Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

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Potential Weak Interaction

Crizotinib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Crizotinib does not inhibit or induce CYPs 2C9, 1A2 or 2C19. However, one case report describes an increased PT and INR after coadministration of crizotinib and warfarin. A similar effect may occur after coadministration with acenocoumarol. The clinical relevance of this interaction is unknown. Monitoring for acenocoumarol toxicity and INR/PT may be required.

Description:

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No Interaction Expected

Crizotinib

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). Crizotinib is an in vitro inhibitor of UGT1A6 and may increase concentrations of acetylsalicylic acid. The clinical relevance of this interaction is unknown. However, no clinically relevant effect on acetylsalicylic acid is expected.

Description:

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No Interaction Expected

Crizotinib

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%). Crizotinib does not inhibit or induce CYPs 1A2, 2C9 or 2C19.

Description:

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No Interaction Expected

Crizotinib

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. Alendronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Crizotinib is unlikely to interfere with this elimination pathway. Although no pharmacokinetic interaction is expected, alendronic acid should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronic acid before taking any other oral medicinal product.

Description:

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Potential Interaction

Crizotinib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Alfentanil undergoes extensive CYP3A4 metabolism and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with alfentanil. If coadministration is unavoidable, monitor closely for alfentanil toxicity and consider a dose reduction for alfentanil. Furthermore, crizotinib and alfentanil have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

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Potential Interaction

Crizotinib

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Alfuzosin is metabolised by CYP3A and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with alfuzosin. If coadministration is unavoidable, monitor closely for alfuzosin toxicity and consider a dose reduction for alfuzosin.

Description:

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Potential Weak Interaction

Crizotinib

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. Aliskiren is also a substrate of P-gp and concentrations may increase due to in vitro inhibition by crizotinib. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Monitoring for aliskiren toxicity and blood pressure may be required.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

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Potential Interaction

Crizotinib

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Crizotinib is a moderate inhibitor of CYP3A4 and may increase alosetron concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with alosetron. If coadministration is unavoidable, monitor closely for alosetron toxicity.

Description:

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Potential Interaction

Crizotinib

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Alprazolam is mainly metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with alprazolam. If coadministration is unavoidable, monitor closely for alprazolam toxicity and consider a dose reduction for alprazolam.

Description:

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No Interaction Expected

Crizotinib

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. Although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with aluminium hydroxide.

Description:

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Potential Weak Interaction

Crizotinib

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken Ambrisentan is metabolized by glucuronidation via UGT1A3, UGT1A9 and UGT2B7 and to a lesser extent by CYP3A4 and CYP2C19. Ambrisentan is also a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro). However, since CYP3A4 is a minor metabolic pathway no clinically relevant effect on ambrisentan exposure is expected. However, the local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Monitoring for ambrisentan toxicity and blood pressure may be required.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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Potential Weak Interaction

Crizotinib

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. Concentrations may increase due to in vitro inhibition of OCT2 by crizotinib. The clinical relevance of this interaction is unknown. Monitoring for amiloride toxicity and blood pressure may be required.

Description:

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Potential Interaction

Crizotinib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Amiodarone is metabolised by CYP3A4 and CYP2C8. Crizotinib is a moderate inhibitor of CYP3A4 and may increase amiodarone concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with amiodarone. If coadministration is unavoidable, monitor closely for amiodarone toxicity and consider a dose reduction for amiodarone. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate) and P-gp (strong). Crizotinib concentrations may increase due to CYP3A4 and P-gp inhibition. No clinically relevant effect on crizotinib exposure from CYP3A4 inhibition is expected. However, the clinical relevance of P-gp inhibition is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and amiodarone have a potential to induce bradycardia and potentially cause QTc interval prolongation. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment. 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

Crizotinib

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). Amisulpride concentrations may increase due to in vitro inhibition of OCT1 and OCT2 by crizotinib. The clinical relevance of this interaction is unknown. Therefore, monitoring for amisulpride toxicity may be required.

Description:

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Potential Interaction

Crizotinib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase amitriptyline concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on amitriptyline exposure is expected. Crizotinib and amitriptyline have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

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Potential Interaction

Crizotinib

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Amlodipine is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with amlodipine. If coadministration is unavoidable, monitor closely for amlodipine toxicity and blood pressure. A dose reduction for amlodipine should also considered.

Description:

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No Interaction Expected

Crizotinib

Amoxicillin

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Weak Interaction

Crizotinib

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. Crizotinib 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

Crizotinib

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

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Crizotinib

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. Although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with antacids.

Description:

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Potential Interaction

Crizotinib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Apixaban is a substrate of P-gp and BCRP, is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase apixaban concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with apixaban. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for apixaban toxicity, anti-Xa activity and reduce the apixaban dose by 25%.

