Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Encorafenib

Acarbose

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this pathway.

Description:

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No Interaction Expected

Encorafenib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Encorafenib

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

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). Encorafenib does not inhibit or induce UGT1A6.

Description:

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No Interaction Expected

Encorafenib

Agomelatine

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Encorafenib

Alendronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant 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 with encorafenib, 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.

Description:

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Potential Weak Interaction

Encorafenib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfentanil undergoes extensive CYP3A4 metabolism. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of alfentanil. The clinical relevance of this interaction is unknown. Monitoring for both alfentanil toxicity and efficacy should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfuzosin is metabolised by CYP3A. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of alfuzosin. The clinical relevance of this interaction is unknown. Monitoring for both alfuzosin toxicity and efficacy should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Aliskiren

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Encorafenib is unlikely to interfere with this elimination pathway. Aliskiren is also a substrate of P-gp. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase concentrations of aliskiren. The clinical relevance of this interaction is unknown. Monitoring for aliskiren toxicity and blood pressure should be considered.

Description:

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No Interaction Expected

Encorafenib

Allopurinol

Quality of Evidence: Very Low

Summary:

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. Allopurinol is also an inhibitor of xanthine oxidase. Encorafenib does not interact with this metabolic pathway.

Description:

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Potential Weak Interaction

Encorafenib

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of alosetron. The clinical relevance of this interaction is unknown. Monitoring for both alosetron toxicity and efficacy should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alprazolam is mainly metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of alprazolam. The clinical relevance of this interaction is unknown. Monitoring for both alprazolam toxicity and efficacy should be considered.

Description:

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No Interaction Expected

Encorafenib

Aluminium hydroxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Coadministration of encorafenib and the proton pump inhibitor, rabeprazole, did not alter encorafenib exposure. Therefore, no clinically relevant effect on encorafenib exposure due to pH elevation from gastric acid reducing agents such as aluminium hydroxide is expected.

Description:

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Potential Weak Interaction

Encorafenib

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ambrisentan is metabolized 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. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of ambrisentan. The clinical relevance of this interaction is unknown. Monitoring for both ambrisentan toxicity and efficacy, and blood pressure should be considered.

Description:

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No Interaction Expected

Encorafenib

Amikacin

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Weak Interaction

Encorafenib

Amiloride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Encorafenib is an in vitro inhibitor of OCT2 at clinically relevant concentrations and may increase concentrations of amiloride. The clinical relevance of this interaction is unknown. Monitoring for amiloride toxicity and blood pressure should be considered.

Description:

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Do Not Coadminister

Encorafenib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amiodarone is metabolised by CYP3A4 and CYP2C8. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of amiodarone. The clinical relevance of this interaction is unknown. Monitoring for amiodarone toxicity and efficacy should be considered. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong), 2B6 (moderate) and P-gp (strong). Encorafenib is a substrate of P-gp and to a lesser extent, encorafenib is metabolised by CYP2D6 and CYP2C19. Encorafenib concentrations may increase due to inhibition by the active metabolite of amiodarone. However, since CYP2D6 and CYP2C19 are minor metabolic pathways, no clinically relevant effect on encorafenib exposure is expected. Encorafenib concentrations may also increase due to CYP3A4 inhibition. If coadministration is unavoidable, monitoring for encorafenib toxicity and, if available, plasma concentrations should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with amiodarone, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

Description:

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Potential Weak Interaction

Encorafenib

Amisulpride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amisulpride is weakly metabolised and is primarily eliminated renally (possibly via OCT). Encorafenib is an in vitro inhibitor of OCT2 at clinically relevant concentrations and may increase amisulpride concentrations. The clinical relevance of this interaction is unknown. Monitoring for amisulpride toxicity should be considered.

Description:

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Do Not Coadminister

Encorafenib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of amitriptyline. The clinical relevance of this interaction is unknown. Monitoring for both amitriptyline toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with amitriptyline, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

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Potential Weak Interaction

Encorafenib

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amlodipine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of amlodipine. The clinical relevance of this interaction is unknown. Monitoring for both amlodipine toxicity and efficacy, and blood pressure should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Amoxicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Encorafenib is an in vitro inhibitor of OAT3 and may increase amoxicillin concentrations. The clinical relevance of this interaction is unknown. Monitoring for amoxicillin toxicity may be required.

Description:

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Potential Weak Interaction

Encorafenib

Amphotericin B

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Encorafenib does not interfere with this metabolic or elimination pathway. However, the European SPC for amphotericin states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension and so monitoring may be required.

Description:

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No Interaction Expected

Encorafenib

Ampicillin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway. 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.

Description:

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No Interaction Expected

Encorafenib

Anidulafungin

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Encorafenib

Antacids

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Coadministration of encorafenib and the proton pump inhibitor, rabeprazole, did not alter encorafenib exposure. Therefore, no clinically relevant effect on encorafenib exposure due to pH elevation from gastric acid reducing agents such as antacids is expected.

Description:

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Potential Weak Interaction

Encorafenib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Apixaban is a substrate of P-gp and BCRP and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp and BCRP at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of apixaban. The clinical relevance of this interaction is unknown. Monitoring for both apixaban toxicity and efficacy should be considered.

Description:

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Potential Interaction

Encorafenib

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of aprepitant. The clinical relevance of this interaction is unknown. Monitoring for both aprepitant toxicity and efficacy should be considered. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase encorafenib concentrations. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with aprepitant. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50% during the few days of coadministration. Monitor closely for encorafenib toxicity including ECG assessment. Moreover, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Encorafenib concentrations may decrease due to CYP3A4 induction. However, this is considered not to be clinically relevant.

Description:

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Potential Weak Interaction

Encorafenib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of aripiprazole. The clinical relevance of this interaction is unknown. Monitoring for both aripiprazole toxicity and efficacy should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Asenapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of asenapine. The clinical relevance of this interaction is unknown. Monitoring for both asenapine toxicity and efficacy should be considered.

Description:

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Do Not Coadminister

Encorafenib

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of astemizole. The clinical relevance of this interaction is unknown. Monitoring for both astemizole toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with astemizole, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

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No Interaction Expected

Encorafenib

Atenolol

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

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Potential Weak Interaction

Encorafenib

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp and OATP1B1 at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of atorvastatin. The clinical relevance of this interaction is unknown. Monitoring for both atorvastatin toxicity and efficacy should be considered.

Description:

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No Interaction Expected

Encorafenib

Azathioprine

Quality of Evidence: Very Low

Summary:

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 by xanthine oxidase. Encorafenib does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Encorafenib

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase azithromycin concentrations. The clinical relevance of this interaction is unknown. Monitoring for azithromycin toxicity may be required if coadministration is unavoidable. Azithromycin is also an inhibitor of P-gp and may increase encorafenib concentrations. The clinical relevance of P-gp inhibition by azithromycin is unknown, but no clinically relevant effect on encorafenib exposure is expected. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with azithromycin, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

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No Interaction Expected

Encorafenib

Beclometasone

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Encorafenib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Bedaquiline is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of bedaquiline. The clinical relevance of this interaction is unknown. Monitoring for both bedaquiline toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with bedaquiline, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

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Potential Weak Interaction

Encorafenib

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase concentrations of bendroflumethiazide. The clinical relevance of this interaction is unknown. Monitoring for bendroflumethiazide toxicity and blood pressure should be considered. In vitro data indicate that bendroflumethiazide inhibits OAT1/3 but a clinically significant interaction is unlikely in the range of observed clinical concentrations. Encorafenib is not transported by OAT1/3.

Description:

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Do Not Coadminister

Encorafenib

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of bepridil. The clinical relevance of this interaction is unknown. Monitoring for both bepridil toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with bepridil, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

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Potential Weak Interaction

Encorafenib

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Betamethasone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of betamethasone. The clinical relevance of this interaction is unknown. Monitoring for both betamethasone toxicity and efficacy should be considered.

Description:

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No Interaction Expected

Encorafenib

Bezafibrate

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Encorafenib

Bisacodyl

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this metabolic or elimination pathway.

Description:

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Potential Weak Interaction

Encorafenib

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of bisoprolol. The clinical relevance of this interaction is unknown. Monitoring for bisoprolol toxicity and efficacy, and blood pressure should be considered.

