposure. The clinical relevance of this interaction is unknown. Monitoring for furosemide toxicity and blood pressure may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gabapentin is cleared mainly by glomerular filtration. Regorafenib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7. Regorafenib does not inhibit or induce UGT2B7. Gemfibrozil is also an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9 but in vivo data showed no clinically relevant effect on CYP2C9. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gentamicin is eliminated unchanged predominantly via glomerular filtration. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glibenclamide is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C19. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is mainly metabolized by CYP2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glipizide is mainly metabolized by CYP2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Granisetron is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. Granisetron is a substrate of P-gp and regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on granisetron is expected in vivo. 

Coadministration has not been studied but should be avoided. Grapefruit juice is known to inhibit CYP3A4 enzymes and may increase regorafenib concentrations. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Regorafenib does not interfere with griseofulvin elimination pathway. Griseofulvin is a liver microsomal enzyme inducer. It may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolized by CYP3A4, such as regorafenib. However, this is unlikely to be clinically relevant. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Regorafenib is an inhibitor of UGT1A9 in vitro. However, a clinically relevant interaction is unlikely since glucuronidation via UGT1A9 is not a major pathway for haloperidol.

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. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but care should be taken. Hydralazine is metabolised via primary oxidative metabolism and acetylation. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Regorafenib concentrations may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. Monitoring for regorafenib toxicity and, if available, regorafenib plasma concentrations may be required.

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. Regorafenib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocortisone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

No clinically significant interactions are expected with the topical use of hydrocortisone. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7. Regorafenib not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys. Regorafenib is unlikely to interfere with this elimination pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Hydroxyzine is partly metabolized by alcohol dehydrogenase and partly by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied. Ibandronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ibuprofen is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Regorafenib does not inhibit or induce CYP2C9 and 2C8. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Iloperidone is metabolized by CYP3A4 and CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipenem/cilastatin are eliminated by glomerular filtration and to a lesser extent, active tubular secretion. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipramine is metabolized by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Indapamide is extensively metabolised by CYPs. Regorafenib does not inhibit or induce CYPs. 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. Regorafenib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has been studied and based on metabolism and clearance a pharmacokinetic interaction is unlikely. Interferon alpha had no effect on the pharmacokinetics of regorafenib. However, coadministration may increase risk of neutropenia, fatigue, and thrombocytopenia. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration. Regorafenib does not interfere with this elimination pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. A small proportion of an inhaled ipratropium dose is systemically absorbed (6.9%). Metabolism is via ester hydrolysis and conjugation. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolized by glucuronidation and oxidation (mainly CYP2C9). Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but should avoided. Itraconazole is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Concentrations of regorafenib may increase due to inhibition of CYP3A4. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration of ketoconazole, a strong CYP3A4 inhibitor, and regorafenib increased regorafenib AUC by ~33%, and decreased the mean exposure of the active metabolites, M-2 and M-5 by ~90%. A similar effect may occur after coadministration with itraconazole. Therefore, coadministration should be avoided as the effect on the steady-state sum exposure of regorafenib and its metabolites is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ivabradine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Kanamycin is eliminated unchanged predominantly via glomerular filtration therefore no pharmacokinetic interaction is expected with regorafenib. Regorafenib does not interact with this metabolic pathway. 

Coadministration of ketoconazole (400 mg for 18 days, a strong CYP3A4 inhibitor) and regorafenib (160 mg single dose on day 5) increased regorafenib AUC by ~33%, and decreased the mean exposure of the active metabolites, M-2 and M-5 by ~90%. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered.

Coadministration has not been studied. Labetalol is mainly glucuronidated (via UGT1A1 and 2B7). Regorafenib is an inhibitor of UGT1A1/1A9 could therefore increase labetolol exposure. The clinical relevance of this interaction is unknown. Care should be taken when regorafenib is coadministered with substrates of UGT1A1/1A9 with a narrow therapeutic index. Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to labetalol. If the combination appears necessary, blood pressure monitoring is recommended. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lacidipine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of lactulose to lactic acid occurs via gastro-intestinal microbial flora only. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and in lesser extent by CYP3A4. Regorafenib does not interact with this pathway. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lercanidipine is mainly metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion. 

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Levofloxacin is eliminated renally mainly by glomerular filtration and active secretion (possibly OCT2). Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levomepromazine is metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolized by deiodination (by enzymes of deiodinase family) and glucuronidation. Regorafenib does not interact with levothyroxine metabolism. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is a substrate for P-gp and is an inhibitor of CYP3A4. Linagliptin may slightly increase regorafenib concentrations due to inhibition of CYP3A4. The clinical relevance of this interaction is unknown. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on linagliptin is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Linezolid undergoes non CYP mediated metabolism. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as liraglutide is degraded by endogenous endopeptidases. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is eliminated unchanged renally via glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. 