Description:

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Potential Interaction

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4 and may increase aprepitant concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with aprepitant. If coadministration is unavoidable, monitor closely for aprepitant toxicity. During treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase crizotinib concentrations. Physiologically-based pharmacokinetic simulations with crizotinib and diltiazem, a moderate CYP3A4 inhibitor, increased crizotinib exposure by only 1.1-fold. A similar effect may occur after coadministration with aprepitant. However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity may be required. Moreover, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Crizotinib concentrations may decrease due to CYP3A4 induction. No clinically relevant effect on crizotinib exposure is expected.

Description:

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Potential Interaction

Crizotinib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of aripiprazole. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with aripiprazole. If coadministration is unavoidable, monitor closely for aripiprazole toxicity and consider a dose reduction for aripiprazole.

Description:

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No Interaction Expected

Crizotinib

Asenapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). Crizotinib is an inhibitor of CYP3A4 (moderate) and UGT1A4 (in vitro) and may increase asenapine concentrations. However, no clinically relevant effect on asenapine exposure is expected.

Description:

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Potential Interaction

Crizotinib

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of astemizole. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with astemizole. If coadministration is unavoidable, monitor closely for astemizole toxicity and consider a dose reduction for astemizole. Furthermore, crizotinib and astemizole potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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Potential Interaction

Crizotinib

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Crizotinib does not inhibit or induce OATP1B1. However, crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase atorvastatin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with atorvastatin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for atorvastatin toxicity and consider a dose reduction for atorvastatin.

Description:

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Potential Weak Interaction

Crizotinib

Azathioprine

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Crizotinib

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Crizotinib is in vitro an inhibitor of P-gp and may increase concentrations of azithromycin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Monitoring for azithromycin toxicity should be considered. However, for administration routes other than oral, no clinically relevant interaction is expected. Azithromycin is also an inhibitor of P-gp and may increase crizotinib concentrations. The clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and azithromycin potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

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Potential Interaction

Crizotinib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Bedaquiline is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with bedaquiline. If coadministration is unavoidable, monitor closely for bedaquline toxicity and consider a dose reduction for bedaquiline. Furthermore, crizotinib and bedaquiline potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

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No Interaction Expected

Crizotinib

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically significant interaction is unlikely in the range of observed clinical concentrations. Crizotinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

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Potential Interaction

Crizotinib

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase bepridil concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on bepridil exposure is expected. Crizotinib and bepridil have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

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Potential Interaction

Crizotinib

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Betamethasone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with betamethasone. If coadministration is unavoidable, monitor closely for betamethasone toxicity and consider a dose reduction for betamethasone.

Description:

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No Interaction Expected

Crizotinib

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

Description:

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No Interaction Expected

Crizotinib

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

Description:

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Potential Interaction

Crizotinib

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Concentrations of bisoprolol may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with bisprolol. If coadministration is unavoidable, monitor closely for bisoprolol toxicity and consider a dose reduction for bisoprolol. Furthermore, crizotinib and bisoprolol have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

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Potential Interaction

Crizotinib

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of bosentan. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with bosentan. If coadministration is unavoidable, monitor closely for bosentan toxicity and blood pressure. A dose reduction for bosentan should also be considered. Furthermore, crizotinib concentrations may decrease due to CYP3A4 induction by bosentan. Imatinib concentrations, on average, decreased by 33% in the presence of bosentan in a phase III clinical study and a similar effect may be expected with crizotinib. If coadministration is unavoidable, monitor closely for crizotinib efficacy and, if available, crizotinib plasma concentrations. A dose increment for crizotinib may be necessary.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on bromazepam exposure is expected. Crizotinib does not inhibit or induce CYP2D6 or CYP1A2.

Description:

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Potential Interaction

Crizotinib

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Budesonide is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with budesonide. If coadministration is unavoidable, monitor closely for budesonide toxicity and consider a dose reduction for budesonide.

Description:

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Potential Interaction

Crizotinib

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Crizotinib is an inhibitor of CYP3A4 (moderate), UGT2B7 (in vitro) and UGT1A1 (in vitro) and may increase concentrations of buprenorphine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with buprenorphine. The clinical relevance of UGT inhibition is unknown. If coadministration is unavoidable, monitor closely for buprenorphine toxicity and consider a dose reduction for buprenorphine.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

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Potential Interaction

Crizotinib

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Buspirone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with buspirone. If coadministration is unavoidable, monitor closely for buspirone toxicity and consider a dose reduction for buspirone.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Crizotinib

Captopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Crizotinib does not inhibit or induce OATs.