Description:

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Potential Interaction

Encorafenib

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of bosentan. The clinical relevance of this interaction is unknown. Monitoring for both bosentan toxicity and efficacy, and blood pressure should be considered. Concentrations of encorafenib may also decrease due to CYP3A4 induction by bosentan. Coadministration is not recommended. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

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No Interaction Expected

Encorafenib

Bromazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of bromazepam. However, since CYP3A4 is a minor pathway no clinically significant effect is expected on encorafenib exposure.

Description:

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Potential Weak Interaction

Encorafenib

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Budesonide is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of budesonide. The clinical relevance of this interaction is unknown. Monitoring for both budesonide toxicity and efficacy should be considered.

Description:

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Potential Weak Interaction

Encorafenib

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of buprenorphine. The clinical relevance of this interaction is unknown. Monitoring for both buprenorphine toxicity and efficacy should be considered.

Description:

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No Interaction Expected

Encorafenib

Bupropion

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Weak Interaction

Encorafenib

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buspirone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of buspirone. The clinical relevance of this interaction is unknown. Monitoring for both buspirone toxicity and efficacy should be considered.

Description:

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No Interaction Expected

Encorafenib

Calcium

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Encorafenib

Candesartan

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Encorafenib

Capreomycin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

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Potential Weak Interaction

Encorafenib

Captopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Captopril is largely excreted in the urine by OAT1. Encorafenib is an in vitro inhibitor of OAT1 at clinically relevant concentrations and may increase concentrations of captopril. The clinical relevance of this interaction is unknown. Monitoring for captopril toxicity and blood pressure should be considered.

Description:

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Do Not Coadminister

Encorafenib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of carbamazepine. However, no clinically relevant effect on carbamazepine exposure is expected since carbamazepine itself is a strong inducer of CYP3A4. Carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6, UGT1A1 and P-gp (moderate). Encorafenib concentrations may decrease due to CYP3A4, CYP2C9 and P-gp induction. The clinical relevance of this interaction is unknown. Therefore, coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

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Potential Weak Interaction

Encorafenib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2. Encorafenib is an inhibitor of UGT1A1 and may increase carvedilol concentrations. The clinical relevance of this interaction is unknown. Monitoring for carvedilol toxicity and blood pressure may be required. Carvedilol is also an inhibitor of P-gp and may increase encorafenib concentrations. However, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

No Interaction Expected

Encorafenib

Caspofungin

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Cefalexin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cefalexin is predominantly eliminated unchanged renally by glomerular filtration and tubular secretion via OAT1 and MATE1. Encorafenib is an in vitro inhibitor of OAT1 at clinically relevant concentrations and may increase cefalexin concentrations. The clinical relevance of this interaction is unknown. Monitoring for cefalexin toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Cefazolin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Encorafenib is an in vitro inhibitor of OAT3 at clinically relevant concentrations and may increase cefazolin concentrations. The clinical relevance of this interaction is unknown. Monitoring for cefazolin toxicity may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Cefixime

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Cefotaxime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Encorafenib is an in vitro inhibitor of OAT3 at clinically relevant concentrations and may increase cefotaxime concentrations. The clinical relevance of this interaction is unknown. Monitoring for cefotaxime toxicity may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Ceftazidime

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Ceftriaxone

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Celecoxib

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Cetirizine

Quality of Evidence: Very Low

Summary:

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 is also an inhibitor of OCT2. Encorafenib is unlikely to interfere with this elimination pathway and is not transported by OCTs.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chloramphenicol is predominantly glucuronidated. Encorafenib is an inhibitor of UGT1A1 and may increase chloramphenicol concentrations. Monitoring for chloramphenicol toxicity may be required. In vitro studies have shown that chloramphenicol can also inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). No clinically relevant effect on encorafenib exposure is expected due to CYP2D6 and CYP2C19 inhibition since these are minor pathways in encorafenib metabolism. However, encorafenib exposure may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations may also be required. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chlordiazepoxide is extensively metabolised by CYP3A4 but does not inhibit or induce cytochromes. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of chlordiazepoxide. The clinical relevance of this interaction is unknown. Monitoring for both chlordiazepoxide toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Chlorphenamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorphenamine is predominantly metabolised in the liver via CYP2D6. Encorafenib does not inhibit or induce CYP2D6.

Description:

See Summary

Do Not Coadminister

Encorafenib

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Encorafenib does not inhibit or induce CYP2D6 or CYP1A2. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with chlorpromazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Chlortalidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase concentrations of chlortalidone. The clinical relevance of this interaction is unknown. Monitoring for chlortalidone toxicity and blood pressure should be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciclosporin is a substrate for CYP3A4 and P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of ciclosporin. The clinical relevance of this interaction is unknown. Monitoring for both ciclosporin toxicity and efficacy is recommended. Monitor ciclosporin concentrations, if available. Ciclosporin also inhibits CYP3A4 and OATP1B1. Concentrations of encorafenib may increase due to moderate inhibition of CYP3A4 by ciclosporin. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with ciclosporin. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating ciclosporin ~2 days after discontinuation of ciclosporin.

Description:

See Summary

No Interaction Expected

Encorafenib

Cilazapril

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Coadministration of encorafenib and the proton pump inhibitor, rabeprazole, did not alter encorafenib exposure. Therefore, no clinically relevant effect on encorafenib exposure due to pH elevation from gastric acid reducing agents such as cimetidine is expected. However, cimetidine is metabolised by CYP450 enzymes. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of cimetidine. The clinical relevance of this interaction is unknown. Monitoring for both cimetidine toxicity and efficacy should be considered. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Cimetidine may increase encorafenib concentrations due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations should also be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciprofloxacin 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. Encorafenib is an in vitro inhibitor of OAT3 at clinically relevant concentrations and may increase ciprofloxacin concentrations. The clinical relevance of this interaction is unknown. Monitoring for ciprofloxacin toxicity may be required. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of encorafenib may increase due to moderate inhibition of CYP3A4. Coadministration should be approached with caution. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with ciprofloxacin. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity including ECG assessment for QT prolongation. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating ciprofloxacin, ~24-36 hours after discontinuation of ciprofloxacin.

Description:

See Summary

Do Not Coadminister

Encorafenib

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cisapride is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of cisapride. The clinical relevance of this interaction is unknown. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with cisapride, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of citalopram. The clinical relevance of this interaction is unknown. Monitoring for both citalopram toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with citalopram, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clarithromycin is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of clarithromycin. The clinical relevance of this interaction is unknown. Monitoring for both clarithromycin toxicity and efficacy should be considered. Clarithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of encorafenib may increase due to strong CYP3A4 inhibition. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure increased by 2.8-fold. A similar effect may occur after coadministration with clarithromycin. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with clarithromycin, a QT prolonging drug, should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of clarithromycin (for example, 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating clarithromycin, 12-20 hours after discontinuation of clarithromycin.

Description:

See Summary

No Interaction Expected

Encorafenib

Clavulanic acid

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Clemastine

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2D6.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clindamycin is metabolised by CYP3A4 and in vitro data suggest that it is a CYP3A4 inhibitor. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of clindamycin. Furthermore, encorafenib exposure may increase due to CYP3A4 inhibition by clindamycin. The clinical relevance of this interactions is unknown. Monitoring for both clindamycin toxicity and efficacy should be considered. Monitoring for encorafenib toxicity and, if available, plasma concentrations may also be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Clobetasol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clofazimine is largely excreted unchanged in the faeces. Encorafenib is unlikely to interfere with this elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor and may increase encorafenib exposure. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations may be required if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with clofazimine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Clofibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clofibrate is hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Encorafenib is an in vitro inhibitor of OAT1 at clinically relevant concentrations and may increase clofibrate concentrations. The clinical relevance of this interaction is unknown. Monitoring for clofibrate toxicity should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are metabolised by CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of clomipramine. The clinical relevance of this interaction is unknown. Monitoring for both clomipramine toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with clomipramine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Clonidine

Quality of Evidence: Very Low

Summary:

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 also a weak inhibitor of OCT2. Encorafenib is unlikely to interfere with this elimination pathway and is not transported by OCT2.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of clopidogrel. The clinical relevance of this interaction is unknown. Monitoring for both clopidogrel toxicity and efficacy should be considered. Clopidogrel is also an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Encorafenib is not metabolised by these CYPs.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of clorazepate and oxazepam toxicity. The clinical relevance of this interaction is unknown. Monitoring for both clorazepate and oxazepam toxicity and clorazepate efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Cloxacillin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Clozapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of clozapine. The clinical relevance of this interaction is unknown. Monitoring for both clozapine toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with clozapine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Codeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolized by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. The metabolite morphine is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4, an inhibitor of UGT1A1 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of codeine and increased toxicity of morphine. The clinical relevance of this interaction is unknown. Monitoring for both codeine and morphine toxicity and codeine efficacy may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Colchicine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of colchicine. The clinical relevance of this interaction is unknown. Monitoring for both colchicine toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Cycloserine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dabigatran is transported via P-gp and is renally excreted. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase dabigatran concentrations. The clinical relevance of this interaction is unknown. Monitoring for dabigatran toxicity and ecarine clotting time (ECT) or diluted thrombin time (dTT) should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Dalteparin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation and is via multiple CYP450 enzymes. Encorafenib is both an inhibitor and inducer of CYP3A4. However, since multiple pathways are involved in dapsone metabolism, no clinically relevant effect on dapsone exposure is expected.

