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. Vemurafenib is unlikely to interfere with this pathway.

Coadministration has not been studied. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Vemurafenib is a moderate inhibitor of CYP1A2 and increased caffeine AUC by 2.6-fold. Vemurafenib has also shown to increase warfarin exposure; a similar effect may occur with acenocoumarol. If coadministration of acenocoumarol and vemurafenib is unavoidable exercise caution and consider additional INR monitoring.

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 metabolised by glucuronidation (by several UGTs, major UGT1A6). Vemurafenib does not inhibit or induce UGT1A6. 

Coadministration has not been studied. Agomelatin is metabolised predominantly via CYP1A2. Vemurafenib is a moderate inhibitor of CYP1A2 and increased caffeine AUC by 2.6-fold; a similar effect may occur with agomelatine. Monitoring for agomelatine toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. 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. Alfentanil undergoes extensive CYP3A4 metabolism. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with alfentanil. As the clinical relevance of this interaction is unknown, monitoring of alfentanil efficacy and dose adjustment may be required. However, since alfentanil has a broad therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Alfuzosin is metabolised by CYP3A. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with alfuzosin. However, since alfuzosin has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. P-gp is a major determinant of aliskiren bioavailability. Vemurafenib is an inhibitor of P-gp and may increase concentrations of aliskiren. Close monitoring for aliskiren toxicity and blood pressure is recommended. Monitoring for aliskiren plasma concentrations should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Vemurafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Vemurafenib is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on alosetron exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. No a priori dose adjustment of alosetron is recommended. However, due to the wide therapeutic index of alosetron, this interaction is unlikely to be clinically relevant.

Coadministration has not been studied. Alprazolam is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with alprazolam. As the clinical relevance of this interaction is unknown, monitoring of alprazolam efficacy may be required. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected.

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. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp (in vitro). Concentrations of ambrisentan may decrease due to CYP3A4 induction but concentrations of ambrisentan may also increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, close monitoring for ambrisentan toxicity is recommended. Monitoring of ambrisentan efficacy may also be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amikacin is eliminated by glomerular filtration. Vemurafenib does not interfere with this elimination pathway.

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. Vemurafenib is not transported by OCT2 and is unlikely to interfere with the elimination of amiloride.

Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP2C8 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and a weak inhibitor of CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80%; a similar effect may occur with amiodarone. The clinical relevance of this interaction is unknown. Due to the narrow therapeutic index of amiodarone, dose increments of approximately 25% should be considered. Close monitoring of efficacy is recommended. Monitoring of amiodarone plasma concentrations should also be considered, if available. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate) and P-gp (strong). Concentrations of vemurafenib may increase due to inhibition of P-gp by amiodarone. Vemurafenib should be used with caution in combination with strong inhibitors of P-gp. Note: Steady state concentrations of amiodarone are reached after approximately a month.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily renally eliminated (possibly via OCT). Vemurafenib is unlikely to affect the elimination of amisulpride. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%, but this is unlikely to be clinically relevant. However, coadministration of vemurafenib and amitriptyline may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Amlodipine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with amlodipine. As the clinical relevance of this interaction is unknown, monitoring of blood pressure is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Vemurafenib does not interfere with this metabolic or elimination pathway. However, coadministration of vemurafenib and amphotericin B may potentially cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. Note: The SPC states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension.

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 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours. Vemurafenib is unlikely to significantly affect the renal elimination of ampicillin.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected.

Coadministration has not been studied. Apixaban is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on apixaban exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with apixaban. No a priori dose adjustment of apixaban is recommended. Close monitoring for anti-Xa activity is recommended.

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. Vemurafenib is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on aprepitant exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with aprepitant. Monitoring for aprepitant toxicity and efficacy may be required. No a priori dose adjustment of aprepitant is recommended. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of vemurafenib during the three days of coadministration. Therefore, coadministration is not recommended. If coadministration is unavoidable, reduce the vemurafenib dose to 50% of the original dose during the few days of coadministration. Monitor closely for vemurafenib toxicity. After treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of vemurafenib may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on aripiprazole exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with aripiprazole. Monitoring of aripiprazole efficacy and toxicity may be required.

Coadministration has not been studied. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 and 2D6 (minor)). Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on asenapine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with asenapine. Monitoring for asenapine toxicity and efficacy may be required. No a priori dose adjustment of asenapine is recommended.

Coadministration has not been studied. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on astemizole exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with astemizole. Monitoring for astemizole toxicity and efficacy may be required. No a priori dose adjustment of astemizole is recommended. Furthermore, coadministration of vemurafenib and astemizole may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%. Vemurafenib is also an inhibitor of P-gp in vitro. It cannot be excluded that vemurafenib may increase the exposure of vemurafenib by P-gp. The net effect on atorvastatin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with atorvastatin. Monitoring for atorvastatin toxicity and efficacy may be required. No a priori dose adjustment of atorvastatin is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azathioprine is converted to 6-mercaptopurine which is metabolised analogously to natural purines. Vemurafenib does not interact with this metabolic pathway.

Coadministration has not been studied. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Vemurafenib is an inhibitor of P-gp and may increase concentrations of azithromycin. As the clinical relevance of this interaction is unknown, monitoring for toxicity may be necessary. Furthermore, coadministration of vemurafenib and azithromycin may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Vemurafenib does not interact with this metabolic pathway. 

Coadministration has not been studied. Bedaquiline is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with bedaquiline. Caution should be taken when vemurafenib is coadministered with bedaquiline. Close monitoring for bedaquiline efficacy is recommended. Furthermore, coadministration of vemurafenib and bedaquiline may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Vemurafenib does not interfere with this metabolic and elimination pathway. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically relevant 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 vemurafenib exposure.

Coadministration has not been studied. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on bepridil exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for bepridil toxicity and efficacy may be required. No a priori dose adjustment of bepridil is recommended. Furthermore, coadministration of vemurafenib and bepridil may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Betamethasone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with betamethasone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of betamethasone may be required.

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

Coadministration has not been studied. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on bisoprolol exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with bisoprolol. Monitoring for bisoprolol efficacy may be required. 

Coadministration has not been studied. Bosentan is an inducer of CYP3A4 and may decrease concentrations of vemurafenib. A decrease in exposure can lead to decreased efficacy. Furthermore, bosentan is metabolised by CYP2C9 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with bosentan. Therefore coadministration is not recommended. If coadministration is unavoidable, monitor closely for decreased efficacy of both vemurafenib and bosentan. Consider monitoring of vemurafenib plasma concentrations, if available.

Coadministration has not been studied. Bromazepam undergoes oxidative biotransformation. Interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may also play a role. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on bromazepam exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with bromazepam. Monitoring for bromazepam toxicity and efficacy may be required. No a priori dose adjustment of bromazepam is recommended. 

Coadministration has not been studied. Budesonide is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with budesonide. As the clinical relevance of this interaction is unknown, monitoring and dose increase of budesonide may be required.

Coadministration has not been studied. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with buprenorphine. As the clinical relevance of this interaction is unknown, monitoring of buprenorphine efficacy and dose adjustment may be required. However, since buprenorphine has a broad therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolised by CYP2B6. Vemurafenib is a weak inducer of CYP2B6 in vitro but no clinical relevant interaction is expected. 

Coadministration has not been studied. Buspirone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with buspirone. As the clinical relevance of this interaction is unknown, monitoring for buspirone efficacy may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine and sweat. Vemurafenib does not interact with these elimination pathways.