Coadministration of live vaccines (such as BCG vaccine; measles, mumps and rubella vaccines; varicella vaccines; typhoid vaccines; rotavirus vaccines; yellow fever vaccines; oral polio vaccine) has not been studied. In patients, who are receiving cytotoxics or other immunosuppressant drugs, use of live vaccines for immunisation is contraindicated. If coadministration is judged clinically necessary, use with extreme caution since generalized infections can occur.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolized by CYP3A4 and CYP2C8. Regorafenib does not inhibit or induce CYPs. Loperamide is a substrate of P-gp and regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on loperamide is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loratadine is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on non-CYP-mediated elimination pathways for lorazepam, no effect on plasma concentrations is expected upon coadministration with regorafenib. 

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated, probably via UGT2B15. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lovastatin is metabolised by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Macitentan is metabolized mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Magnesium is eliminated in kidney, mainly by glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Maprotiline is mainly metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolized by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Regorafenib does not inhibit or induce CYPs, but is an inhibitor of UGT1A1/1A9. However, a clinically relevant interaction is unlikely, since glucuronidation of via UGT1A9 is not the major pathway involved in mefenamic acid elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Megestrol acetate is mainly eliminated in the urine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney and in vitro data suggest that it is a substrate of the renal transporters OAT3>OAT1. Regorafenib does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mesalazine is metabolized to N-acetyl-mesalazine by N-acetyltransferase. Regorafenib does not interfere with this pathway. 

Coadministration has not been studied, but should be approached with caution. Metamizole may decrease regorafenib concentrations due to induction of CYP3A4. Decreases in regorafenib exposure can lead to decreased efficacy. Selection of an alternative concomitant medication with no or minimal enzyme or transporter induction potential is recommended. The clinical relevance of this interaction is unknown, monitoring and dose adjustment may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine (via OCT2). Regorafenib does not interact with metformin metabolic and elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methadone is demethylated by CYP3A4. Regorafenib does not inhibit or induce CYP3A4. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methyldopa is excreted in urine largely by glomerular filtration, primarily unchanged and as the mono-O-sulfate conjugate. It is unlikely to affect the disposition of regorafenib, or to be altered by coadministration with regorafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent and does not inhibit cytochrome P450s. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylprednisolone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolized by CYP450 system (mainly CYP2D6). Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely as metolazone is largely excreted unchanged in the urine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoprolol is mainly metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, cyclosporine) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with axitinib cannot be excluded.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mexiletine is metabolized mainly by CYP2D6 and to a lesser extent CYP1A2. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mianserin is metabolized by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied. Miconazole inhibits CYP2C9 and CYP3A4 and could potentially increase regorafenib concentrations. Oromucosal application may increase regorafenib concentrations due to inhibition of CYP3A4. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered. Note, no a priori dosage adjustment is recommended for regorafenib with dermal application of miconazole, since systemic exposure of miconazole is limited when used topically.

Coadministration of regorafenib (160 mg once daily for 14 days) and midazolam (2 mg dose single oral dose) showed no clinically relevant effects on the pharmacokinetics of midazolam. Midazolam is metabolized by CYP3A4 and glucuronidated via UGT1A4, 2B7 and 2B4. Regorafenib does not inhibit or induce these CYPs or UGTs.

Coadministration with parenteral midazolam has not been studied. Coadministration of regorafenib (160 mg once daily for 14 days) and midazolam (2 mg dose single oral dose) showed no clinically relevant effects on the pharmacokinetics of oral midazolam. No relevant effects on the pharmacokinetics of parenteral midazolam are expected. Midazolam is metabolized by CYP3A4 and glucuronidated via UGT1A4, 2B7 and 2B4. Regorafenib does not inhibit or induce these CYPs or UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). Regorafenib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mometasone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Montelukast is mainly metabolized by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Regorafenib does not interact with this metabolic pathway.

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). Regorafenib is an inhibitor of UGT1A1/1A9. However, a clinically relevant interaction is unlikely, since glucuronidation of morphine via UGT1A1 is not a major pathway involved in morphine elimination.