Description:

See Summary

Do Not Coadminister

Encorafenib

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Desipramine is metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with desipramine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19). The metabolism of etonogestrel is mediated by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of desogestrel. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking desogestrel in combination with encorafenib should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dexamethasone is a substrate of CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of dexamethasone. Dexamethasone has also been described as a weak inducer of CYP3A4 and could possibly decrease encorafenib plasma concentrations. However, the clinical relevance of this interaction is not known and CYP3A4 induction by dexamethasone has not yet been established. Monitoring for both dexamethasone toxicity and efficacy should be considered. Monitoring for encorafenib efficacy and, if available, plasma concentrations may also be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dextropropoxyphene is mainly metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of dextropropoxyphene. The clinical relevance of this interaction is unknown. Monitoring for both dextropropoxyphene toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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). Morphine is also a substrate of P-gp. Encorafenib is an inhibitor of UGT1A1 and P-gp (in vitro) and may increase concentrations of diamorphine and morphine. The clinical relevance of this interaction is unknown. Monitoring for diamorphine and morphine toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of diazepam and temazepam toxicity. The clinical relevance of this interaction is unknown. Monitoring for both diazepam and temazepam toxicity and diazepam efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Diclofenac

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9 or UGT2B7.

Description:

See Summary

Potential Interaction

Encorafenib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Digoxin is eliminated renally via OATP4C1 and P-gp. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase concentrations of digoxin. The clinical relevance of this interaction is unknown. Close monitoring for digoxin toxicity and, if available, plasma concentrations is recommended.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Encorafenib is both an inhibitor and inducer of CYP3A4, but no clinically relevant effect is expected on dihydrocodeine exposure since CYP3A4 is a minor metabolic pathway. However, encorafenib is also an inhibitor of UGT1A1 and may increase dihydrocodeine concentrations. The clinical relevance of this interaction is unknown. Monitoring for dihydrocodeine toxicity may be required.

Description:

See Summary

Potential Interaction

Encorafenib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Diltiazem is metabolised by CYP3A4 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of diltiazem. The clinical relevance of this interaction is unknown. Monitoring for both diltiazem toxicity and efficacy, and blood pressure should be considered. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp and may increase concentrations of encorafenib. The clinical relevance of P-gp inhibition by diltiazem is unknown. In healthy patients (n=16), coadministration of encorafenib (50 mg single dose, day 1) and diltiazem (240 mg twice daily for 4 days) increased encorafenib exposure by 1.8-fold due to CYP3A4 inhibition. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating diltiazem 24-40 hours after discontinuation of diltiazem.

Description:

See Summary

Do Not Coadminister

Encorafenib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Encorafenib does not inhibit or induce these CYPs. Diphenhydramine is also a weak inhibitor of CYP2D6. To a lesser extent, encorafenib is metabolised by CYP2D6 and concentrations may increase due to CYP2D6 inhibition by diphenhydramine. Since CYP2D6 is a minor pathway, no clinically relevant effect on encorafenib exposure is expected. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with diphenhydramine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Encorafenib is an in vitro inhibitor of UGT1A1 and may increase concentrations of dipyridamole. The clinical relevance of this interaction is unknown. Monitoring for dipyridamole toxicity may be required.

Description:

See Summary

Do Not Coadminister

Encorafenib

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Encorafenib is unlikely to interfere with this elimination pathway. However, encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of disopyramide. The clinical relevance of this interaction is unknown. Monitoring for both disopyramide toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with disopyramide, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. 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%). Encorafenib is an inhibitor of UGT1A1 and may increase dolasetron concentrations. The clinical relevance of this interaction is unknown. Monitoring for dolasetron toxicity may be required. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with dolasetron, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Domperidone is mainly metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of domperidone. The clinical relevance of this interaction is unknown. Monitoring for both domperidone toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with domperidone, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Dopamine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Doxazosin is metabolised mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of doxazosin. The clinical relevance of this interaction is unknown. Monitoring for both doxazosin toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Doxepin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Doxycycline

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway. Between 40-60% of an administered dose can be accounted for in the urine.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dronabinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of dronabinol. The clinical relevance of this interaction is unknown. Monitoring for both dronabinol toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Drospirenone is metabolised to a minor extent via CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of drospirenone. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking drospirenone in combination with encorafenib should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Dulaglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases. Encorafenib does not interact with this metabolic pathway. 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.

Description:

See Summary

No Interaction Expected

Encorafenib

Duloxetine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dutasteride is mainly metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of dutasteride. The clinical relevance of this interaction is unknown. Monitoring for both dutasteride toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of dydrogesterone. The clinical relevance of this interaction is unknown. Monitoring for both dydrogesterone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Edoxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of edoxaban. The clinical relevance of this interaction is unknown. Monitoring for both edoxaban toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Encorafenib is an inhibitor of UGT1A1 and may increase concentrations of eltrombopag. The clinical relevance of this interaction is unknown. Monitoring for eltrombopag toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Enalapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Enalapril is hydrolysed to enalaprilat which is eliminated renally (possibly via OATs). Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase concentrations of enalapril. The clinical relevance of this interaction is unknown. Monitoring for enalapril toxicity and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Enoxaparin

Quality of Evidence: Very Low

Summary:

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 predominantly renally excreted. Encorafenib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Eprosartan

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Ertapenem

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Erythromycin is a substrate of CYP3A4 and P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of P-gp in vitro at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of erythromycin. The clinical relevance of this interaction is unknown. Monitoring for both erythromycin toxicity and efficacy should be considered if coadministration is unavoidable. Moreover, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Concentrations of encorafenib may increase due to moderate inhibition of CYP3A4. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with erythromycin. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating erythromycin, approximately 4.5-7.5 hours after discontinuation of erythromycin. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with erythromycin, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of escitalopram. The clinical relevance of this interaction is unknown. Monitoring for both escitalopram toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with escitalopram, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Coadministration of encorafenib and the proton pump inhibitor, rabeprazole, did not alter encorafenib exposure. Therefore, no clinically relevant effect on encorafenib exposure due to pH elevation from gastric acid reducing agents such as esomeprazole is expected. However, esomeprazole is metabolised by CYP2C19 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of esomeprazole. The clinical relevance of this interaction is unknown. Monitoring for both esomeprazole toxicity and efficacy should be considered. Esomeprazole is also an inhibitor of CYP2C19. To a lesser extent, encorafenib is metabolised by CYP2C19 and concentrations may increase due to CYP2C19 inhibition by esomeprazole. However, since CYP2C19 is a minor pathway, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of estazolam. The clinical relevance of this interaction is unknown. Monitoring for both estazolam toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of estradiol. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking estradiol in combination with encorafenib should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Ethambutol

Quality of Evidence: Very Low

Summary:

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%). Encorafenib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of ethinylestradiol. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking ethinylestradiol in combination with encorafenib should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Ethionamide

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Etonogestrel is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of etonogestrel. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking etonogestrel in combination with encorafenib should be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of everolimus. The clinical relevance of this interaction is unknown. Monitoring for both everolimus toxicity and efficacy is recommended. Monitor everolimus plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Encorafenib

Exenatide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ezetimibe

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Encorafenib is an inhibitor of UGT1A1 and may increase ezetimibe concentrations. The clinical relevance of this interaction is unknown. Monitoring for ezetimibe toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Famotidine