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. Vemurafenib 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. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Vemurafenib is an inhibitor of CYP2C8 in vitro. Furthermore, vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with carbamazepine. Carbamazepine is an inducer of CYPs 3A4 (strong), 2C8 (strong), 2C9 (strong), 1A2 (weak), 2B6 and UGT1A1. Carbamazepine may significantly decrease concentrations of vemurafenib due to induction of CYP3A4 and UGT. Decreased vemurafenib exposure can lead to decreased efficacy. Therefore coadministration should be avoided.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2. Vemurafenib is a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition); a similar effect may occur with carvedilol. As the clinical relevance of this interaction is unknown, monitoring of blood pressure and heart rate 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. Vemurafenib does not interfere with this metabolic pathway. 

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

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefixime is renally excreted predominantly by glomerular filtration. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolised 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. Vemurafenib does not interfere with this elimination pathway.

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

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. Vemurafenib does not interfere with this elimination pathway.

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

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. Vemurafenib is not transported by OCT2 and does not interfere with the metabolism or elimination of cetirizine.

Coadministration has not been studied. Chloramphenicol is predominately glucuronidated. Vemurafenib does not inhibit or induce UGTs. In vitro studies have shown that chloramphenicol inhibits CYP3A4 and may increase concentrations of vemurafenib, thus potentially increasing the risk of adverse events. As the clinical significance of this interaction is unknown, close monitoring for vemurafenib induced toxicity is recommended. Consider monitoring of vemurafenib plasma concentrations, if available. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction. 

Coadministration has not been studied. Chlordiazepoxide is extensively metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with chlordiazepoxide. As the clinical relevance of this interaction is unknown, monitoring for chlordiazepoxide efficacy may be required.

Coadministration has not been studied. Chlorphenamine is predominantly metabolised in the liver via CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. As the clinical relevance of this interaction is unknown, monitoring for chlorphenamine toxicity may be required.

Coadministration has not been studied. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4, a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on chlorpromazine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for toxicity and efficacy of chlorpromazine is recommended. Monitoring for chlorpromazine plasma concentrations should be considered, if available. Furthermore, coadministration of vemurafenib and chlorpromazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Ciclosporin is a substrate of CYP3A4 (main route) and P-gp. Vemurafenib is an inhibitor of P-gp and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on ciclosporin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for ciclosporin toxicity and efficacy may be required. No a priori dose adjustment of ciclosporin is recommended. Furthermore, ciclosporin inhibits CYP3A4 and OATP1B1, and may increase vemurafenib concentrations. If coadministration is unavoidable, monitor closely for vemurafenib toxicity. Consider monitoring of vemurafenib plasma concentrations, if available.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a potential inhibitor of cytochrome P450 enzymes and may therefore modestly increase the exposure to vemurafenib. However, this is not considered to be clinically relevant. Furthermore, the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8. No clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected.

Coadministration has not been studied. Ciprofloxacin is a strong inhibitor of CYP1A2 and is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Vemurafenib does not interfere with this metabolic or elimination pathway. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Monitoring for vemurafenib toxicity may be required. Consider monitoring of vemurafenib plasma concentrations, if available. Furthermore, coadministration of vemurafenib and ciprofloxacin may potentially cause QTc interval prolongation in a concentration-dependent manner. The clinical relevance of this interaction is unknown but monitoring, including ECG assessment, may be required.

Coadministration has not been studied. Cisapride is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with cisapride. As the clinical relevance of this interaction is unknown, close monitoring of cisapride efficacy is recommended. Furthermore, cisapride has a known risk of Torsade de Pointes. Vemurafenib may cause QTc interval prolongation. If coadministration is unavoidable, close monitoring including ECG is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on citalopram exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with citalopram. No a priori dose adjustment of citalopram is recommended. Furthermore, coadministration of vemurafenib and citalopram may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but is not recommended. Clarithromycin is metabolised by CYP3A4. Vemurafenib is an inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with clarithromycin. Clarithromycin is an inhibitor of CYP3A4 and P-gp, and may increase concentrations of vemurafenib. Coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for vemurafenib toxicity, including ECG monitoring. Consider monitoring of vemurafenib plasma concentrations, if available. Clarithromycin efficacy should also be closely monitored and an increased dose of clarithromycin should be considered. Furthermore, monitor clarithromycin plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolised (likely non-CYP mediated pathway) and excreted in the urine by glomerular filtration. Vemurafenib does not interfere with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clemastine is predominantly metabolised in the liver via CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. Since clemastine has a wide therapeutic index, a clinically relevant interaction is unlikely.  

Coadministration has not been studied. Clindamycin is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with clindamycin. Care should be taken when vemurafenib is coadministered with clindamycin. Close monitoring for clindamycin efficacy is recommended. Consider monitoring of clindamycin plasma concentrations, if available.

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 but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. Vemurafenib does not interact with this elimination pathway. However, coadministration of vemurafenib and clofazimine may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Vemurafenib does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but should be approached with caution. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on clomipramine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with clomipramine. Monitoring for clomipramine toxicity and efficacy may be required. No a priori dose adjustment of clomipramine is recommended. Coadministration of vemurafenib and clomipramine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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 the form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 but is unlikely to interact with vemurafenib elimination. In addition, vemurafenib does not interfere with the elimination of clonidine.

Coadministration has not been studied. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Vemurafenib is a moderate inducer of CYP3A4, a weak inducer of CYP2B6 (in vitro) and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on clopidogrel exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with clopidogrel. Monitoring for clopidogrel toxicity and efficacy may be required. No a priori dose adjustment of clopidogrel is recommended.

Coadministration has not been studied. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with clorazepate and thus oxazepam concentrations may increase. As the clinical relevance of this interaction is unknown, monitoring for oxazepam toxicity may be required.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied and should be approached with caution. Clozapine is mainly metabolized by CYP1A2 and CYP3A4 and to a lesser extent by CYP2C19 and CYP2D6. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on clozapine exposure is unknown. Monitoring for clozapine toxicity and efficacy may be required. No a priori dose adjustment of clozapine is recommended. Furthermore, coadministration of vemurafenib and clozapine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. 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. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Vemurafenib is a weak inhibitor of CYP2D6, a moderate inducer of CYP3A4 and is an inhibitor of P-gp in vitro. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on codeine and morphine exposure is unknown since multiple pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with codeine. Monitoring for codeine and morphine toxicity and efficacy may be required. No a priori dose adjustment of codeine is recommended.

Coadministration has not been studied. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Vemurafenib is an inhibitor of P-gp and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on colchicine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with colchicine. Monitoring for colchicine toxicity and efficacy may be required. No a priori dose adjustment of colchicine is recommended.

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

Coadministration has not been studied. Dabigatran is transported via P-gp and is renally excreted. Vemurafenib is an inhibitor of P-gp in vitro and may increase dabigatran concentrations. As the clinical relevance of this interaction is unknown, close monitoring for dabigatran toxicity is recommended.

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. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP450 enzymes. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on dapsone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with dapsone. Monitoring for dapsone toxicity and efficacy may be required. No a priori dose adjustment of dapsone is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Desipramine is metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan by 47%, but this is unlikely to be clinically relevant. However, coadministration of vemurafenib and desipramine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with desogestrel. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease vemurafenib concentrations. However, the clinical relevance of this interaction is unknown as CYP3A4 induction by dexamethasone has not yet been established. If coadministration is unavoidable, monitoring vemurafenib efficacy may be necessary. Consider monitoring of vemurafenib plasma concentrations, if available.

Coadministration has not been studied. Dextropropoxyphene is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with dextropropoxyphene. As the clinical relevance of this interaction is unknown, monitoring of dextropropoxyphene efficacy and dose adjustment may be required. However, since dextropropoxyphene has a broad therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diamorphine is rapidly metabolised 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). Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with diazepam. As the clinical relevance of this interaction is unknown, monitoring for diazepam efficacy may be required.

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 oxidised by CYP2C9. Vemurafenib does not inhibit or induce CYP2C9 or UGTs.