Description:

See summary

Do Not Coadminister

Crizotinib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Crizotinib may increase carbamazepine concentrations due to CYP3A4 inhibition. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with carbamazepine. Moreover, carbamazepine is an inducer of CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong), CYP1A2 (weak), CYP2B6, P-gp (moderate) and UGT1A1. Crizotinib is an in vitro substrate of P-gp and concentrations may decrease due to induction by carbamazepine. However, the clinical relevance of this interaction is unknown. Crizotinib concentrations may also decrease due to CYP3A4 induction. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with carbamazepine. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

Potential Interaction

Crizotinib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYP2C9 and CYP1A2. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of carvedilol. 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 crizotinib concentrations. However the clinical relevance of P-gp inhibition by carvedilol is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and carvedilol have a potential to induce bradycardia. Therefore, coadministration with carvedilol should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Cefalexin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

Cefazolin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Cefotaxime

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

Potential Weak Interaction

Crizotinib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chloramphenicol is predominantly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of chloramphenicol. The clinical relevance of this interaction is unknown. Monitoring for chloramphenicol toxicity may be required. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong) and CYP2D6 (weak). Crizotinib concentrations may increase due to CYP3A4 inhibition by chloramphenicol. However, the clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Description:

See summary

Potential Interaction

Crizotinib

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Chlordiazepoxide is extensively metabolised by CYP3A4, but does not inhibit or induce cytochromes. Chlordiazepoxide concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with chlordiazepoxide. If coadministration is unavoidable, monitor closely for chlordiazepoxide toxicity and consider a dose reduction for chlordiazepoxide.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Crizotinib

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Crizotinib does not inhibit or induce CYP2D6 or CYP1A2. However, crizotinib and chlorpromazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

Chlortalidone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Crizotinib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ciclosporin is a substrate of CYP3A4 and P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase ciclosporin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ciclosporin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for ciclosporin toxicity. Monitor ciclosporin plasma concentrations, if available, and adjust dose accordingly. Ciclosporin is also an inhibitor of CYP3A4 and OATP1B1 and may increase concentrations of crizotinib. Physiologically-based pharmacokinetic simulations with crizotinib and diltiazem, a moderate CYP3A4 inhibitor, increased crizotinib exposure by only 1.1-fold. A similar effect may occur after coadministration with ciclosporin. However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cimetidine is metabolised by CYP450 enzymes. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of cimetidine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with cimetidine. If coadministration is unavoidable, monitor closely for cimetidine toxicity. 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. Crizotinib concentrations may increase due to CYP3A4 inhibition by cimetidine. However, no clinically relevant effect on crizotinib exposure is expected. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with cimetidine.

Description:

See summary

Potential Weak Interaction

Crizotinib

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Crizotinib is unlikely to interfere with this metabolic or elimination pathway. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Crizotinib concentrations may increase due to CYP3A4 inhibition by ciprofloxacin. Physiologically-based pharmacokinetic simulations with crizotinib and diltiazem, a moderate CYP3A4 inhibitor, increased crizotinib exposure by only 1.1-fold. A similar effect may occur after coadministration with ciprofloxacin. However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. In addition, crizotinib and ciprofloxacin potentially cause QTc interval prolongation. Although the risk is low, care should be taken. Monitoring of ECG may be required.

Description:

See summary

Do Not Coadminister

Crizotinib

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cisapride is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with cisapride. If coadministration is unavoidable, monitor closely for cisapride toxicity and consider a dose reduction for cisapride. Furthermore, crizotinib and cisapride potentially cause QTc interval prolongation. Coadministration of cisapride with other drugs that prolong the QTc interval should be avoided. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of citalopram. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with citalopram. If coadministration is unavoidable, monitor closely for citalopram toxicity and consider a dose reduction for citalopram. Furthermore, crizotinib and citalopram potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Do Not Coadminister

Crizotinib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clarithromycin is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with clarithromycin. If coadministration is unavoidable, monitor closely for clarithromycin toxicity and consider a dose reduction for clarithromycin. Clarithromycin is also an inhibitor of CYP3A4 (strong) and P-gp and may increase crizotinib concentrations. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with clarithromycin, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should be considered. Furthermore, crizotinib and clarithromycin potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Crizotinib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clindamycin is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with clindamycin. If coadministration is unavoidable, monitor closely for clindamycin toxicity and consider a dose reduction for clindamycin. Moreover, in vitro data suggest that clindamycin is a CYP3A4 inhibitor and may therefore increase crizotinib concentrations. However, the clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Interaction

Crizotinib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clofazimine is largely excreted unchanged in the faeces. Crizotinib is unlikely to interfere with clofazimine elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor and may, therefore, increase crizotinib concentrations. However, the clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and clofazimine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

Clofibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Crizotinib does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Crizotinib

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of clomipramine and decrease desmethylclomipramine concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with clomipramine. If coadministration is unavoidable, monitor closely for both clomipramine toxicity and efficacy. Furthermore, crizotinib and clomipramine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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 form of the unchanged parent drug (40-60% of the dose). Clonidine is also a weak inhibitor of OCT2. Crizotinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYP3A4, 2B6 and 1A2 playing a minor role. Crizotinib is a moderate inhibitor of CYP3A4 and may increase clopidogrel concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on clopidogrel exposure is expected. Clopidogrel is also an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and in vitro of CYP2C9 at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Crizotinib is not metabolised by these CYPs.