Coadministration has not been studied. Moxifloxacin is predominantly glucuronidated by UGT1A1. Regorafenib is an inhibitor of UGT1A1/1A9 and could therefore potentially increase moxifloxacin exposure. The clinical relevance of this interaction is unknown. Care should be taken when regorafenib is coadministered with substrates of UGT1A1/1A9 with a narrow therapeutic index and close monitoring for signs and symptoms of increased exposure to UGT1A1/1A9 substrates is recommended.

Coadministration has not been studied. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Regorafenib is an inhibitor of UGT1A1/1A9 and could increase mycophenolate exposure. The clinical relevance of this interaction is unknown. Care should be taken when regorafenib is coadministered with substrates of UGT1A1/1A9 with a narrow therapeutic index. Therefore, it is recommended to monitor patients closely for signs and symptoms of increased exposure to mycophenolate. Inhibition of OAT1/OAT3 renal transporters by mycophenolic acid (active metabolite) is unlikely to interfere with regorafenib elimination. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nadroparin is renally excreted by a nonsaturable mechanism. Regorafenib does not interact with this elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Regorafenib does not inhibit or induce these CYPs or UGTs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nateglinide is mainly metabolized by CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nebivolol metabolism involves CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Nefazodone is metabolized mainly by CYP3A4 and is an inhibitor of CYP3A4. Nefazodone could potentially increase regorafenib exposure by inhibition of CYP3A4. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered.

Coadministration has not been studied. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2D6 and 2C8. Regorafenib does not inhibit or induce CYPs. However, nicardipine inhibits CYP3A4 and could potentially increase regorafenib concentrations. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicotinamide is converted to N-methylnicotinamide by nicotinamide methyltransferase which in turn is metabolized by xanthine oxidase and aldehyde oxidase. Regorafenib does not interact with this metabolic pathway. In addition, nicotinic acid and its metabolites do not inhibit CYP-mediated reactions in vitro and therefore are unlikely to impact regorafenib exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nifedipine is metabolised mainly by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nimesulide is extensively metabolized in the liver following multiple pathways including CYP2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nisoldipine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrendipine is extensively metabolized mainly by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrofurantoin is partly metabolized in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norelgestromin is metabolized to norgestrel (possibly by CYP3A4). Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation via UGT1A1. Regorafenib is an inhibitor of UGT1A1/1A9 and could potentially increase ethinylestradiol exposure. The clinical relevance of this interaction is unknown. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolized via CYP450. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolized by CYP3A4. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nortriptyline is metabolized mainly by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Systemic absorption of nystatin from oral or topical dosage forms is not significant, therefore no drug interactions are expected. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Ofloxacin is eliminated unchanged renally by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Regorafenib is unlikely to interfere with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olanzapine is metabolized mainly by CYP1A2, but also by glucuronidation (UGT1A4). Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olmesartan medoxomil is de-esterified to the active metabolite olmesartan which is eliminated in the faeces and urine. 

Coadministratio of regorafenib (160 mg once daily for 14 days) and omeprazole (40 mg single dose) showed no clinically relevant effects on the pharmacokinetics of omeprazole were observed. Omeprazole is mainly metabolised by CYP2C19 and in lesser extent by CYP3A4. Regorafenib does not inhibit or induce CYPs. Omeprazole induces CYP1A2 and inhibits CYP2C19, but regorafenib does not interact with this pathway. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ondansetron is metabolized mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Regorafenib does not inhibit or induce CYPs. Ondansetron is a substrate of P-gp and regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on ondansetron is expected in vivo.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated via UGT2B15, 2B6 and 1A9. Regorafenib is an inhibitor of UGT1A1/1A9. However, a clinically relevant interaction is unlikely, since glucuronidation of oxazepam via UGT1A9 is not a major pathway involved in oxazepam elimination.

Coadministration has not been studied and should be avoided. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4 by oxcarbazepine. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolized via glucuronidation regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Palonosetron is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Regorafenib does not inhibit or induce CYPs. Palonosetron is a substrate of P-gp and regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on palonosetron is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pamidronic acid is not metabolised and is eliminated renally as unchanged drug. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and in lesser extent by CYPs 3A4, 2D6 and 2C9. Regorafenib does not inhibit or induce CYPs. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied. Paracetamol is mainly metabolized by glucuronidation (via UGT1A9 (major), UGT1A6, UGT1A1, UGT2B15) and sulfation and, to a lesser extent, by oxidation (CYP2E1 (major), 1A2, 3A4 and 2D6). Regorafenib inhibits UGT1A9 and may increase exposure to paracetamol. The clinical relevance of this interaction is unknown. Consideration should be given to decreasing the paracetamol dose by 50% when it is being used for more than one day. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.  Paroxetine is mainly metabolized by CYP2D6 and CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied, but based on metabolism and clearance a pharmacokinetic interaction is unlikely. However, coadministration may increase risk of neutropenia, fatigue, and thrombocytopenia. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Regorafenib does not interfere with elimination of penicillins.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perazine is demethylated via CYP3A4 and to a lesser extent by CYP2C9, and oxidated via FMO3. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perindopril is hydrolysed to the active metabolite perindoprilat and is metabolized to other inactive metabolites. Elimination occurs predominantly via the urine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perphenazine is metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pethidine is metabolized mainly by CYP2B6 and to a lesser extent by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on the metabolic profiles of both drugs there is little potential for pharmacokinetic interaction. Phenelzine is primarily metabolized by oxidation via monoamine oxidase and to a lesser extent acetylation. 