Digoxin is renally eliminated via the renal transporters OATP4C1 and P-gp. Vemurafenib is an inhibitor of P-gp. In patients with BRAFV600 mutation-positive metastatic malignancy (n=27), coadministration of vemurafenib (960 mg twice daily for 21 days) and digoxin (single dose of 0.25 mg) increased digoxin AUC and Cmax by 82% and 47%, respectively. Caution should be exercised when coadministering vemurafenib and digoxin. If coadministration is unavoidable, close monitoring of digoxin toxicity is recommended. Monitor digoxin plasma concentrations, if available. 

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.  Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with dihydrocodeine. However, since CYP3A4 mediated metabolism is a minor pathway, a clinical relevant interaction is unlikely.

Coadministration has not been studied. Diltiazem is metabolised by CYP3A4 and CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on diltiazem exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with diltiazem. Monitoring for diltiazem toxicity and efficacy may be required. No a priori dose adjustment of diltiazem is recommended. Furthermore, diltiazem is a moderate inhibitor of CYP3A4 and may potentially increase vemurafenib exposure. Concurrent use of diltiazem and vemurafenib is not recommended. If coadministration is unavoidable, close monitoring of vemurafenib toxicity is recommended. Monitoring of vemurafenib plasma concentrations should be considered, if available.

Coadministration has not been studied. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). As the clinical relevance of this interaction is unknown, monitoring for diphenhydramine toxicity is recommended. Furthermore, coadministration of vemurafenib and diphenhydramine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Vemurafenib does not inhibit or induce UGTs. 

Coadministration has not been studied. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with disopyramide. However, since CYP3A4 mediated metabolism is a minor pathway, this is unlikely to be clinically relevant. However, coadministration of vemurafenib and disopyramide may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic 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%). Vemurafenib is a moderate inducer of CYP3A4 and a weak inhibitor of CYP2D6. Since CYP-mediated metabolism is only a minor pathway, this is unlikely to be clinically relevant. However, coadministration of vemurafenib and dolasetron may potentially cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

Coadministration has not been studied. Domperidone is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with domperidone. Monitoring of domperidone efficacy is recommended. Furthermore, coadministration of vemurafenib and domperidone may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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 the disposition of vemurafenib, or to be affected if coadministered with vemurafenib.

Coadministration has not been studied. Doxazosin is metabolised mainly by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with doxazosin. Close monitoring of blood pressure is recommended. 

Coadministration has not been studied. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%, but this is unlikely to be clinically relevant.

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. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with dronabinol. However, since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely. Consider monitoring for dronabinol efficacy.

Coadministration has not been studied. Drospirenone is metabolised to a minor extent via CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with drospirenone. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The clinical relevance of delayed absorption is considered to be limited.

Coadministration has not been studied. Duloxetine is metabolised by CYP2D6 and CYP1A2. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib increased dextromethorphan AUC by 47% and increased caffeine AUC by 2.6-fold. The clinical relevance of this interaction is unknown and monitoring for duloxetine toxicity is required. Monitoring of plasma concentrations and dose adjustments for duloxetine should be considered, if available.

Coadministration has not been studied. Dutasteride is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with dutasteride. However, since dutasteride has a wide therapeutic index, a clinically relevant interaction is unlikely. Monitoring for dutasteride efficacy may be required.

Coadministration has not been studied. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with dydrogesterone. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Vemurafenib is an inducer of CYP3A4 and decreased midazolam AUC by 39-80%. However, since CYP3A4 mediated metabolism is only a minor pathway, this is unlikely to be clinically relevant. Furthermore, vemurafenib is an inhibitor of P-gp and may increase concentrations of edoxaban. Close monitoring for edoxaban toxicity is recommended.

Coadministration has not been studied. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Vemurafenib is a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2C8 in vitro. Vemurafenib increased caffeine AUC by 2.6-fold; a similar effect may occur with eltrombopag. Close monitoring for thrombocyte count is recommended. Adjust dose if necessary.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is renally eliminated (possibly via OATs). Vemurafenib does not interfere with this metabolic or elimination pathway.

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. Vemurafenib does not interfere with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eprosartan is largely excreted in bile and urine as unchanged drug. Vemurafenib does not interfere with this elimination pathway.

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 role. Vemurafenib does not interact with this elimination pathway.

Coadministration has not been studied but should be avoided. Erythromycin is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with erythromycin. Furthermore, erythromycin is an inhibitor of CYP3A4 and may increase vemurafenib concentrations. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for vemurafenib toxicity, including ECG. Consider monitoring of vemurafenib plasma concentrations, if available. Erythromycin efficacy should also be closely monitored and a dose increase for erythromycin should be considered.

Coadministration has not been studied but should be approached with caution. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on escitalopram exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for escitalopram toxicity and efficacy may be required. No a priori dose adjustment of escitalopram is recommended. Furthermore, coadministration of vemurafenib and escitalopram may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with esomeprazole. However, since esomeprazole has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with estazolam. As the clinical relevance of this interaction is unknown, monitoring for estazolam efficacy may be required.

Coadministration has not been studied. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Vemurafenib is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on estradiol exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with estradiol. No a priori dose adjustment of estradiol is recommended. However, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

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

Coadministration has not been studied. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with ethinylestradiol. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethionamide is extensively metabolised in the liver; animal studies suggest involvement of flavin-containing monooxygenases. Vemurafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied. Etonogestrel is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with etonogestrel. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Everolimus is metabolised via CYP3A4 and is a substrate for P-gp. Vemurafenib is an inhibitor of P-gp and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on everolimus exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with everolimus. Monitoring for everolimus toxicity and efficacy may be required. No a priori dose adjustment of everolimus is recommended. Monitoring of everolimus plasma concentrations is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Exenatide is cleared mainly by glomerular filtration. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. 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. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Furthermore, famotidine is excreted via OAT1/OAT3. Vemurafenib does not interact with this elimination pathway.

Coadministration has not been studied. Felodipine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with felodipine. As the clinical relevance of this interaction is unknown, monitoring of blood pressure is recommended.

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

Coadministration has not been studied. Fentanyl undergoes extensive CYP3A4 metabolism. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with fentanyl. As the clinical relevance of this interaction is unknown, monitoring of fentanyl efficacy and dose adjustment may be required. 

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Finasteride is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with finasteride. However, since finasteride has a wide therapeutic index, a clinically relevant interaction is unlikely.

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

Coadministration has not been studied. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47% (CYP2D6 inhibition); a similar effect may occur with flecainide. The clinical relevance of this interaction is unknown. As flecainide has a narrow therapeutic index, monitoring for flecainide toxicity is recommended. Furthermore, coadministration of vemurafenib and flecainide may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Vemurafenib does not interfere with this elimination pathway. However, flucloxacillin was shown to induce CYP3A4 and P-gp and may potentially decrease vemurafenib concentrations. Close monitoring of vemurafenib efficacy is recommended. Consider monitoring of vemurafenib plasma concentrations, if available.

Coadministration has not been studied. Fluconazole is cleared primarily by renal excretion. Vemurafenib is unlikely to interfere with this elimination pathway. However, fluconazole is an inhibitor of CYPs 2C19, 3A4 and 2C9, and may increase vemurafenib concentrations. Coadministration should be used with caution. If coadministration is unavoidable, monitor closely for vemurafenib toxicity. Monitoring of vemurafenib plasma concentrations should be considered, if available. Furthermore, coadministration of vemurafenib and fluconazole may cause QTc interval prolongation in a concentration-dependent manner, and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil which is further metabolised by dihydropyrimidine dehydrogenase. Vemurafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with fludrocortisone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of fludrocortisone may be required.