Description:

See summary

Potential Interaction

Crizotinib

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with clorazepate. Furthermore, oxazepam is mainly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of oxazepam. If coadministration is unavoidable, monitor closely for clorazepate and oxazepam toxicity and oxazepam efficacy. A dose reduction for clorazepate should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

Potential Interaction

Crizotinib

Clozapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of clozapine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with clozapine. If coadministration is unavoidable, monitor closely for clozapine toxicity and consider a dose reduction for clozapine. In addition, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered. Furthermore, crizotinib and clozapine potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Codeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Codeine is also converted via CYP3A4 to norcodeine, an inactive metabolite. Crizotinib is a moderate inhibitor of CYP3A4 and may increase codeine concentrations, the effect on morphine exposure is unknown. Morphine is further metabolized by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of morphine. The clinical relevance of this interaction is unknown. Additionally, morphine is a substrate of P-gp. Crizotinib is an in vitro inhibitor of P-gp. However, no clinically relevant effect on morphine exposure is expected due to P-gp inhibition. If coadministration is unavoidable, monitor closely for codeine and morphine toxicity. A dose reduction for codeine should also be considered. Furthermore, crizotinib and morphine have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Colchicine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase colchicine concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with colchicine. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for colchicine toxicity and consider a dose reduction for colchicine.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dabigatran is transported via P-gp and is renally excreted. Crizotinib is in vitro an inhibitor of P-gp and may increase concentrations of dabigatran. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, close monitoring for dabigatran toxicity and ecarine clotting time (ECT) or diluted thrombine time (dTT) is recommended. Administer dabigatran 2 hours before crizotinib in a fasted state to circumvent the intestinal P-gp interaction.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation and is via multiple CYP450 enzymes. Crizotinib is a moderate inhibitor of CYP3A4 and may increase dapsone concentrations. However, the clinical relevance of this interaction is unknown. Monitoring for dapsone toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Desipramine is metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and desipramine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19). Concentrations of desogestrel may decrease due to in vitro induction of CYP2C9 by crizotinib, therefore increasing concentrations of etonogestrel. Furthermore, the metabolism of etonogestrel is mediated by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with desogestrel. If coadministration is unavoidable, monitor closely for etonogestrel toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and is not recommended. Dexamethasone has been described as a weak inducer of CYP3A4 and could decrease crizotinib concentrations. However, the induction of CYP3A4 by dexamethasone has not been established yet. Moreover, in non-small cell lung cancer patients (n=15), coadministration of crizotinib (150 mg twice daily) with dexamethasone (chronic use >21 days) did not decrease crizotnib exposure to a clinically relevant extent (AUC ratio = 0.98). Dexamethasone is also a substrate of CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with dexamethasone. If coadministration is unavoidable, monitor closely for dexamethasone toxicity and consider a dose reduction for dexamethasone.

Description:

See summary

Potential Interaction

Crizotinib

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Dextropropoxyphene is mainly metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with dextropropoxyphene. If coadministration is unavoidable, monitor closely for dextropropoxyphene toxicity and consider a dose reduction for dextropropoxyphene.

Description:

See summary

Potential Interaction

Crizotinib

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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). Crizotinib is an in vitro inhibitor of UGT2B7 and UGT1A1 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. Additionally, morphine is a substrate of P-gp. Crizotinib is in vitro an inhibitor of P-gp. However, no clinically relevant effect on morphine exposure is expected due to P-gp inhibition. Furthermore, crizotinib and morphine have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Concentrations of diazepam may increase due to CYP3A4 inhibition of CYP3A4 by crizotinib. Furthermore, temazepam is mainly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of temazepam. If coadministration is unavoidable, monitor closely for diazepam and temazepam toxicity and temazepam efficacy. A dose reduction for diazepam should also be considered.

Description:

See summary

Potential Weak Interaction

Crizotinib

Diclofenac

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Crizotinib is an in vitro inhibitor of UGT2B7 and may increase concentrations of diclofenac. The clinical relevance of this interaction is unknown. Monitoring for diclofenac toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp. Crizotinib is an in vitro inhibitor of P-gp and may increase concentrations of digoxin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, close monitoring for digoxin toxicity and, if available, digoxin plasma concentrations, is recommended. For administration routes other than oral, no clinically relevant interaction is expected. Furthermore, crizotinib and digoxine have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an inhibitor or CYP3A4 (moderate), UGT2B7 (in vitro) and UGT1A1 (in vitro) and may increase dihydrocodeine concentrations. No clinically relevant effect from CYP3A4 inhibition is expected, since CYP3A4 is only a minor metabolic pathway. The clinical relevance of UGT inhibition is unknown. Therefore, monitoring for dihydrocodeine toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Diltiazem is metabolised by CYP3A4 and CYP2D6. Concentrations of diltiazem may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with diltiazem. If coadministration is unavoidable, monitor closely for diltiazem toxicity and blood pressure. A dose reduction for diltiazem should also be considered. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp and will increase crizotinib concentrations. A physiologically-based pharmacokinetic simulation in healthy subjects (n=15), showed that coadministration of crizotinib (150 mg twice daily) and diltiazem (120 mg twice daily), only increased crizotinib exposure 1.1-fold relative to a control group (n=15, crizotinib only). However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and diltiazem have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Moreover, diphenhydramine is a weak inhibitor of CYP2D6. Crizotinib does not interact with this metabolic pathway. However, crizotinib and diphenhydramine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib 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