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Potential Weak Interaction

Encorafenib

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Felodipine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of felodipine. The clinical relevance of this interaction is unknown. Monitoring for both felodipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Fenofibrate

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fentanyl undergoes extensive CYP3A4 metabolism. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of fentanyl. The clinical relevance of this interaction is unknown. Monitoring for both fentanyl toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fexofenadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fexofenadine is a substrate of P-gp. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase concentrations of fexofenadine. The clinical relevance of this interaction is unknown. Monitoring for fexofenadine toxicity should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Finasteride is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of finasteride. The clinical relevance of this interaction is unknown. Monitoring for both finasteride toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Fish oils

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Encorafenib is unlikely to interfere with this elimination pathway and does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with flecainide, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Flucloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Encorafenib is an in vitro inhibitor of OAT1 at clinically relevant concentrations and may increase concentrations of flucloxacillin. Furthermore, flucloxacillin is described as a CYP3A4 inducer and may decrease encorafenib exposure. However, the mechanism and clinical relevance CYP3A4 induction by flucloxacillin is unknown. The clinical relevance of this interaction is unknown. Monitoring for encorafenib efficacy and, if available, plasma concentrations may be required. Monitoring for flucloxacillin toxicity should also be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fluconazole is cleared primarily by renal excretion and is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Encorafenib is unlikely to interfere with this elimination pathway. However, concentrations of encorafenib may increase due to moderate inhibition of CYP3A4 by fluconazole. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with fluconazole. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating fluconazole 4-6 days after discontinuation of fluconazole. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with fluconazole, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Flucytosine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase (DPD) to an inactive metabolite. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of fludrocortisone. The clinical relevance of this interaction is unknown. Monitoring for both fludrocortisone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of flunitrazepam. The clinical relevance of this interaction is unknown. Monitoring for both flunitrazepam toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fluoxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluoxetine is mainly metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of fluoxetine. The clinical relevance of this interaction is unknown. Monitoring for both fluoxetine toxicity and efficacy should be considered. Furthermore, fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. To a lesser extent, encorafenib is metabolised by CYP2C19 and concentrations may increase due to CYP2C19 inhibition by fluoxetine. However, since CYP2C19 is a minor metabolic pathway, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

Do Not Coadminister

Encorafenib

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fluphenazine is metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with fluphenazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Flurazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. The metabolism of flurazepam is most likely CYP-mediated. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of flurazepam. The clinical relevance of this interaction is unknown. Monitoring for both flurazepam toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluticasone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of fluticasone. The clinical relevance of this interaction is unknown. Monitoring for both fluticasone toxicity and efficacy should be considered. Note: A clinically significant interaction is unlikely with the topical use of fluticasone.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Moreover, fluvastatin potentially inhibits CYP2C9, but the clinical relevance of CYP2C9 inhibition is unknown. Encorafenib is not metabolized by CYP2C9. However, encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of fluvastatin. The clinical relevance of this interaction is unknown. Monitoring for both fluvastatin toxicity and efficacy should be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Encorafenib does not inhibit or induce CYP2D6 or CYP1A2. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of encorafenib may increase due to inhibition of CYPs 3A4, 2C19 and 2D6. Coadministration of encorafenib with fluvoxamine should be approached with caution. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with fluvoxamine. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating fluvoxamine, 3-5 days after discontinuation of fluvoxamine.

Description:

See Summary

No Interaction Expected

Encorafenib

Fondaparinux

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Formoterol

Quality of Evidence: Very Low

Summary:

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. Encorafenib is an inhibitor of UGT1A1 and may increase formoterol concentrations. However, as multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low.

Description:

See Summary

Potential Interaction

Encorafenib

Fosaprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Encorafenib does not interact with this metabolic pathway. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of aprepitant. The clinical relevance of this interaction is unknown. Monitoring for both aprepitant toxicity and efficacy should be considered. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase encorafenib concentrations. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with fosaprepitant. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50% on the day of coadministration and the day after administration of fosaprepitant. Monitor closely for encorafenib toxicity including ECG assessment. Moreover, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Encorafenib concentrations may decrease due to CYP3A4 induction. However, this is considered to be not clinically relevant.

Description:

See Summary

Do Not Coadminister

Encorafenib

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Encorafenib does not interact with this metabolic pathway. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Encorafenib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Encorafenib concentrations may decrease due to CYP3A4 and P-gp induction. The clinical relevance of this interaction is unknown. Therefore, coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Furosemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an inhibitor of UGT1A1 and an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase furosemide concentrations. The clinical relevance of this interaction is unknown. Monitoring for furosemide toxicity and blood pressure should be considered. Additionally, in vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3. Encorafenib is not transported by OATs.

Description:

See Summary

No Interaction Expected

Encorafenib

Gabapentin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Gemfibrozil

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Gentamicin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of gestodene. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking gestodene in combination with encorafenib should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of glibenclamide. The clinical relevance of this interaction is unknown. Monitoring for both glibenclamide toxicity and blood glucose levels should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Gliclazide

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9 or CYP2C19.

Description:

See Summary

No Interaction Expected

Encorafenib

Glimepiride

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Glipizide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of granisetron. The clinical relevance of this interaction is unknown. Monitoring for both granisetron toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with granisetron, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Grapefruit juice is known to inhibit CYP3A4 enzymes and may increase encorafenib concentrations. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure increased by 2.8-fold. A similar effect may occur after coadministration with grapefruit juice. Therefore, coadministration of encorafenib with grapefruit juice is contraindicated.

Description:

See Summary

No Interaction Expected

Encorafenib

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolised by CYP3A4, such as encorafenib. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Encorafenib

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of haloperidol. The clinical relevance of this interaction is unknown. Monitoring for both haloperidol toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with haloperidol, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Heparin

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Hydralazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase hydrochlorothiazide concentrations. The clinical relevance of this interaction is unknown. Monitoring for hydrochlorothiazide toxicity and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of hydrocodone. The clinical relevance of this interaction is unknown. Monitoring for both hydrocodone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocortisone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of hydrocortisone. The clinical relevance of this interaction is unknown. Monitoring for both hydrocortisone toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Hydrocortisone (topical)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Hydromorphone

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce UGT2B7.

Description:

See Summary

No Interaction Expected

Encorafenib

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of hydroxyzine. The clinical relevance of this interaction is unknown. Monitoring for both hydroxyzine toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with hydroxyzine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Ibandronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant 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 with encorafenib, 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.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ibuprofen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Encorafenib does not inhibit or induce CYP2C9 or CYP2C8. However, encorafenib is an inhibitor of UGT1A1 and may increase concentrations of ibuprofen. The clinical relevance of this interaction is unknown. Monitoring for ibuprofen toxicity may be required.

Description:

See Summary

Do Not Coadminister

Encorafenib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Iloperidone is metabolised by CYP3A4 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of iloperidone. The clinical relevance of this interaction is unknown. Monitoring for both iloperidone toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with iloperidone, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Imipenem/Cilastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are metabolised by CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of imipramine. The clinical relevance of this interaction is unknown. Monitoring for both imipramine toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with imipramine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Indapamide is extensively metabolised by CYP450s. Encorafenib is both an inhibitor and inducer of CYP3A4 and may alter indapamide concentrations. However, since multiple CYP enzymes are involved in the metabolism of indapamide, no clinically relevant effect on indapamide exposure is expected. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase indapamide concentrations. The clinical relevance of this interaction is unknown. Monitoring for indapamide toxicity and blood pressure should be considered. Moreover, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with indapamide, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Insulin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Interferon alpha

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Ipratropium bromide

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Irbesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Encorafenib is an inhibitor of UGTA1A1 and may increase Irbesartan concentrations. The clinical relevance of this interaction is unknown. Monitoring for irbesartan toxicity and blood pressure may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Iron supplements

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Isoniazid

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nitric oxide. The clinical relevance of this interaction is unknown. Monitoring for both nitric oxide toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Itraconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Itraconazole is primarily metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of itraconazole. The clinical relevance of this interaction is unknown. Monitoring for both itraconazole toxicity and efficacy should be considered. Furthermore, concentrations of encorafenib may increase due to strong inhibition of CYP3A4 by itraconazole. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure increased by 2.8-fold. A similar effect may occur after coadministration with itraconazole. Therefore, coadministration of encorafenib with itraconazole should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of itraconazole (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating itraconazole 5-9 days after discontinuation of itraconazole.