Coadministration has not been studied. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with flunitrazepam. As the clinical relevance of this interaction is unknown, monitoring for flunitrazepam efficacy may be required.

Coadministration has not been studied. Fluoxetine is metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on fluoxetine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with fluoxetine. No a priori dose adjustment of fluoxetine is recommended.

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur with fluphenazine. Monitoring for fluphenazine toxicity may be required. Furthermore, coadministration of vemurafenib and fluphenazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. The metabolism of flurazepam is most likely CYP-mediated. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). However, since multiple metabolic pathways are involved and flurazepam does not have a narrow therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Fluticasone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with fluticasone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of fluticasone may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvastatin is mainly metabolised by CYP2C9. Vemurafenib does not inhibit or induce CYP2C9.

Coadministration has not been studied. Fluvoxamine is an inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib increased dextromethorphan AUC by 47% and increased caffeine AUC by 2.6-fold. Monitoring for fluvoxamine and vemurafenib toxicity is recommended. Monitor vemurafenib and fluvoxamine plasma concentrations, if available.

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. Vemurafenib does not interfere with this metabolic or elimination 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. As multiple CYP450 and UGT enzymes catalyse 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. Vemurafenib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Vemurafenib is a moderate inducer of CYP3A4 and a moderate inhibitor of CYP1A2. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The net effect on aprepitant exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with aprepitant. Monitoring for aprepitant toxicity and efficacy may be required. No a priori dose adjustment of aprepitant is recommended. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of vemurafenib during the three days of coadministration. Therefore, coadministration is not recommended. If coadministration is unavoidable, reduce the vemurafenib dose to 50% of the original dose during the few days of coadministration. Monitor closely for vemurafenib toxicity. After treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of vemurafenib may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied 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. Vemurafenib does not interact with this pathway. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp, and may decrease concentrations of vemurafenib. Therefore, coadministration should be avoided, since a decrease in exposure can lead to decreased efficacy. Selection of an alternative concomitant medication with no or minimal enzyme or transporter induction potential is recommended. If coadministration is clinically necessary, monitor closely for decreased vemurafenib efficacy. Consider monitoring of vemurafenib plasma concentrations and subsequent dose adjustment, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally (via OATs). In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3. Vemurafenib is not transported by OAT1/OAT3 and does not interfere with the metabolism or elimination of furosemide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gabapentin is cleared mainly by glomerular filtration. Vemurafenib does not 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. Vemurafenib does not inhibit or induce UGTs.  Furthermore, gemfibrozil is an inhibitor of CYP2C8. Vemurafenib 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. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with gestodene. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with glibenclamide. Monitoring of blood glucose levels is recommended and adjust glibenclamide dose accordingly.

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

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

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

Coadministration has not been studied but should be approached with caution. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Vemurafenib is an inhibitor of P-gp and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on granisetron exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for granisetron toxicity and efficacy may be required. No a priori dose adjustment of granisetron is recommended. Furthermore, coadministration of vemurafenib and granisetron may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration should be avoided. Grapefruit juice is a known inhibitor of CYP3A4 and may potentially increase vemurafenib concentrations. However, the magnitude of this potential interaction is difficult to predict as the effect of grapefruit juice is concentration-, dose- and preparation-dependent and varies widely across brands. Therefore, coadministration should be avoided.

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

Coadministration has not been studied. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Vemurafenib does not interfere with this elimination pathway. However, griseofulvin is a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy, of concomitantly administered medicinal products metabolised by CYP3A4, such as vemurafenib. 

Coadministration has not been studied but should be approached with caution. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on haloperidol exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for haloperidol toxicity and efficacy may be required. Furthermore, coadministration of vemurafenib and haloperidol may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

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. Vemurafenib does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydralazine is metabolised via primary oxidative metabolism and acetylation. Although in vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6, it is not expected that this will lead to a clinical relevant interaction with vemurafenib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant drug concentrations. Significant interactions are not expected with vemurafenib.

Coadministration has not been studied. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on hydrocodone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with hydrocodone. Monitoring for hydrocodone toxicity and efficacy may be required. No a priori dose adjustment is recommended for hydrocodone.

Coadministration has not been studied. Hydrocortisone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with hydrocortisone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of hydrocortisone 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 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. Vemurafenib does not inhibit or induce UGT2B7. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is not a substrate of CYP enzymes or P-gp. Vemurafenib is unlikely to interfere with the metabolism or elimination of hydroxyurea.

Coadministration has not been studied but should be approached with caution. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with hydroxyzine. Since multiple metabolic pathways are involved and hydroxyzine does not have a narrow therapeutic index, this is unlikely to be clinically relevant. However, coadministration of vemurafenib and hydroxyzine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. 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 metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Vemurafenib is a weak inhibitor of CYP2C8 in vitro. The clinical relevance of this interaction is unknown. However, since ibuprofen has a broad therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but should be approached with caution. Iloperidone is metabolised by CYP3A4 and CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on iloperidone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for iloperidone toxicity may be required. Furthermore, coadministration of vemurafenib and iloperidone may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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

Coadministration has not been studied but should be approached with caution. Imipramine is metabolised by CYP2D6 (major) and CYPs 3A4, 2C19 and 1A2 (minor) to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on imipramine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for imipramine toxicity and efficacy may be required. No a priori dose adjustment of imipramine is recommended. Furthermore, coadministration of vemurafenib and imipramine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but should be approached with caution. Indapamide is extensively metabolised by CYP450. Vemurafenib is an inducer of CYP3A4 (moderate) and CYP2B6 (weak, in vitro). In addition, vemurafenib is an inhibitor of CYPs 1A2 (moderate), 2D6 (weak) and 2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on indapamide exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for blood pressure may be required. No a priori dose adjustment of indapamide is recommended. Furthermore, coadministration of vemurafenib and indapamide may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Interferon alpha is not a substrate of CYP enzymes or P-gp. Vemurafenib is unlikely to interfere with the metabolism or elimination of interferon alpha.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration. Vemurafenib does not interact with this elimination pathway.

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. Vemurafenib 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 metabolised by glucuronidation and oxidation (mainly CYP2C9). Vemurafenib does not inhibit or induce UGTs or CYP2C9.

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. Vemurafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with isosorbide dinitrate. As the clinical relevance of this interaction is unknown, monitoring for isosorbide dinitrate toxicity may be required.

Coadministration has not been studied but should be avoided. Itraconazole is primarily metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with itraconazole. The clinical relevance of this interaction is unknown. Consider dose adjustments for itraconazole. Monitoring for itraconazole plasma concentrations is recommended, if available. Itraconazole is an inhibitor of P-gp and a strong inhibitor of CYP3A4. Concentrations of vemurafenib may increase due to inhibition of CYP3A4 and P-gp. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for vemurafenib toxicity. Monitor vemurafenib plasma concentrations, if available. Furthermore, coadministration of vemurafenib and itraconazole may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Ivabradine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with ivabradine. Monitoring of blood pressure and heart rate is recommended. Furthermore, coadministration of vemurafenib and ivabradine may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but should be avoided. Ketoconazole is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with ketoconazole. Ketoconazole is a strong inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for vemurafenib and ketoconazole toxicity. Consider monitoring of vemurafenib and ketoconazole plasma concentrations, if available. Furthermore, coadministration of vemurafenib and ketoconazole may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Vemurafenib does not inhibit or induce UGTs. 

Coadministration has not been studied. Lacidipine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with lacidipine. Monitoring of blood pressure and heart rate is recommended.

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. 