Coadministration has not been studied and should be avoided. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4 by phenobarbital. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Regorafenib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of regorafenib may decrease due to induction of CYP3A4 and P-gp. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Coadministration should be avoided as influence on the steady-state exposure of regorafenib and its metabolites is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An in vitro study found that the only CYP450 enzyme involved in phytomenadione metabolism was CYP4F2. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as pimozide is mainly metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolized to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Regorafenib is not expected to interfere with pindolol elimination. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolized mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piroxicam is primarily metabolized by CYP2C9. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pitavastatin is metabolized by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied. Posaconazole may increase regorafenib concentrations due to moderate inhibition of CYP3A4. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered. 

Coadministration has not been studied but based on limited data available an interaction appears unlikely. Potassium is eliminated renally. 

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Regorafenib does not inhibit or induce OATP1B1. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prazosin is extensively metabolized, primarily by demethylation and conjugation. Regorafenib is unlikely to interact with prazosin. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisolone undergoes hepatic metabolism via CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as pregabalin is cleared mainly by glomerular filtration. Regorafenib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Promethazine is metabolized by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propafenone is metabolized mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolized by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prucalopride is minimally metabolised and mainly eliminated renally, partly by active secretion by renal transporters (of note no clinically relevant interactions were observed when prucalopride was coadministered with inhibitors of renal P-gp, OAT and OCT transporters). 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolized by xanthine oxidase. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quinapril is de-esterified to the active metabolite quinaprilat which is eliminated primarily by renal excretion via OAT3. Regorafenib does not impact this renal transporter. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quinidine is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and in lesser extent by CYP2C19 and 3A4. Regorafenib does not inhibit or induce CYPs. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolized to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Regorafenib is not expected to interfere with these metabolic pathways. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Decreased absorption of regorafenib is not expected in combination with H2-antagonists and proton pump inhibitors as the aqueous solubility of regorafenib is not expected to be pH dependent.

Coadministration has not been studied. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro but no clinically significant effect on regorafenib is expected in vivo. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of regorafenib may increase due to weak inhibition of CYP3A4, but this is unlikely to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Reboxetine is metabolized by CYP3A4. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. Regorafenib does not interact with reboxetine metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolized by CYP2C8 and CYP3A4 and clinical data seem to indicate that it is a substrate of the hepatic transporter OATP1B1. Regorafenib does not interact with this metabolic pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver. Retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied and should be avoided. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4 by rifabutin. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration should be avoided. Administration of rifampicin (600 mg for 9 days, a strong CYP3A4 inducer) and a single dose of regorafenib (160 mg on day 7) decreased regorafenib AUC by ~50%,increased the mean exposure of the active metabolite M-5 by 3-4-fold, but had no effect on the exposure of active metabolite M-2. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied and should be avoided. Decreases in regorafenib plasma concentrations may occur due to induction of CYP3A4 by rifapentine. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Rifaximin is mainly excreted in faeces, almost entirely as unchanged drug. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Risperidone is metabolized by CYP2D6 and to a lesser extent by CYP3A4 and is a substrate for P-gp. Regorafenib does not inhibit or induce CYPs. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on risperidone is expected in vivo.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Rivaroxaban is partly metabolized in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine (by P-gp and BCRP). Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on rivaroxaban is expected in vivo.

No clinically relevant effects on the pharmacokinetics of midazolam were observed when regorafenib (160 mg once daily for 14 days) and rosiglitazone (4 mg single dose) were coadministered.  Rosiglitazone is metabolized mainly by CYP2C8 and to a lesser extent 2C9. Regorafenib does not inhibit or induce CYPs.