Potential Interaction

Crizotinib

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Crizotinib is a moderate inhibitor of CYP3A4 and may increase disopyramide concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on disopyramide exposure is expected. Crizotinib and disopyramide have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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%). Crizotinib is an inhibitor of CYP3A4 (moderate), UGT1A1 (in vitro) and UGT2B7 (in vitro) and may increase dolasetron concentrations. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on dolasetron exposure is expected. However, the clinical relevance of UGT1A1 and UGT2B7 inhibition is unknown. Therefore, monitoring for dolasetron toxicity may be required. Furthermore, crizotinib and dolasetron have a potential to induce bradycardia and potentially cause QTc interval prolongation. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Domperidone is mainly metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with aprepitant. If coadministration is unavoidable, monitor closely for aprepitant toxicity and consider a dose reduction for domperidone. Furthermore, crizotinib and domperidone potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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 crizotinib, or to be affected if co-administered with crizotinib.

Description:

See summary

Potential Interaction

Crizotinib

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Doxazosin is metabolised mainly by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with doxazosin. If coadministration is unavoidable, monitor closely for doxazosin toxicity and blood pressure. A dose reduction for doxazosin should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. In addition, doxepin and nordoxepin are metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2C19 or CYP2D6.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

No Interaction Expected

Crizotinib

Dronabinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase dronabinol concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on dronabinol exposure is expected. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Crizotinib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolised to a minor extent via CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on drospirenone exposure is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib 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

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6 or CYP1A2.

Description:

See summary

Potential Interaction

Crizotinib

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Dutasteride is mainly metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with dutasteride. If coadministration is unavoidable, monitor closely for dutasteride toxicity and consider a dose reduction for dutasteride.

Description:

See summary

Potential Interaction

Crizotinib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Crizotinib is a moderate inhibitor of CYP3A4 and may increase dydrogesterone concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with dydrogesterone. If coadministration is unavoidable, monitor closely for dydrogesterone toxicity.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase edoxaban concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on edoxaban exposure is expected. Crizotinib is also an in vitro inhibitor of P-gp and may increase concentrations of edoxaban. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Monitoring for edoxaban toxicity and anti-Xa activity may be required.

Description:

See summary

Potential Weak Interaction

Crizotinib

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). Crizotinib is an in vitro 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

No Interaction Expected

Crizotinib

Enalapril

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Doxycycline is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase erythromycin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with erythromycin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for erythromycin toxicity and consider a dose reduction for erythromycin. Moreover, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Crizotinib concentrations will increase due to CYP3A4 inhibition. Physiologically-based pharmacokinetic simulations in healthy subjects (n=15), showed that coadministration of crizotinib (150 mg twice daily) and erythromycin (500 mg three times daily), increased crizotinib exposure 1.6-fold relative to a control group (n=15, crizotinib only). However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and erythromycin potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of escitalopram. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with escitalopram. If coadministration is unavoidable, monitor closely for escitalopram toxicity and consider a dose reduction for escitalopram. Furthermore, crizotinib and escitalopram potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of esomeprazole. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with esomeprazole. If coadministration is unavoidable, monitor closely for esomeprazole toxicity and consider a dose reduction for esomeprazole. Esomeprazole is also an inhibitor of CYP2C19. Crizotinib is not metabolised by CYP2C19. Although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. In healthy subjects (n=16), coadministration of crizotinib (250 mg single dose) with esomeprazole (40 mg once daily for 5 days) decreased crizotinib exposure by only 10%. This is not considered to be clinically relevant.

Description:

See summary

Potential Interaction

Crizotinib

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with estazolam. If coadministration is unavoidable, monitor closely for estazolam toxicity and consider a dose reduction for estazolam.

Description:

See summary

Potential Interaction

Crizotinib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of estradiol. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with estradiol. If coadministration is unavoidable, monitor closely for estradiol toxicity.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

Potential Interaction

Crizotinib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Crizotinib is an inhibitor of CYP3A4 (moderate) and UGT1A1 (in vitro) and may increase concentrations of ethinylestradiol. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with estradiol. If coadministration is unavoidable, monitor closely for ethinylestradiol toxicity. Moreover, ethinylestradiol concentrations may decrease due to in vitro induction of CYP2C9 by crizotinib. The clinical relevance of this interaction is unknown. Although no clinically relevant effect on ethinylestradiol exposure is expected, the addition of a barrier method as a second form of contraception while taking ethinylestradiol in coadministration with crizotinib should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Etonogestrel is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with etonogestrel. If coadministration is unavoidable, monitor closely for etonogestrel toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase everolimus concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with everolimus. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for everolimus toxicity. Monitor everolimus plasma concentrations, if available, and adjust dose accordingly. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib 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

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of ezetimibe. The clinical relevance of this interaction is unknown. Monitoring for ezetimibe toxicity may be required.