Description:

See Summary

Do Not Coadminister

Encorafenib

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ivabradine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of ivabradine. The clinical relevance of this interaction is unknown. Monitoring for both ivabradine toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with ivabradine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Kanamycin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ketoconazole is a substrate of CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of ketoconazole. The clinical relevance of this interaction is unknown. Monitoring for both ketoconazole toxicity and efficacy should be considered if coadministration is unavoidable. Ketoconazole is also an inhibitor of CYP3A4 (strong) and P-gp and may increase concentrations of encorafenib. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure increased by 2.8-fold. A similar effect may occur after coadministration with ketoconazole. Therefore, coadministration of encorafenib with ketoconazole should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of ketoconazole (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating ketoconazole 1-2 days after discontinuation of ketoconazole. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with ketoconazole, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Labetalol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lacidipine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of lacidipine. The clinical relevance of this interaction is unknown. Monitoring for both lacidipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Lactulose

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lansoprazole

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lercanidipine is mainly metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of lercanidipine. The clinical relevance of this interaction is unknown. Monitoring for both lercanidipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Levocetirizine

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Encorafenib is an in vitro inhibitor of OCT2 at clinically relevant concentrations and may increase concentrations of levofloxacin. The clinical relevance of this interaction is unknown. Monitoring for levofloxacin toxicity may be required if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with levofloxacin, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Levomepromazine is metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with levomepromazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of levonorgestrel. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking levonorgestrel in combination with encorafenib should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Potential Weak Interaction

Encorafenib

Levothyroxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation. Encorafenib is an inhibitor of UGT1A1 and may increase levothyroxine concentrations. The clinical relevance of this interaction is unknown. Monitoring for levothyroxine toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of lidocaine. The clinical relevance of this interaction is unknown. Monitoring for both lidocaine toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Linagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of linagliptin. Furthermore, linagliptin is a weak inhibitor of CYP3A4 and may increase encorafenib concentrations. The clinical relevance of this interaction is unknown. Monitoring for both linagliptin toxicity and blood glucose levels should be considered. Monitoring for encorafenib toxicity and, if available, plasma concentrations should also be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Linezolid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Liraglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Liraglutide is degraded by endogenous endopeptidases. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Lisinopril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. 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, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with lithium, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Live vaccines

Quality of Evidence: Very Low

Summary:

Coadministration of live vaccines (such as BCG vaccine; measles, mumps and rubella vaccines; varicella vaccines; typhoid vaccines; rotavirus vaccines; yellow fever vaccines; oral polio vaccine) has not been studied. In patients, who are receiving cytotoxics or other immunosuppressant drugs, use of live vaccines for immunisation is contraindicated. However, encorafenib is not an immunosuppressant, immunomodulatory or bone marrow toxic drug. Therefore, no pharmacodynamic interaction is expected with live vaccines.

Description:

See Summary

No Interaction Expected

Encorafenib

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolised by CYP3A4 and CYP2C8 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of loperamide. However, since loperamide has a broad therapeutic index, no clinically relevant effect on loperamide exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of loratadine. The clinical relevance of this interaction is unknown. Monitoring for both loratadine toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Lorazepam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lormetazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lormetazepam is mainly glucuronidated. Encorafenib is an inhibitor of UGT1A1 and my increase concentrations of lormetazepam. The clinical relevance of this interaction is unknown. Monitoring for lormetazepam toxicity may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Losartan

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lovastatin is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of lovastatin. The clinical relevance of this interaction is unknown. Monitoring for both lovastatin toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of macitentan. The clinical relevance of this interaction is unknown. Monitoring for both macitentan toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Magnesium

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Maprotiline

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Medroxyprogesterone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of medroxyprogesterone. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking medroxyprogesterone in combination with encorafenib should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Medroxyprogesterone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in an increased toxicity or loss of efficacy of medroxyprogesterone. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking medroxyprogesterone in combination with encorafenib should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Mefenamic acid

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9, UGT2B7 or UGT1A9.

Description:

See Summary

No Interaction Expected

Encorafenib

Megestrol acetate

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Meropenem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of the renal transporters OAT3>OAT1. Encorafenib is an in vitro inhibitor of OAT3 and OAT1 at clinically relevant concentrations and may increase meropenem concentrations. The clinical relevance of this interaction is unknown. Monitoring for meropenem toxicity may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Mesalazine

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Interaction

Encorafenib

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Encorafenib is unlikely to interfere with this metabolic or elimination pathway. Metamizole is also an inducer of CYP3A4 and may decrease encorafenib concentrations. The clinical relevance of this interaction is unknown. Coadministration is not recommended. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Metformin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Encorafenib is an in vitro inhibitor of OCT2 at clinically relevant concentrations and may increase concentrations of metformin. The clinical relevance of this interaction is unknown. Monitoring for metformin toxicity should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Methadone is demethylated by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of methadone. The clinical relevance of this interaction is unknown. Monitoring for both methadone toxicity and efficacy may be required. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with methadone, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Methyldopa

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Methylphenidate

Quality of Evidence: Very Low

Summary:

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. Therefore, there is little potential for methylphenidate to affect disposition of encorafenib, or to be affected if coadministered with encorafenib.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Methylprednisolone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of methylprednisolone. The clinical relevance of this interaction is unknown. Monitoring for both methylprednisolone toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Metoclopramide

Quality of Evidence: Very Low

Summary:

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). Encorafenib does not inhibit or induce CYP2D6.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Metolazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro of OAT1/3 at clinically relevant concentrations and may increase concentrations of metolazone. The clinical relevance of this interaction is unknown. Monitoring for metolazone toxicity and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Metoprolol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Metronidazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metronidazole is eliminated via glomerular filtration. Encorafenib is unlikely to interfere with this elimination pathway. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) 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 encorafenib cannot be excluded. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Encorafenib

Mexiletine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mianserin is metabolised by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of mianserin. The clinical relevance of this interaction is unknown. Monitoring for both mianserin toxicity and efficacy should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Miconazole is extensively metabolized by the liver. Encorafenib is unlikely to interfere with this unspecified metabolic pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of encorafenib may increase due to strong inhibition of CYP3A4 by miconazole. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure was increased by 2.8-fold. A similar effect may occur after coadministration with miconazole. Coadministration of encorafenib with miconazole should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of miconazole (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating miconazole 3-5 days after discontinuation of miconazole. Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinically relevant interaction is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Midazolam (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Midazolam is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of midazolam. The clinical relevance of this interaction is unknown. Monitoring for both midazolam toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Potential Weak Interaction

Encorafenib

Milnacipran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). Encorafenib is an inhibitor of UGT1A1 and may increase milnacipran concentrations. The clinical relevance of this interaction is unknown. Monitoring for milnacipran toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of mirtazapine. The clinical relevance of this interaction is unknown. Monitoring for both mirtazapine toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mometasone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of mometasone. The clinical relevance of this interaction is unknown. Monitoring for both mometasone toxicity and efficacy should be considered. Note: No clinically relevant interaction is expected with the topical use of mometasone.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Montelukast

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of montelukast. The clinical relevance of this interaction is unknown. Monitoring for both montelukast toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Encorafenib is an inhibitor of UGT1A1 and P-gp (in vitro) and may increase morphine concentrations. The clinical relevance of this interaction is unknown. Monitoring for morphine toxicity may be required.