Coadministration has not been studied. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Lansoprazole is mainly metabolised by CYP2C19 and to lesser extent by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with lansoprazole. However, since lansoprazole has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Lercanidipine is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with lercanidipine. Monitoring of blood pressure and heart rate is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Vemurafenib does not interfere with this elimination pathway. However, coadministration of vemurafenib and levofloxacin may potentially cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Levomepromazine is metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur with levomepromazine. Monitoring for levomepromazine toxicity may be required. Furthermore, coadministration of vemurafenib and levomepromazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

Coadministration has not been studied. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with levonorgestrel. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with levonorgestrel. Caution should be taken when vemurafenib is coadministered with levonorgestrel.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation. Vemurafenib does not interact with these metabolic pathways.

Coadministration has not been studied. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Vemurafenib is a moderate inhibitor of CYP1A2 and a moderate inducer of CYP3A4. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). Since CYP1A2 is the dominant metabolic pathway, vemurafenib may increase lidocaine plasma concentrations. Monitoring for toxicity is recommended and dose adjustment may be required.

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. In addition, linagliptin is a substrate of P-gp. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp. Vemurafenib decreased midazolam AUC by 39-80%; a similar effect may occur with linagliptin. Furthermore, linagliptin is an inhibitor of CYP3A4 and may increase concentrations of vemurafenib. If coadministration is unavoidable, monitoring of blood glucose and vemurafenib plasma concentrations is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linezolid undergoes non-CYP mediated metabolism. Vemurafenib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Liraglutide is degraded by endogenous endopeptidases. Vemurafenib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is renally eliminated unchanged via glomerular filtration. Vemurafenib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic 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. However, coadministration of vemurafenib and lithium may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration of live vaccines (BCG vaccine; measles, mumps and rubella vaccines; varicella vaccines; typhoid vaccines; rota virus 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 generalised infections can occur.

Coadministration has not been studied. Loperamide is mainly metabolised by CYP3A4 and CYP2C8. Loperamide is also a substrate of P-gp. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp and CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on loperamide exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. No a priori dose adjustment of loperamide is recommended. However, since loperamide has a wide therapeutic index, a clinically relevant interaction is unlikely. 

Coadministration has not been studied. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). Since loratadine has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lorazepam is eliminated by non-CYP mediated pathways and no effect on plasma concentrations is expected when coadministered with vemurafenib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated. Vemurafenib does not inhibit or induce UGTs.

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. Vemurafenib does not inhibit or induce CYP2C9.

Coadministration has not been studied. Lovastatin is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with lovastatin. Monitoring of cholesterol concentrations is recommended and adjust dose accordingly.

Coadministration has not been studied. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of CYP2C8 in vitro. Vemurafenib decreased midazolam AUC by 39-80%; a similar effect may occur with macitentan. Monitoring of blood pressure and heart rate is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Magnesium is eliminated in the kidney, mainly by glomerular filtration. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Maprotiline is mainly metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. The clinical relevance of this interaction is unknown, but it is unlikely to be clinical significant. 

Coadministration has not been studied. Medroxyprogesterone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with medroxyprogesterone. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Medroxyprogesterone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with medroxyprogesterone. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Vemurafenib does not inhibit or induce CYP2C9, UGT2B7 or UGT1A9.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of the renal transporters OAT3>OAT1. Vemurafenib 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 metabolised to N-acetyl-mesalazine by N-acetyltransferase. Vemurafenib does not interfere with this metabolic pathway. 

Coadministration has not been studied. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Metamizole is also an inducer of CYP3A4 and may decrease vemurafenib concentrations. 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. Metformin is mainly eliminated unchanged in the urine (via OCT2). Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied. Methadone is demethylated by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with methadone. The clinical relevance of this interaction is unknown, monitoring of methadone efficacy and dose adjustment may be required. Coadministration of vemurafenib and methadone may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolised by CYP450s to a clinically relevant extent and does not inhibit or induce CYP450s. 

Coadministration has not been studied. Methylprednisolone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with methylprednisolone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of methylprednisolone may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolised by the CYP450 system (mainly CYP2D6). Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. However, since CYP-mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metolazone is largely excreted unchanged in the urine. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied and based on metabolism and clearance a clinically significant interaction is unlikely. Metoprolol is mainly metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. However, no clinically relevant interaction is expected.

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 vemurafenib cannot be excluded and close monitoring is recommended.

Coadministration has not been studied. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and also increased caffeine AUC by 2.6-fold (CYP1A2 inhibition). The clinical relevance of this interaction is unknown. Monitoring for mexiletine toxicity is recommended.

Coadministration has not been studied. Mianserin is metabolised by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on mianserin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with mianserin. Monitoring for mianserin toxicity and efficacy may be required. No a priori dose adjustment of mianserin is recommended. 

Coadministration has not been studied. Miconazole is metabolised via O-dealkylation and oxidative N-dealkylation, potentially CYP-mediated. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on miconazole exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for miconazole efficacy and toxicity may be required. Miconazole is an inhibitor of CYP2C9 and CYP3A4, and could potentially increase vemurafenib concentrations. Dermal application: No a priori dosage adjustment is recommended for vemurafenib, since miconazole is used topically and systemic exposure is limited. Oromucosal application: Coadministration may increase vemurafenib concentrations due to inhibition of CYP3A4. Concurrent use of CYP3A4 inhibitors should be avoided. If coadministration is unavoidable, close monitoring of vemurafenib toxicity is recommended. Monitoring of vemurafenib plasma concentrations should be considered, if available. Furthermore, coadministration of vemurafenib and miconazole may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Midazolam is metabolised by CYP3A4. In patients with metastatic melanoma (n=20), coadministration of vemurafenib (960 mg twice daily for 14 days) and oral midazolam (single dose administered as a drug cocktail with other probe drugs) decreased midazolam AUC by 39% (average, maximum 80%). Midazolam Cmax also decreased on average by 35%. Monitoring for midazolam efficacy is recommended.

Midazolam is metabolised by CYP3A4. In patients with metastatic melanoma (n=20), coadministration of vemurafenib (960 mg twice daily for 14 days) and oral midazolam (single dose administered as a drug cocktail with other probe drugs) decreased midazolam AUC by 39% (average, maximum 80%). Midazolam Cmax also decreased on average by 35%. Monitoring for midazolam efficacy is recommended.

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%). Vemurafenib is unlikely to interfere with these pathways.

Coadministration has not been studied. Mirtazapine is metabolised mainly by CYP3A4 to N-desmethylmirtazapine (active metabolite), and to 8-hydroxymirtazapine by CYP2D6 and CYP1A2. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on mirtazapine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with mirtazapine. Monitoring for mirtazapine toxicity and efficacy may be required. No a priori dose adjustment of mirtazapine is recommended.

Coadministration has not been studied. Mometasone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with mometasone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of mometasone may be required.

Coadministration has not been studied. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of CYP2C8 in vitro. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on montelukast exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with montelukast. Monitoring for montelukast toxicity and efficacy may be required. No a priori dose adjustment of montelukast is recommended.

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). Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. Vemurafenib does not inhibit or induce UGTs. However, coadministration of vemurafenib and moxifloxacin may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Vemurafenib does not inhibit or induce UGTs. In addition, inhibition of OAT1/OAT3 renal transporters by mycophenolic acid (active metabolite) is unlikely to interfere with the elimination of vemurafenib.

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. Vemurafenib 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 metabolised in the liver by alpha-reductase. Vemurafenib 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. Vemurafenib is a moderate inhibitor of CYP1A2 and increased caffeine AUC by 2.6-fold; a similar effect may occur with naproxen. However, since CYP1A2 mediated metabolism is a minor pathway and naproxen has a broad therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with nateglinide. Monitoring of blood glucose levels is recommended

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nebivolol metabolism involves CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. However, no clinically relevant interaction is expected.