Description:

See summary

No Interaction Expected

Crizotinib

Famotidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Crizotinib does not inhibit or induce OATs. Although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with famotidine.

Description:

See summary

Potential Interaction

Crizotinib

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Felodipine is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with felodipine. If coadministration is unavoidable, monitor closely for felodipine toxicity and blood pressure. A dose reduction for felodipine should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

Potential Interaction

Crizotinib

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fentanyl undergoes extensive CYP3A4 metabolism and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with fentanyl. If coadministration is unavoidable, monitor closely for fentanyl toxicity and consider a dose reduction for fentanyl. Furthermore, crizotinib and sublingual fentanyl have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

Fexofenadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fexofenadine is a substrate of P-gp. Crizotinib is in vitro an inhibitor of P-gp and may increase concentrations of fexofenadine. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for fexofenadine toxicity should be considered.

Description:

See summary

Potential Interaction

Crizotinib

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Finasteride is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with finasteride. If coadministration is unavoidable, monitor closely for finasteride toxicity and consider a dose reduction for finasteride.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Interaction

Crizotinib

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Crizotinib does not inhibit or induce CYP2D6 and is unlikely to interfere with this elimination pathway. However, crizotinib and flecainide have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration with flecainide should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs. Flucloxacillin is described as a CYP3A4 inducer and may decrease crizotinib concentrations. However, the mechanism and clinical relevance of this interaction is unknown. Monitoring of crizotinib efficacy and, if available, crizotinib plasma concentrations, may be required.

Description:

See summary

Potential Interaction

Crizotinib

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Fluconazole is cleared primarily by renal excretion. Crizotinib is unlikely to interfere with this elimination pathway. Fluconazole is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Crizotinib concentrations will increase due to CYP3A4 inhibition. Physiologically-based pharmacokinetic simulations in healthy subjects (n=15), showed that coadministration of crizotinib (150 mg twice daily) and fluconazole (200 mg once daily), increased crizotinib exposure 1.8-fold relative to a control group (n=15, crizotinib only). However, the clinical relevance of this interaction is unknown. Monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. Furthermore, crizotinib and fluconazole potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Weak Interaction

Crizotinib

Flucytosine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Crizotinib

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with fludrocortisone. If coadministration is unavoidable, monitor closely for fludrocortisone toxicity and consider a dose reduction for fludrocortisone.

Description:

See summary

Potential Interaction

Crizotinib

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of flunitrazepam. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with flunitrazepam. If coadministration is unavoidable, monitor closely for flunitrazepam toxicity and consider a dose reduction for flunitrazepam.

Description:

See summary

No Interaction Expected

Crizotinib

Fluoxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is mainly metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Crizotinib is a moderate inhibitor of CYP3A4 and may increase fluoxetine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on fluoxetine exposure is expected. Fluoxetine is also a strong inhibitor of CYP2D6 and CYP2C19. Crizotinib is not metabolised by CYP2D6 or CYP2C19.

Description:

See summary

Potential Interaction

Crizotinib

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluphenazine is metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and fluphenazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Flurazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. The metabolism of flurazepam is most likely CYP-mediated and concentrations may increase due to CYP3A4 inhibition of CYP3A4 by crizotinib. The clinical relevance of this interaction is unknown. If coadministration is unavoidable, monitor closely for flurazepam toxicity and consider a dose reduction for flurazepam.

Description:

See summary

Potential Interaction

Crizotinib

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fluticasone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with fluticasone. If coadministration is unavoidable, monitor closely for fluticasone toxicity and consider a dose reduction for fluticasone. Note: A clinically significant interaction is also unlikely with the topical use of fluticasone.

Description:

See summary

No Interaction Expected

Crizotinib

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Crizotinib is a moderate inhibitor of CYP3A4 and may increase fluvastatin concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on fluvastatin exposure is expected. Fluvastatin also potentially inhibits CYP2C9. However, the clinical relevance of CYP2C9 inhibition is unknown. Crizotinib is not metabolised by CYP2C9.

Description:

See summary

Potential Weak Interaction

Crizotinib

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and care should be taken. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Crizotinib 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 CYP2D6 (weak). Crizotinib concentrations will increase due to CYP3A4 inhibition. Physiologically-based pharmacokinetic simulations in healthy subjects (n=15), showed that coadministration of crizotinib (150 mg twice daily) and fluvoxamine (50 mg once daily) had no effect on crizotinib exposure relative to a control group (n=15, crizotinib only). However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase foromoterol concentrations. However, as multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low.