Description:

See Summary

Do Not Coadminister

Encorafenib

Moxifloxacin

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be avoided. Moxifloxacin is predominantly glucuronidated by UGT1A1. Encorafenib is an inhibitor of UGT1A1 and may increase concentrations of moxifloxacin. The clinical relevance of this interaction is unknown. Monitoring for moxifloxacin toxicity may be required if coadministration is unavoidable. However, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as encorafenib. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with moxifloxacin, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Mycophenolate

Quality of Evidence: Very Low

Summary:

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. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Nadroparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Nandrolone

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Naproxen

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce these CYPs or UGT2B7.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nateglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nateglinide. The clinical relevance of this interaction is unknown. Monitoring for both nateglinide toxicity and blood glucose levels should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Nebivolol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nefazodone is metabolised mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nefazodone. The clinical relevance of this interaction is unknown. Monitoring for both nefazodone toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, nefazodone is a strong inhibitor of CYP3A4 and may increase concentrations of encorafenib. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure was increased by 2.8-fold. A similar effect may occur after coadministration with nefazodone. Therefore, coadministration of encorafenib with nefazodone should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of nefazodone (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating nefazodone 12-20 hours after discontinuation of nefazodone.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nicardipine. The clinical relevance of this interaction is unknown. Monitoring for both nicardipine toxicity and efficacy, and blood pressure should be considered. Moreover, nicardipine is a weak inhibitor of CYP3A4 and may increase encorafenib concentrations. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations should also be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Nicotinamide (Niacinamide)

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nifedipine is metabolised mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nifedipine. The clinical relevance of this interaction is unknown. Monitoring for both nifedipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Nimesulide

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nisoldipine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nisoldipine. The clinical relevance of this interaction is unknown. Monitoring for both nisoldipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of nitrendipine. The clinical relevance of this interaction is unknown. Monitoring for both nitrendipine toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Encorafenib is an inhibitor of UGT1A1 and may increase nitrofurantoin concentrations. The clinical relevance of this interaction is unknown. Monitoring for nitrofurantoin toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of norelgestromin. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking norelgestromin in combination with encorafenib should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

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. Encorafenib is an inhibitor of UGT1A1 and may increase concentrations of norethisterone. However, no clinically relevant effect on norethisterone exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of norgestimate. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking norgestimate in combination with encorafenib should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolized by CYP3A4 and is glucuronidated to a minor extent. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of levonorgestrel. The clinical relevance of this interaction is unknown. The addition of a barrier method as a second form of contraception while taking norgestrel in combination with encorafenib should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nortriptyline is metabolised mainly by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with nortriptyline, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Nystatin

Quality of Evidence: Very Low

Summary:

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.

Description:

See Summary

Do Not Coadminister

Encorafenib

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Encorafenib is unlikely to interfere with this elimination pathway. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with ofloxacin, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Olanzapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). Encorafenib does not inhibit or induce CYP1A2, CYP2D6 or UGT1A4.

Description:

See Summary

No Interaction Expected

Encorafenib

Olmesartan

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Omeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Coadministration of encorafenib and the proton pump inhibitor, rabeprazole, did not alter encorafenib exposure. Therefore, no clinically relevant effect on encorafenib exposure due to pH elevation from gastric acid reducing agents such as omeprazole is expected. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of omeprazole. The clinical relevance of this interaction is unknown. Monitoring for both omeprazole toxicity and efficacy should be considered. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. To a lesser extent, encorafenib is metabolised by CYP2C19 and concentrations may increase due to CYP2C19 inhibition by omeprazole. However, since CYP2C19 is a minor pathway, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

Do Not Coadminister

Encorafenib

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of ondansetron. The clinical relevance of this interaction is unknown. Monitoring for both ondansetron toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with ondansetron, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Oxazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxazepam is mainly glucuronidated. Encorafenib is an inhibitor of UGT1A1 and my increase concentrations of oxazepam. The clinical relevance of this interaction is unknown. Monitoring for oxazepam toxicity may be required.

Description:

See Summary

Do Not Coadminister

Encorafenib

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Oxcarbazepine is extensively metabolized to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Encorafenib does not interact with this metabolic pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. To a lesser extent, encorafenib is metabolised by CYP2C19 and concentrations may increase due to inhibition by oxcarbazepine and MHD. Since CYP2C19 is a minor metabolic pathway, no clinically relevant effect on encorafenib exposure is expected. However, concentrations of encorafenib may decrease due to CYP3A4 induction by oxcarbazepine. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Oxprenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxprenolol is largely metabolised via glucuronidation. Encorafenib is an inhibitor of UGT1A1 and may increase oxprenolol concentrations. The clinical relevance of this interaction is unknown. Monitoring for oxprenolol toxicity and blood pressure may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of oxycodone. The clinical relevance of this interaction is unknown. Monitoring for both oxycodone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Paliperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of OCT2 at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of paliperidone. The clinical relevance of this interaction is unknown. Monitoring for both paliperidone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of palonosetron. The clinical relevance of this interaction is unknown. Monitoring for both palonosetron toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Pamidronic acid

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Pantoprazole

Quality of Evidence: Very Low

Summary:

Description:

See Summary

No Interaction Expected

Encorafenib

Para-aminosalicylic acid

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Paracetamol (Acetaminophen)

Quality of Evidence: Very Low

Summary:

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). Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1 and may increase concentrations of paracetamol. However, since CYP3A4 and UGT1A1 are minor metabolic pathways, no clinically relevant effect on paracetamol exposure is expected.

Description:

See Summary

No Interaction Expected

Encorafenib

Paroxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paroxetine is mainly metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. Paroxetine is also an inhibitor of CYP2D6 (strong) and CYP2C9. To a lesser extent, encorafenib is metabolised by CYP2D6 and concentrations may increase due to CYP2D6 inhibition by paroxetine. However, since CYP2D6 is a minor pathway, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

No Interaction Expected

Encorafenib

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Penicillins

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Encorafenib is an in vitro inhibitor of OAT1 and OAT3 at clinically relevant concentrations and may increase penicillins concentrations. The clinical relevance of this interaction is unknown. Monitoring for penicillins toxicity should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of perazine. The clinical relevance of this interaction is unknown. Monitoring for both perazine toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Periciazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Perindopril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Perphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Perphenazine is metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with perphenazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of pethidine. The clinical relevance of this interaction is unknown. Monitoring for both pethidine toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Phenelzine

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Phenobarbital is metabolized by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Encorafenib does not inhibit or induce these CYPs. Phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Concentrations of encorafenib may decrease due to induction of CYP3A4 by phenobarbital. The clinical relevance of this interaction is unknown. Therefore, coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of phenprocoumon. The clinical relevance of this interaction is unknown. Monitoring for phenprocoumon toxicity and efficacy, and INR/PT should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Encorafenib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Encorafenib concentrations may decrease due to CYP3A4 and P-gp induction. The clinical relevance of this interaction is unknown. Therefore, coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Encorafenib

Phytomenadione (Vitamin K)

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP4F2.

Description:

See Summary

Do Not Coadminister

Encorafenib

Pimozide

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of pimozide. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as encorafenib. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration is therefore contraindicated.

Description:

See Summary

No Interaction Expected

Encorafenib

Pindolol

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2D6 and is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Pioglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of pioglitazone. The clinical relevance of this interaction is unknown. Monitoring for both pioglitazone toxicity and blood glucose levels should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with pipotiazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Piroxicam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Pitavastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Pitavastatin is also a substrate of OATP1B1. Encorafenib is an in vitro inhibitor of OATP1B1 at clinically relevant concentrations and may increase concentrations of pitavastatin. The clinical relevance of this interaction is unknown. Monitoring for pitavastatin toxicity should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be avoided. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Encorafenib is an inhibitor of UGT1A1 and P-gp in vitro at clinically relevant concentrations and may increase concentrations with posaconazole. The clinical relevance of this interaction is unknown. Posaconazole is also a strong inhibitor of CYP3A4 and will increase concentrations of encorafenib. In healthy subjects (n=16), coadministration of encorafenib (50 mg single dose, day 1 and 7) with posaconazole (400 mg twice daily for 9 days), increased encorafenib exposure by 2.8-fold. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use with posaconazole (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating posaconazole 5-7 days after discontinuation with posaconazole. Monitoring for posaconazole toxicity may also be required. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with posaconazole, a QT prolonging drug, should be avoided.