Coadministration has not been studied. Nefazodone is metabolised by CYP3A4. Vemurafenib is an inducer of CYP3A4 and decreased midazolam AUC by 39-80%. Monitoring of nefazodone efficacy is recommended. Furthermore, nefazodone is an inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Concurrent use of CYP3A4 inhibitors and vemurafenib should be avoided. If coadministration is unavoidable, close monitoring of vemurafenib toxicity and efficacy is recommended. Monitoring of vemurafenib plasma concentrations should be considered, if available.

Coadministration has not been studied. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Vemurafenib is a moderate inducer of CYP3A4, a weak inhibitor of CYP2D6 and an inhibitor of CYP2C8 in vitro. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on codeine exposure is unknown since multiple metabolic pathways are affected but it is likely that concentrations of nicardipine may decrease. Monitoring of blood pressure is recommended. Furthermore, nicardipine inhibits CYP3A4 and could potentially increase vemurafenib concentrations. Close monitoring of vemurafenib tolerability is recommended.

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 metabolised by xanthine oxidase and aldehyde oxidase. Vemurafenib does not interact with this metabolic pathway. 

Coadministration has not been studied. Nifedipine is metabolised mainly by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with nifedipine. The clinical relevance of this interaction is unknown, monitoring of blood pressure is recommended.

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

Coadministration has not been studied. Nisoldipine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with nisoldipine. The clinical relevance of this interaction is unknown, monitoring of blood pressure is recommended.

Coadministration has not been studied. Nitrendipine is extensively metabolised mainly by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with nitrendipine. The clinical relevance of this interaction is unknown, monitoring of blood pressure is recommended.

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

Coadministration has not been studied. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with norelgestromin. Therefore, woman using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Vemurafenib does not interact with these metabolic pathways. 

Coadministration has not been studied. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Vemurafenib is a moderate inducer of CYP3A4 and CYP2B6 (in vitro), and an inhibitor of CYP1A2 (moderate), CYP2D6 (weak) and CYP2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on norgestimate exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. No a priori dose adjustment of norgestimate is recommended. Caution should be taken when vemurafenib is coadministered with norgestimate. Women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with norgestrel. Therefore, women using hormonal contraceptives should add a barrier method as a second form of contraception while taking vemurafenib and for one month after stopping treatment.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolised mainly by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%, but this is unlikely to be clinically relevant. However, coadministration of vemurafenib and nortriptyline may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

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 pharmacokinetic interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Vemurafenib is unlikely to interfere with this elimination pathway. However, coadministration of vemurafenib and ofloxacin may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Olanzapine is metabolised mainly by CYP1A2 and CYP2D6, but also by glucuronidation (UGT1A4). Vemurafenib is a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition); a similar effect may occur with olanzapine. Monitoring for olanzapine toxicity is recommended. Monitor olanzapine plasma concentrations, if available.

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. Vemurafenib is unlikely to interact with this metabolic pathway.

Coadministration has not been studied. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Omeprazole is mainly metabolised by CYP2C19 and to lesser extent by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with omeprazole. However, since omeprazole has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but should be approached with caution. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Vemurafenib is a moderate inducer of CYP3A4, moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and P-gp. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on ondansetron exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for ondansetron toxicity and efficacy may be required. No a priori dose adjustment of ondansetron is recommended. Furthermore, coadministration of vemurafenib and ondansetron may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated. Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied but should be approached with caution. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Vemurafenib does not interact with this pathway. However, both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Oxcarbazepine may significantly decrease concentrations of vemurafenib. Decreased vemurafenib exposure can lead to decreased efficacy. If coadministration is unavoidable, monitor closely for decreased efficacy of vemurafenib. Consider monitoring of vemurafenib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolised via glucuronidation. Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on oxycodone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with oxycodone. Monitoring for oxycodone toxicity and efficacy may be required. No a priori dose adjustment of oxycodone is recommended. However, since oxycodone has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on paliperidone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. However since these are minor metabolic pathways, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6 and P-gp. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on palonosetron exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with palonosetron. Monitoring for palonosetron toxicity and efficacy is recommended. No a priori dose adjustment of palonosetron is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pamidronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Vemurafenib does not interact with this pathway.

Coadministration has not been studied. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Pantoprazole is mainly metabolised by CYP2C19 and to lesser extent by CYPs 3A4, 2D6 and 2C9. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on pantoprazole exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. No a priori dose adjustment of pantoprazole is recommended. However, since pantoprazole has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1 and 2B15), sulfation, and to a lesser extent, by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Vemurafenib is a moderate inhibitor of CYP1A2, a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. However, since these enzymes have only a minor contribution to paracetamol metabolism, a clinically relevant interaction is unlikely. 

Coadministration has not been studied. Paroxetine is mainly metabolised by CYP2D6 and CYP3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on paroxetine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for paroxetine toxicity and efficacy may be required. No a priori dose adjustment of paroxetine is recommended. Monitoring of paroxetine plasma concentrations should be considered, if available.

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. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Vemurafenib does not interfere with the elimination of penicillins.

Coadministration has not been studied. Perazine is mainly metabolised by CYPs 1A2, 3A4 and 2C19, and to a lesser extent by CYPs 2C9, 2D6 and 2E1, with oxidation via FMO3. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on perazine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Close monitoring for perazine efficacy and toxicity is recommended. Monitor perazine plasma concentrations, if available.

Coadministration has not been studied. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur with periciazine. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied. Perindopril is hydrolysed to the active metabolite perindoprilat potentially via CYP3A4 and is metabolised to other inactive metabolites. Elimination occurs predominantly via the urine. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with perindopril, thus increasing concentrations of the active metabolite. Monitoring of blood pressure and heart is recommended. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perphenazine is metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur with perphenazine. As the clinical relevance of this interaction is unknown, monitoring may be required. Furthermore, coadministration of vemurafenib and perphenazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

Coadministration has not been studied. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and a weak inducer of CYP2B6 in vitro. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction); a similar effect may occur with pethidine. The clinical relevance of this interaction is unknown, monitoring of pethidine efficacy and dose adjustment may be required. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenelzine is primarily metabolised by oxidation via monoamine oxidase and to a lesser extent by acetylation. Vemurafenib does not interfere with these metabolic pathways.

Coadministration has not been studied but should be avoided. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Vemurafenib does not inhibit or induce these CYPs. Phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Therefore, phenobarbital may decrease concentrations of vemurafenib due to CYP3A4 and UGT induction. Decreased vemurafenib exposure can lead to decreased efficacy. Therefore coadministration should be avoided.

Coadministration has not been studied. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80% (CYP3A4 induction). Vemurafenib has also shown to increase warfarin exposure; a similar effect may occur with phenprocoumon. The clinical relevance of this interaction is unknown. Care should be taken when vemurafenib is coadministered with phenprocoumon. If coadministration of phenprocoumon and vemurafenib is unavoidable, exercise caution and consider additional INR monitoring. No a priori dose adjustment of phenprocoumon is recommended.

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Vemurafenib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp, and may decrease concentrations of vemurafenib. Therefore, coadministration should be avoided, since a decrease in exposure can lead to decreased efficacy. Selection of an alternative concomitant medication with no or minimal enzyme or transporter induction potential is recommended. If coadministration is clinically necessary, monitor closely for decreased efficacy of vemurafenib. Consider monitoring of vemurafenib plasma concentrations and subsequent dose adjustment, if available.

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. Vemurafenib does not inhibit or induce CYP4F2. 

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6, and to a lesser extent by CYP1A2. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on pimozide exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. The clinical relevance of this interaction is unknown. Furthermore, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as vemurafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. However, no clinically relevant interaction is expected.

Coadministration has not been studied. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Vemurafenib is a weak inhibitor of CYP2C8 (in vitro), a moderate inhibitor of CYP1A2 and moderate inducer of CYP3A4. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on pioglitazone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with pioglitazone. Monitoring for blood glucose levels may be required. No a priori dose adjustment of pioglitazone is recommended.