Description:

See summary

Potential Interaction

Crizotinib

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. Crizotinib does not interact with this metabolic pathway. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Crizotinib is an inhibitor of CYP3A4 and may increase aprepitant concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with aprepitant. If coadministration is unavoidable, monitor closely for aprepitant toxicity. During treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase crizotinib concentrations. Physiologically-based pharmacokinetic simulations with crizotinib and diltiazem, a moderate CYP3A4 inhibitor, increased crizotinib exposure by only 1.1-fold. A similar effect may occur after coadministration with fosaprepitant. However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity may be required. Moreover, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Crizotinib concentrations may decrease due to CYP3A4 induction. However, no clinically relevant effect on crizotinib exposure is expected.

Description:

See summary

Do Not Coadminister

Crizotinib

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Crizotinib does not interact with this metabolic pathway. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Crizotinib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Crizotinib is an in vitro substrate of P-gp and concentrations may decrease due to induction by carbamazepine. However, the clinical relevance of this interaction is unknown. Crizotinib concentrations may also decrease due to CYP3A4 induction. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with fosphenytoin. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

Furosemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). Crizotinib is an in vitro inhibitor of UGT1A1 and UGT1A9. However, no clinically relevant effect on furosemide exposure is expected. 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. In vitro data indicate that furosemide is also an inhibitor of the renal transporters OAT1/OAT3. Crizotinib does not inhibit or induce OATs and is not a substrate of OATs.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Gemfibrozil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Gemfibrozil is metabolised by UGT2B7. Crizotinib is an in vitro inhibitor of UGT2B7 and may increase concentrations of gemfibrozil. The clinical relevance of this interaction is unknown. Monitoring for gemfibrozil toxicity may be required. 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. Crizotinib concentrations may increase due to OATP1B1 inhibition. The clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Crizotinib is an in vitro inducer of CYP2C9. However, no clinically relevant effect from CYP2C9 induction is expected. Although no clinically relevant effect on gestodene exposure is expected, the addition of a barrier method as a second form of contraception while taking gestodene in combination with crizotinib should be considered. Crizotinib is also a moderate inhibitor of CYP3A4 and may increase concentrations of gestodene. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with gestodene. If coadministration is unavoidable, monitor closely for gestodene toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Glibenclamide concentration may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with glibenclamide. If coadministration is unavoidable, monitor closely for glibenclamide toxicity, blood glucose levels and consider a dose reduction for glibenclamide.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9 or CYP2C19.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase granisetron concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with granisetron. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for granisetron toxicity and consider a dose reduction for granisetron. Furthermore, crizotinib and granisetron potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Do Not Coadminister

Crizotinib

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 crizotinib concentrations. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with grapefruit juice. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Interaction

Crizotinib

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Crizotinib is unlikely to interfere with this metabolic or elimination pathway. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolised by CYPs, such as crizotinib. The clinical relevance of this interaction is unknown. A decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, monitor closely for crizotinib efficacy and, if available, crizotinib plasma concentrations. A dose increment for crizotinib may also be necessary.

Description:

See summary

Potential Interaction

Crizotinib

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Crizotinib is an inhibitor of CYP3A4 (moderate) and in vitro of UGTs 2B7, 1A4 and 1A9 and may increase haloperidol concentrations. If coadministration is unavoidable, monitor closely for haloperidol toxicity and consider a dose reduction for haloperidol. Furthermore, crizotinib and haloperidol potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib 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. Crizotinib concentrations may increase due to CYP3A4 inhibition. However, the clinical relevance of this interaction is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Crizotinib

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. 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. Crizotinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Crizotinib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Hydrocodone concentrations may increase due to CYP3A4 inhibition of CYP3A4 by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with hydrocodone. If coadministration is unavoidable, monitor closely for hydrocodone toxicity and consider a dose reduction for hydrocodone.

Description:

See summary

Potential Interaction

Crizotinib

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Hydrocortisone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with hydrocortisone. If coadministration is unavoidable, monitor closely for hydrocortisone toxicity and consider a dose reduction for hydrocortisone.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Weak Interaction

Crizotinib

Hydromorphone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7. Crizotinib is an in vitro inhibitor of UGT2B7 and may increase concentrations of hydromorphone. The clinical relevance of this interaction is unknown. Monitoring for hydromorphone toxicity may be required.