Description:

See Summary

No Interaction Expected

Encorafenib

Potassium

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of prasugrel. The clinical relevance of this interaction is unknown. Monitoring for both prasugrel toxicity and efficacy should be considered. Thrombocyte aggregation tests should also be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Pravastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Encorafenib is an in vitro inhibitor of OATP1B1 at clinically relevant concentrations and may increase pravastatin concentrations. The clinical relevance of this interaction is unknown. Monitoring for pravastatin toxicity should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Prazosin

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisolone undergoes hepatic metabolism via CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of prednisolone. The clinical relevance of this interaction is unknown. Monitoring for both prednisolone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Encorafenib does not interact with this pathway. Prednisolone is then metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of prednisolone. The clinical relevance of this interaction is unknown. Monitoring for both prednisolone toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Pregabalin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pregabalin is cleared mainly by glomerular filtration (90% as unchanged drug). Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Encorafenib does not inhibit or induce CYP2D6 or CYP2C19. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with prochlorperazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Do Not Coadminister

Encorafenib

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Promethazine is metabolised by CYP2D6. Encorafenib does not inhibit or induce CYP2D6. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with promethazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of propafenone. The clinical relevance of this interaction is unknown. Monitoring for both propafenone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Propranolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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). Encorafenib is an inhibitor of UGT1A1 and may increase propranolol concentrations. The clinical relevance of this interaction is unknown. Monitoring for propranolol toxicity and blood pressure may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Prucalopride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prucalopride is minimally metabolised and mainly eliminated renally, partly by active secretion by renal transporters. Prucalopride is also a substrate of P-gp. Encorafenib is an in vitro inhibitor of P-gp and may increase concentrations of prucalopride. The clinical relevance of this interaction is unknown. Monitoring for prucalopride toxicity should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Pyrazinamide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Pyridoxine (Vitamin B6)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quetiapine is primarily metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of quetiapine. The clinical relevance of this interaction is unknown. Monitoring for both quetiapine toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Quinapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quinapril is de-esterified to the active metabolite quinaprilat which is eliminated primarily by renal excretion via OAT3. Encorafenib is an in vitro inhibitor of OAT3 at clinically relevant concentrations and may increase concentrations of quinapril. The clinical relevance of this interaction is unknown. Monitoring for quinapril toxicity and blood pressure should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of P-gp in vitro at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of quinidine. The clinical relevance of this interaction is unknown. Monitoring for both quinidine toxicity and efficacy should also be considered. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate) and may increase encorafenib concentrations. The clinical relevance of this interaction is unknown. Monitoring for encorafenib toxicity and, if available, plasma concentrations should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with quinidine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and care should be taken. In healthy volunteers (n=15), coadministration of rabeprazole (20 mg daily for 5 days) and encorafenib (100 mg single dose), had no clinically relevant effect on encorafenib exposure. However, rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of rabeprazole. The clinical relevance of this interaction is unknown. Monitoring for both rabeprazole toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ramipril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ranitidine

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Do Not Coadminister

Encorafenib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of ranolazine. The clinical relevance of this interaction is unknown. Monitoring for both ranolazine toxicity and efficacy, and blood pressure should be considered. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6 and may increase encorafenib concentrations. Monitoring for encorafenib toxicity and, if available, plasma concentrations should also be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with ranolazine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Reboxetine is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of reboxetine. The clinical relevance of this interaction is unknown. Monitoring for both reboxetine toxicity and efficacy should be considered. Furthermore, in vitro data indicate reboxetine to be a weak inhibitor of CYP3A4, but in vivo data showed no inhibitory effect on CYP3A4. Therefore, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of OATP1B1 at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of repaglinide. The clinical relevance of this interaction is unknown. Monitoring for both repaglinide toxicity and blood glucose levels should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Retinol (Vitamin A)

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Riboflavin (Vitamin B2)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of rifabutin. However, no clinically relevant effect on rifabutin exposure is expected since rifabutin is a strong CYP3A4 inducer itself. Rifabutin is a strong CYP3A4 and P-gp inducer and may decrease encorafenib exposure. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Encorafenib

Rifampicin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Rifampicin is metabolised via deacetylation. Encorafenib does not interact with this pathway. Rifampicin is also a strong CYP3A4 and P-gp inducer and may decrease encorafenib exposure. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Encorafenib

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Rifapentine is metabolised via deacetylation. Encorafenib does not interact with this pathway. Rifapentine is also a strong CYP3A4, CYP2C8 and P-gp inducer. Concentrations of encorafenib may decrease due to CYP3A4 and P-gp induction by rifapentine. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically unavoidable, closely monitor encorafenib efficacy and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Encorafenib

Rifaximin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Risperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Risperidone is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and is an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of risperidone. The clinical relevance of this interaction is unknown. Monitoring for both risperidone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is also a substrate of P-gp and BCRP. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp and BCRP at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of rivaroxaban. The clinical relevance of this interaction is unknown. Monitoring for rivaroxaban toxicity and efficacy, and anti-Xa activity should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Rosiglitazone

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C8 or CYP2C9.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Encorafenib is an in vitro inhibitor of OATP1B1 and BCRP at clinically relevant concentrations and may increase concentrations of rosuvastatin. The clinical relevance of this interaction is unknown. Monitoring for rosuvastatin toxicity should be considered

Description:

See Summary

No Interaction Expected

Encorafenib

Salbutamol

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Salmeterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of salmeterol. However, systemic exposure of salmeterol is low and no clinically relevant effect on salmeterol systemic exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of saxagliptin. The clinical relevance of this interaction is unknown. Monitoring for both saxagliptin toxicity and blood glucose levels should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Senna

Quality of Evidence: Very Low

Summary:

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.

Description:

See Summary

Do Not Coadminister

Encorafenib

Sertindole

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of sertindole. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as encorafenib. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec).

Description:

See Summary

Potential Weak Interaction

Encorafenib

Sertraline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of sertraline. The clinical relevance of this interaction is unknown. Monitoring for both sertraline toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of sildenafil. The clinical relevance of this interaction is unknown. Monitoring for both sildenafil toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4. Simvastatin is also a substrate of BCRP, and the active metabolite is a substrate of OATP1B1. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of OATP1B1 and BCRP at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of simvastatin. The clinical relevance of this interaction is unknown. Monitoring for both simvastatin toxicity and efficacy should be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of sirolimus. The clinical relevance of this interaction is unknown. Monitoring for both sirolimus toxicity and efficacy is recommended. Monitor sirolimus plasma concentrations, if available.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Sitagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents a minor metabolic pathway. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of OAT3 and P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of sitagliptin. The clinical relevance of this interaction is unknown. Monitoring for both sitagliptin toxicity and blood glucose levels should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Sodium nitroprusside

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Sotalol

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be avoided. Sotalol is excreted unchanged via renal elimination. Encorafenib is unlikely to interfere with this elimination pathway. However, the product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval, such as encorafenib. Encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with sotalol should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

No Interaction Expected

Encorafenib

Spectinomycin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Spironolactone

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Stanozolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Stanozolol undergoes hepatic metabolism. Encorafenib is unlikely to interfere with this unspecified metabolic pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

St John's Wort

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. St John’s wort is a P-gp and CYP3A4 inducer and may decrease encorafenib concentrations. A decrease in exposure can lead to a decreased efficacy. Therefore, coadministration is contraindicated.

Description:

See Summary

No Interaction Expected

Encorafenib

Streptokinase

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Streptomycin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Sulfadiazine

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2C9.

Description:

See Summary

Do Not Coadminister

Encorafenib

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Encorafenib is unlikely to interfere with this elimination pathway. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with sulpiride, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Interaction

Encorafenib

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tacrolimus is metabolised mainly by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4 and an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of tacrolimus. The clinical relevance of this interaction is unknown. Monitoring for both tacrolimus toxicity and efficacy is recommended. Monitor tacrolimus plasma concentrations, if available. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Therefore, no clinically relevant effect on encorafenib exposure is expected due to CYP3A4 inhibition.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tadalafil is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of tadalafil. The clinical relevance of this interaction is unknown. Monitoring for both tadalafil toxicity and efficacy, and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of tamsulosin. The clinical relevance of this interaction is unknown. Monitoring for both tamsulosin toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Tazobactam

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of telithromycin. The clinical relevance of this interaction is unknown. Monitoring for both telithromycin toxicity and efficacy should be considered. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp and may increase encorafenib concentrations. No clinically relevant effect is expected from P-gp inhibition. However, after coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure was increased by 2.8-fold. A similar effect may occur after coadministration with telithromycin. Therefore, coadministration of encorafenib with telithromycin should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of telithromycin (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating telithromycin 1-2 days after discontinuation of telithromycin.

Description:

See Summary

No Interaction Expected

Encorafenib

Telmisartan

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Temazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Temazepam is mainly glucuronidated. Encorafenib is an inhibitor of UGT1A1 and my increase concentrations of temazepam. The clinical relevance of this interaction is unknown. Monitoring for temazepam toxicity may be required.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of terbinafine. The clinical relevance of this interaction is unknown. Monitoring for both terbinafine toxicity and efficacy should be considered. Terbinafine is also a moderate-strong inhibitor of CYP2D6. To a lesser extent, encorafenib is metabolised by CYP2D6 and concentrations may increase due to CYP2D6 inhibition by terbinafine. However, since CYP2D6 is a minor pathway, no clinically relevant effect on encorafenib exposure is expected.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Testosterone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of testosterone. The clinical relevance of this interaction is unknown. Monitoring for both testosterone toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Tetracycline

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Theophylline

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Thiamine (Vitamin B1)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Thioridazine

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of thioridazine. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as encorafenib. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration is therefore contraindicated.