Coadministration of regorafenib (160 mg for 14 days) and rosuvastatin (5 mg single dose, a BCRP substrate) increased rosuvastatin AUC by 3.8-fold and Cmax by 4.6-fold. Monitor patients closely for signs and symptoms of exposure related toxicity to rosuvastatin. Consider starting with the lowest dose and titrate up to the desired clinical effect while monitoring for safety.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salbutamol is metabolized to the inactive salbutamol-4’-O-sulphate. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied. Saxagliptin is mainly metabolized by CYP3A4 and is a substrate of P-gp. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on saxagliptin is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Senna glycosides are hydrolysed by colonic bacteria in the intestinal tract and the active anthraquinones liberated into the colon. Excretion occurs in the urine and the faeces and also in other secretions. No clinically significant drug interactions are known. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertindole is metabolized by CYP2D6 and CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolized by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sildenafil is metabolized mainly by CYP3A4 and to a lesser extent by CYP2C9. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Simvastatin is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied and based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sirolimus is metabolized by CYP3A4 and is a substrate of P-gp. Regorafenib does not inhibit or induce CYPs. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on sirolimus is expected in vivo. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, P-gp) and metabolism by CYP3A4 represents a minor elimination pathway. Regorafenib is an inhibitor of P-gp in vitro. However, no clinically significant effect on sitagliptin is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase. There is little potential for sodium nitroprusside to affect the disposition of regorafenib, or to be affected if co-administered with regorafenib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sotalol is excreted unchanged via renal elimination.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Spectinomycin is predominantly eliminated unchanged in the kidneys via glomerular filtration. Regorafenib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spironolactone is partly metabolized by the flavin containing monooxygenases. Regorafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Stanozolol undergoes hepatic metabolism. Regorafenib does not interact with this metabolic pathway.

Coadministration is not recommended as St John’s wort (a P-gp and CYP3A4 inducer) may cause significant and unpredictable decreases in the plasma concentrations of regorafenib. Subsequently, exposure of the active metabolite of regorafenib may increase markedly. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Streptokinase is unlikely to affect the disposition of tyrosine kinase inhibitors, or to be affected if co-administered with tyrosine kinase inhibitors.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Streptomycin is eliminated by glomerular filtration therefore no pharmacokinetic interaction is expected with regorafenib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Regorafenib does not interfere with sulfadiazine metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. 

Coadministration has not been studied. Regorafenib is metabolised mainly by CYP3A4. Tacrolimus inhibits CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Tacrolimus could potentially increase regorafenib concentrations although to a modest extent. Subsequently, exposure of the active metabolites of regorafenib may decrease. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as tadalafil is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is excreted as unchanged drug (approximately 80%) and inactive metabolite (approximately 20%) in the urine. Regorafenib does not interact with this elimination pathway.

Coadministration has not been studied but should be avoided. Concentrations of regorafenib may increase due to inhibition of CYP3A4 by telithromycin. Subsequently, exposure of the active metabolites of regorafenib may decrease markedly. Coadministration should be avoided as the effect on the steady-state exposure of regorafenib and its metabolites is unknown. If coadministration is unavoidable, the dose of regorafenib may need to be decreased with careful monitoring of tolerability. A dose decrease to 80-120 mg once daily should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telmisartan is mainly glucuronidated by UGT1A3. Regorafenib not interact with this metabolic pathway. 

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated via UGT2B15, 2B6 and 1A9. Regorafenib is an inhibitor of UGT1A1/1A9. However, a clinically relevant interaction is unlikely, since glucuronidation of temazepam via UGT1A9 is not a major pathway involved in temazepam elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolized by CYP1A2, 2C9, 3A4 and to a lesser extent CYP2C8 and 2C19. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolized by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tetracycline is eliminated unchanged primarily by glomerular filtration. Regorafenib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Theophylline is mainly metabolized by CYP1A2. Regorafenib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Thioridazine is metabolized by CYP2D6 and to a lesser extent by CYP3A4. Regorafenib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as tiapride is excreted largely unchanged in urine. 

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Ticagrelor undergoes extensive CYP3A4 metabolism and is only a mild inhibitor of CYP3A4. Ticagrelor is unlikely to be affected if coadministered with regorafenib. Regorafenib concentrations may be slightly increased if co-administered with ticagrelor. However, this is unlikely to be clinically relevant. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Timolol is predominantly metabolised in the liver by CYP2D6. Regorafenib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tinzaparin is renally excreted as unchanged or almost unchanged drug. Regorafenib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tolbutamide is mainly metabolized by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Regorafenib does not interact with this metabolic pathway.