Coadministration has not been studied. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. As the clinical relevance of this interaction is unknown, monitoring may be required. Furthermore, coadministration of vemurafenib and pipotiazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Vemurafenib is an inhibitor of CYP2C8 in vitro but since CYP2C8 is only a minor metabolic pathway, a clinically relevant interaction is unlikely.

Coadministration has not been studied but should be avoided. Posaconazole is a substrate of UGT and P-gp. Vemurafenib is an inhibitor of P-gp and may increase concentrations of posaconazole. Close monitoring for posaconazole toxicity and plasma concentrations is recommended, if available. Posaconazole is a strong inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for vemurafenib toxicity. Consider monitoring of vemurafenib plasma concentrations, if available. Furthermore, coadministration of vemurafenib and posaconazole may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but based on limited data available an interaction appears unlikely. Potassium is renally eliminated. Vemurafenib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Vemurafenib is a moderate inducer of CYP3A4 and a weak inducer of CYP2B6 (in vitro). Vemurafenib decreased midazolam AUC by 39-80%; a similar effect may occur with prasugrel. Concentrations of the active metabolite of prasugrel may increase due to induction of CYP3A4 and CYP2B6. The clinical relevance of this interaction is unknown. Care should be taken when vemurafenib is coadministered with prasugrel. Monitoring for prasugrel toxicity is recommended. 

Coadministration has not been studied. Pravastatin is metabolised by CYP3A4 and is a substrate of OATP1B1. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with pravastatin. Monitoring of cholesterol concentrations is recommended and adjust dose accordingly.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prazosin is extensively metabolised, primarily by demethylation and conjugation. Vemurafenib does not interact with this metabolic pathway.

Coadministration has not been studied. Prednisolone undergoes hepatic metabolism via CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with prednisolone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of prednisolone may be required.

Coadministration has not been studied. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with prednisone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of prednisone may be required.

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

Coadministration has not been studied. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%. As the clinical relevance of this interaction is unknown, monitoring for prochlorperazine toxicity may be necessary. Furthermore, coadministration of vemurafenib and prochlorperazine may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Promethazine is metabolised by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur to promethazine. As the clinical relevance of this interaction is unknown, monitoring for promethazine toxicity may be necessary. Furthermore, coadministration of vemurafenib and promethazine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and a weak inhibitor of CYP2D6. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on propafenone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with propafenone. Monitoring for propafenone toxicity and efficacy may be required. No a priori dose adjustment of propafenone is recommended.

Coadministration has not been studied. Propranolol is metabolised by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inhibitor of CYP1A2. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition); a similar effect may occur with propranolol. As the clinical relevance of this interaction is unknown, monitoring of blood pressure and heart rate is recommended.

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. Prucalopride is a substrate of P-gp, but no clinically relevant interactions were observed when prucalopride was coadministered with inhibitors of renal P-gp, OAT and OCT transporters. Therefore, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolised by xanthine oxidase. Vemurafenib 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. Quetiapine is primarily metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with quetiapine. As the clinical relevance of this interaction is unknown, monitoring of quetiapine efficacy may be required.

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. Vemurafenib does interact with this elimination pathway.

Coadministration has not been studied. Quinidine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with quinidine. As quinidine has a narrow therapeutic index, a dose increase of quinidine should be considered. Monitor quinidine plasma concentrations, if available. Furthermore, coadministration of vemurafenib and quinidine may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with rabeprazole. However, since CYP3A4 mediated metabolism is a minor pathway and rabeprazole has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Ramipril is hydrolysed to the active metabolite ramiprilat potentially via CYP3A4, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with ramipril and thus concentrations of the active metabolite may increase. The clinical relevance of this interaction is unknown and close monitoring of blood pressure may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Vemurafenib does not interact with this elimination pathway. Furthermore, although the aqueous solubility of vemurafenib is pH dependent with limited solubility at pH > 6.8, no clinically significant effect of gastric pH increasing drugs on vemurafenib exposure is expected.

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. Vemurafenib is an inhibitor of P-gp and CYP2D6 (weak), and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on ranolazine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for ranolazine toxicity and efficacy may be required. No a priori dose adjustment of ranolazine is recommended. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of vemurafenib may increase due to inhibition of CYP3A4. Coadministration of inhibitors of CYP3A4 is not recommended and selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. Furthermore, coadministration of vemurafenib and ranolazine may cause QTc interval prolongation in a concentration-dependent manner. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Reboxetine is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with reboxetine. Monitoring for reboxetine efficacy is recommended. Monitoring of reboxetine plasma concentrations should be considered, if available. Note: In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4.  

Coadministration has not been studied. Repaglinide is metabolised by CYP2C8 and CYP3A4 with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Vemurafenib is a moderate inducer of CYP3A4 and a weak inhibitor of CYP2C8 in vitro. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction); a similar effect may occur with repaglinide. Close monitoring of blood glucose levels is recommended.

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 but retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Vemurafenib 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 should be avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with rifabutin. Furthermore, rifabutin is an inducer of CYP3A4 and may decrease concentrations of vemurafenib. A decrease in vemurafenib exposure can lead to decreased efficacy. Therefore strong inducers of CYP3A4 should be avoided. 

Coadministration has not been studied but should be avoided. Rifampicin is metabolised via deacetylation. Vemurafenib is unlikely to interfere with this metabolic pathway. However, rifampicin is an inducer of CYP3A4 and may decrease concentrations of vemurafenib. A decrease in vemurafenib exposure can lead to decreased efficacy. Therefore strong inducers of CYP3A4 should be avoided.

Coadministration has not been studied but should be avoided. Rifapentine is metabolised via deacetylation. Vemurafenib is unlikely to interfere with this metabolic pathway. However, rifapentine is an inducer of CYP3A4 and CYP2C8 and may decrease concentrations of vemurafenib due to CYP3A4 induction. A decrease in vemurafenib exposure can lead to decreased efficacy. Therefore strong inducers of CYP3A4 should be avoided.

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. Vemurafenib does not interfere with this elimination pathway. 

Coadministration has not been studied. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Risperidone is also a substrate of P-gp. Vemurafenib is an inhibitor of P-gp, a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on risperidone exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with risperidone. Monitoring for risperidone toxicity and efficacy may be required. No a priori dose adjustment of risperidone is recommended.

Coadministration has not been studied but should be approached with caution. Rivaroxaban is partly metabolised in the liver by CYP3A4, CYP2J2 and hydrolytic enzymes and partly eliminated unchanged in urine by P-gp and BCRP. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp and BCRP (in vitro). Vemurafenib decreased midazolam AUC by 39-80%; a similar effect may occur with rivaroxaban. The net effect on rivaroxaban exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Therefore, close monitoring of anti-Xa activity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Vemurafenib is a weak inhibitor of CYP2C8 in vitro and may increase rosiglitazone concentrations. However, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1. Rosuvastatin is also a substrate of BCRP. Vemurafenib is a BCRP inhibitor in vitro and may increase concentrations of rosuvastatin. 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. Salbutamol is metabolised to the inactive salbutamol-4’-O-sulphate. Vemurafenib does not interact with this metabolic pathway.

Coadministration has not been studied. Salmeterol is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with salmeterol. Although the systemic absorption of salmeterol after bronchial administration is low, increased systemic exposure to salmeterol may occur. Therefore, monitoring for toxicity may be required.

Coadministration has not been studied. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on saxagliptin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with saxagliptin. Monitoring of blood glucose levels may be required. No a priori dose adjustment of saxagliptin is recommended. 

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 interactions are known. 