Description:

See Summary

Do Not Coadminister

Encorafenib

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tiapride is excreted largely unchanged in urine. Encorafenib is unlikely to interfere with this elimination pathway. However, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with tiapride, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ticagrelor is a substrate and mild inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp. Encorafenib is both an inhibitor and inducer of CYP3A4 and is also an in vitro inhibitor of P-gp at clinically relevant concentrations. This may result in increased toxicity or loss of efficacy of ticagrelor. Furthermore, ticagrelor may increase encorafenib concentrations due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. Monitoring for ticagrelor toxicity and efficacy, and thrombocyte aggregation tests should be considered. Monitoring for encorafenib toxicity and, if available, plasma concentrations should also be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Timolol

Quality of Evidence: Very Low

Summary:

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. Encorafenib does not inhibit or induce CYP2D6.

Description:

See Summary

No Interaction Expected

Encorafenib

Tinzaparin

Quality of Evidence: Very Low

Summary:

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. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Tolbutamide

Quality of Evidence: Very Low

Summary:

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 CYPs 2C8 and 2C19. Encorafenib does not inhibit or induce these CYPs.

Description:

See Summary

Do Not Coadminister

Encorafenib

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of tolterodine. The clinical relevance of this interaction is unknown. Monitoring for both tolterodine toxicity and efficacy should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with tolterodine, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Torasemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Torasemide is metabolised mainly by CYP2C9. Encorafenib does not inhibit or induce CYP2C9. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro inhibitor of OAT1/3 at clinically relevant concentrations and may increase torasemide concentrations. The clinical relevance of this interaction is unknown. Monitoring for torasemide toxicity and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of tramadol. The clinical relevance of this interaction is unknown. Monitoring for both tramadol toxicity and efficacy should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trandolapril is hydrolysed to trandolaprilat. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Tranexamic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Encorafenib

Tranylcypromine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tranylcypromine is hydroxylated and acetylated. Encorafenib does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Encorafenib

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Trazodone is primarily metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of trazodone. The clinical relevance of this interaction is unknown. Monitoring for both trazodone toxicity and efficacy should be considered if coadministration is unavoidable. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with trazodone, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triamcinolone is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of triamcinolone. The clinical relevance of this interaction is unknown. Monitoring for both triamcinolone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triazolam is metabolised by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of triazolam. The clinical relevance of this interaction is unknown. Monitoring for both triazolam toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Sulfamethoxazole is metabolised by CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of trimethoprim. The clinical relevance of this interaction is unknown. Monitoring for both trimethoprim toxicity and efficacy should be considered. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is a weak inhibitor of CYP2C9. Encorafenib is not metabolised or transported by these enzymes or transporters.

Description:

See Summary

No Interaction Expected

Encorafenib

Trimipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trimipramine is metabolised mainly by CYP2D6. Encorafenib does not inhibit or induce CYP2D6.

Description:

See Summary

Do Not Coadminister

Encorafenib

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tropisetron is metabolised mainly by CYP2D6. Tropisetron is also a substrate of P-gp. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase concentrations of tropisetron. The clinical relevance of this interaction is unknown. Monitoring for tropisetron toxicity should be considered. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Therefore, coadministration of encorafenib with tropisetron, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent CYP1A2 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of ulipristal. The clinical relevance of this interaction is unknown.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Valproic acid is primarily metabolized by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolized by CYP2C9 and CYP2C19. Encorafenib is an inhibitor of UGT1A1 and may increase valproic acid concentrations. The clinical relevance of this interaction is unknown. Monitoring for valproic acid toxicity and, if available, plasma concentrations may be required. Additionally, valproic acid is an inhibitor of CYP2C9. Encorafenib is not metabolised by CYP2C9.

Description:

See Summary

No Interaction Expected

Encorafenib

Valsartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valsartan is eliminated unchanged mostly through biliary excretion. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Encorafenib

Vancomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vancomycin is excreted unchanged via glomerular filtration. Encorafenib is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of venlafaxine. The clinical relevance of this interaction is unknown. Monitoring for both venlafaxine toxicity and efficacy should be considered.

Description:

See Summary

Potential Interaction

Encorafenib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of verapamil. The clinical relevance of this interaction is unknown. Monitoring for both verapamil toxicity and efficacy, and blood pressure should be considered. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong) and may increase concentrations of encorafenib. After coadministration of diltiazem, a moderate CYP3A4 inhibitor, encorafenib exposure increased by 1.8-fold. A similar effect may occur after coadministration with verapamil. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, reduce the encorafenib dose up to 50%. Monitor closely for encorafenib toxicity including ECG assessment. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating verapamil 24-36 hours after discontinuation of verapamil.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Vildagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Encorafenib is an in vitro inhibitor of P-gp at clinically relevant concentrations and may increase concentrations of vildagliptin. The clinical relevance of this interaction is unknown. Monitoring for vildagliptin toxicity should be considered.

Description:

See Summary

No Interaction Expected

Encorafenib

Vitamin E

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Encorafenib

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Voriconazole is metabolised by CYP2C19 (major pathway) and to a lesser extent by CYP3A4 and CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of voriconazole. The clinical relevance of this interaction is unknown. Monitoring for both voriconazole toxicity and efficacy should be considered if coadministration is unavoidable. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Encorafenib concentrations may increase due to CYP3A4 and CYP2C19 inhibition by voriconazole. After coadministration with posaconazole, a strong CYP3A4 inhibitor, encorafenib exposure increased by 2.8-fold. A similar effect may occur after coadministration with voriconazole. Therefore, coadministration of encorafenib with voriconazole should be avoided. If coadministration is unavoidable, reduce the encorafenib dose to ~33% of the dose prior to the concurrent use of voriconazole (for example 150 mg instead of 450 mg; 100 mg instead of 300 mg; 75 mg instead of 200 mg). Monitor closely for encorafenib toxicity. Monitor encorafenib plasma concentrations, if available. Resume the encorafenib dose taken prior to initiating voriconazole approximately 18-30 hours after discontinuation of voriconazole. Furthermore, encorafenib shows QT interval prolongation. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration of encorafenib with voriconazole, a QT prolonging drug, should be avoided. If coadministration is clinically unavoidable, monitor ECG closely.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of warfarin. The clinical relevance of this interaction is unknown. Monitoring for warfarin toxicity and efficacy, and INR/PT should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Encorafenib is an in vitro of OAT1/3 at clinically relevant concentrations and may increase xipamide concentrations. The clinical relevance of this interaction is unknown. Monitoring for xipamide toxicity and blood pressure should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of zaleplon. The clinical relevance of this interaction is unknown. Monitoring for both zaleplon toxicity and efficacy should be considered.

Description:

See Summary

Do Not Coadminister

Encorafenib

Ziprasidone

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of ziprasidone. However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval, such as encorafenib. A mean change of 19.9 msec (90% CI: 13.3-26.5 msec) from baseline was estimated at a steady-state Cmax after administration of the recommended dose of 450 mg once daily. In the presence of 45 mg binimetinib twice daily, encorafenib increased the QTc interval by 18.7 msec (90% CI: 14.4-22.1 msec). Coadministration is therefore contraindicated.

Description:

See Summary

No Interaction Expected

Encorafenib

Zoledronic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Encorafenib

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 1A2. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of zolpidem. The clinical relevance of this interaction is unknown. Monitoring for both zolpidem toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of zopiclone. The clinical relevance of this interaction is unknown. Monitoring for both zopiclone toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Encorafenib is both an inhibitor and inducer of CYP3A4. This may result in increased toxicity or loss of efficacy of zotepine. The clinical relevance of this interaction is unknown. Monitoring for both zotepine toxicity and efficacy should be considered.

Description:

See Summary

Potential Weak Interaction

Encorafenib

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Encorafenib is both an inhibitor and inducer of CYP3A4 and an inhibitor of UGT1A1. This may result in increased toxicity or loss of efficacy of zuclopenthixol. The clinical relevance of this interaction is unknown. Monitoring for both zuclopenthixol toxicity and efficacy should be considered.

Description:

See Summary