Coadministration has not been studied but should be approached with caution. Sertindole is metabolised by CYP2D6 and CYP3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on sertindole exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Monitoring for sertindole toxicity and efficacy may be required. No a priori dose adjustment of sertindole is recommended. Furthermore, coadministration of vemurafenib and sertindole may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Vemurafenib is a weak inhibitor of CYP2D6, a weak inducer of CYP2B6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on sertraline exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. No a priori dose adjustment of sertraline is recommended. Since CYP3A4 and CYP2D6 mediated metabolism are minor pathways, a clinical relevant interaction is not expected.

Coadministration has not been studied. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with sildenafil. Therefore, monitoring of blood pressure is recommended.

Coadministration has not been studied. Simvastatin is metabolised by CYP3A4 to its active metabolite. Simvastatin is also a substrate of BCRP and the active metabolite is a substrate of OATP1B1. Vemurafenib is an inhibitor of BCRP in vitro and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction) and it cannot be excluded that vemurafenib may increase simvastatin concentrations due to BCRP inhibition. The clinical relevance of this interaction is unknown. 

Coadministration has not been studied. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Vemurafenib is an inhibitor of P-gp and a moderate inducer of CYP3A4. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on sirolimus exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with sirolimus. Monitoring for sirolimus toxicity and efficacy may be required. No a priori dose adjustment of sirolimus is recommended.

Coadministration has not been studied. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents a minor elimination pathway. Vemurafenib is a moderate inducer of CYP3A4 and an inhibitor of P-gp. Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on sitagliptin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with sitagliptin. Monitoring of blood glucose levels may be required. 

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. Vemurafenib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but should be approached with caution. Based on metabolism and clearance a pharmacokinetic interaction is unlikely as sotalol is excreted unchanged via renal elimination. Vemurafenib does not interact with this elimination pathway. However, the product labels for sotalol advises extreme caution if given with other drugs that prolong the QT interval, such as vemurafenib.

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. Vemurafenib does not interfere with this elimination pathway. 

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

Coadministration has not been studied. Stanozolol undergoes hepatic metabolism. Vemurafenib is an inducer of CYP3A4 (moderate) and CYP2B6 (weak, in vitro). In addition, vemurafenib is an inhibitor of CYPs 1A2 (moderate), 2D6 (weak) and 2C8 (in vitro). Vemurafenib decreased midazolam AUC by 39-80% (CYP3A4 induction), increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and increased dextromethorphan AUC by 47% (CYP2D6 inhibition). The net effect on stanozolol exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with stanozolol. Monitoring for blood pressure may be required. No a priori dose adjustment of stanozolol is recommended. 

Coadministration has not been studied but should be avoided. St John’s wort may cause significant and unpredictable decreases in the plasma concentrations of vemurafenib due to induction of CYP3A4 and P-gp. A decrease in exposure can lead to decreased efficacy. 

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 coadministered 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. Vemurafenib does not interfere with this elimination pathway.

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. Vemurafenib does not inhibit or induce CYP2C9.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Vemurafenib does not interact with this elimination pathway. However, coadministration of vemurafenib and sulpiride may cause QTc interval prolongation in a concentration-dependent manner and caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied but should be approached with caution. Tacrolimus is an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Tacrolimus could potentially increase vemurafenib concentrations although to a modest extent. Tacrolimus is metabolised mainly by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with tacrolimus. Monitoring of tacrolimus efficacy and vemurafenib toxicity is recommended. Monitor tacrolimus and vemurafenib plasma concentrations, if available. Furthermore, coadministration of vemurafenib and tacrolimus may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Tadalafil is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with tadalafil. Therefore, monitoring of blood pressure is recommended.

Coadministration has not been studied. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on tamsulosin exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. However, since tamsulosin has a wide therapeutic index, a clinically relevant interaction is unlikely.

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. Vemurafenib does not interact with this elimination pathway.

Coadministration has not been studied. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Vemurafenib is an inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with telithromycin. Telithromycin is an inhibitor of CYP3A4 and may increase concentrations of vemurafenib. Concurrent use of CYP3A4 inhibitors should be avoided. If coadministration is unavoidable, close monitoring of telithromycin efficacy and vemurafenib toxicity is recommended, including ECG. Monitoring of vemurafenib plasma concentrations should be considered, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telmisartan is mainly glucuronidated by UGT1A3. Vemurafenib does not inhibit or induce UGT1A3. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated. Vemurafenib does not inhibit or induce UGTs.

Coadministration has not been studied. Terbinafine is metabolised by CYPs 1A2, 2C9 and 3A4, and to a lesser extent by CYP2C8 and CYP2C19. Vemurafenib is a moderate inducer of CYP3A4, a moderate inhibitor of CYP1A2 and an inhibitor of CYP2C8 in vitro. Vemurafenib increased caffeine AUC by 2.6-fold (CYP1A2 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on terbinafine exposure is unknown since multiple metabolic pathways are affected by vemurafenib in different directions. Care should be taken when vemurafenib is coadministered with terbinafine. Monitoring for terbinafine toxicity and efficacy may be required. No a priori dose adjustment of terbinafine is recommended.

Coadministration has not been studied. Testosterone is metabolised by CYP3A4. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with testosterone. As the clinical relevance of this interaction is unknown, monitoring and dose increase of testosterone may be required.

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. Vemurafenib does not interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Theophylline is mainly metabolised by CYP1A2. Vemurafenib is a moderate inhibitor of CYP1A2 and increased caffeine AUC by 2.6-fold; a similar effect may occur with theophylline. Monitor closely for theophylline toxicity. Monitor theophylline plasma concentrations, if available.

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

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Vemurafenib is a weak inhibitor of CYP2D6 and a moderate inducer of CYP3A4. Vemurafenib increased dextromethorphan AUC by 47% (CYP2D6 inhibition) and decreased midazolam AUC by 39-80% (CYP3A4 induction). The net effect on thioridazine exposure is unknown, but it is likely that thioridazine concentrations may increase. Monitoring for thioridazine toxicity may be required. The product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as vemurafenib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tiapride is excreted largely unchanged in urine. Vemurafenib does not interact with this elimination pathway. However, coadministration of vemurafenib and tiapride may cause QTc interval prolongation in a concentration-dependent manner. Caution is needed when vemurafenib is coadministered with a drug with a known risk of Torsade de Pointes. If coadministration is necessary, close monitoring including ECG assessment is recommended. If QTc increase meets values of both >500 ms and >60 ms from baseline, discontinue permanently. If QTc increase meets values of >500 ms and change from baseline value remains <60 ms, interrupt treatment temporarily until QTc decreases below 500 ms and resume dosing at a decreased dose level. Discontinue permanently if the dose has already been lowered to 480 mg twice daily.

Coadministration has not been studied. Ticagrelor is a weak inhibitor of CYP3A4 and may slightly increase concentrations of vemurafenib. However, this is unlikely to be clinically relevant. Ticagrelor undergoes extensive CYP3A4 metabolism. Vemurafenib is a moderate inducer of CYP3A4 and decreased midazolam AUC by 39-80%; a similar effect may occur with ticagrelor. Care should be taken when vemurafenib is coadministered with ticagrelor.

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. Vemurafenib is a weak inhibitor of CYP2D6 and increased dextromethorphan AUC by 47%; a similar effect may occur with timolol. However, the systemic absorption of timolol after ocular administration is low. Therefore, a clinically relevant interaction via CYP2D6 is unlikely. 

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. Vemurafenib 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 metabolised by CYP2C9 and to a lesser extent by CYP2C8 and CYP2C19. Vemurafenib is a weak inhibitor of CYP2C8 in vitro and may increase tolbutamide concentrations. Since CYP2C8 is only a minor pathway, a clinically relevant interaction is unlikely.