Description:

See summary

Potential Weak Interaction

Crizotinib

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Crizotinib

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase hydroxyzine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on hydroxyzine exposure is expected. However, crizotinib and hydroxyzine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway. Although no pharmacokinetic interaction is expected, ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT2B7 and 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

Potential Interaction

Crizotinib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Iloperidone is metabolised by CYP3A4 and CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of iloperidone. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with iloperidone. If coadministration is unavoidable, monitor closely for iloperidone toxicity and consider a dose reduction for iloperidone. Furthermore, crizotinib and iloperidone potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of imipramine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with escitalopram. If coadministration is unavoidable, monitor closely for imipramine toxicity and consider a dose reduction for imipramine. Furthermore, crizotinib and imipramine potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Indapamide is extensively metabolised by CYP450s. Crizotinib is a moderate inhibitor of CYP3A4 and may increase indapamide concentrations. However, as multiple CYP450s may be involved in metabolism the clinical relevance of this interaction is unknown. Monitoring for indapamide toxicity and blood pressure may be required. 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. Crizotinib does not inhibit or induce OATs. Furthermore, crizotinib and indapamide potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Weak Interaction

Crizotinib

Interferon alpha

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Crizotinib

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Irbesartan

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with isosorbide dinitrate. If coadministration is unavoidable, monitor closely for isosorbide dinitrate toxicity and blood pressure. A dose reduction for isosorbide dinitrate should also be considered.

Description:

See summary

Do Not Coadminister

Crizotinib

Itraconazole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be avoided. Itraconazole is primarily metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with itraconazole. If coadministration is unavoidable, monitor closely for itraconazole toxicity and consider a dose reduction for itraconazole. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Crizotinib concentrations will increase due to CYP3A4 and P-gp inhibition by itraconazole. In advanced cancer patients (n=18), coadministration of crizotinib (250 mg single dose) and itraconazole (200 mg single dose) increased crizotinib exposure by 57%. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should also be considered.

Description:

See summary

Potential Interaction

Crizotinib

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ivabradine is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ivabradine. If coadministration is unavoidable, monitor closely for ivabradine toxicity and blood pressure. A dose reduction for ivabradine should also be considered. Furthermore, crizotinib and ivabradine have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Do Not Coadminister

Crizotinib

Ketoconazole

Quality of Evidence: Moderate

Summary:

Coadministration has been studied and should be avoided. Ketoconazole is a substrate of CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ketoconazole. If coadministration is unavoidable, monitor closely for ketoconazole toxicity and consider a dose reduction for ketoconazole. Ketoconazole is also an inhibitor of CYP3A4 (strong) and P-gp and will increase crizotinib exposure. In healthy subjects (n=15), coadministration of crizotinib (150 mg single dose) and ketoconazole (200 mg twice daily) increased crizotinib exposure 3.2-fold relative to crizotinib alone. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should also be considered. Furthermore, crizotinib and ketoconazole potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Weak Interaction

Crizotinib

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). Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 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 Interaction

Crizotinib

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Lacidipine is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with lacidipine. If coadministration is unavoidable, monitor closely for lacidipine toxicity and blood pressure. A dose reduction for lacidipine should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase lansoprazole concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on lansoprazole exposure is expected. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with lansoprazole.

Description:

See summary

Potential Interaction

Crizotinib

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Lercanidipine is mainly metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. , After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with lercanidipine. If coadministration is unavoidable, monitor closely for lercanidipine toxicity and blood pressure. A dose reduction for lercanidipine should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

Potential Interaction

Crizotinib

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Concentrations may increase due to in vitro inhibition of OCT2 by crizotinib. The clinical relevance of this interaction is unknown. Monitoring for levofloxacin toxicity may be required. Furthermore, crizotinib and levofloxacin potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levomepromazine is metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and levomepromazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levonorgestrel mainly is metabolised by CYP3A4 and is glucuronidated to a minor extent. Crizotinib is an inhibitor of CYP3A4 (moderate), UGT1A1 (in vitro) and UGT2B7 (in vitro) and may increase levonorgestrel concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with levonorgestrel. If coadministration is unavoidable, monitor closely for levonorgestrel toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of levothyroxine. The clinical relevance of this interaction is unknown. Monitoring for levothyroxine toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase lidocaine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on lidocaine exposure is expected. Crizotinib and lidocaine have a potential to induce bradycardia. Therefore, coadministration with lidocaine should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase linagliptin concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on linagliptin exposure is expected. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for linagliptin toxicity and blood glucose levels may be required. Linagliptin is also a weak inhibitor of CYP3A4 and may increase crizotinib concentrations. However, no clinically relevant effect on crizotinib exposure is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this unspecified metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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. Crizotinib and lithium have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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 but based on metabolism and clearance a clinically significant interaction is unlikely. In patients, who are receiving cytotoxics or other immunosuppressant drugs, use of live vaccines for immunisation is contraindicated. However, since crizotinib is not an immunosuppressant drug, no additional unwanted effects are expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Concentrations of loperamide may increase due to inhibition of CYP3A4 (moderate) and P-gp (in vitro) by crizotinib. However, since loperamide has a very broad therapeutic index, no clinically relevant effect on loperamide exposure is expected.

Description:

See summary

Potential Interaction

Crizotinib

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Crizotinib may increase loratadine concentrations due to CYP3A4 inhibition. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with loratadine. If coadministration is unavoidable, monitor closely for loratadine toxicity and consider a dose reduction for loratadine.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this unspecified metabolic pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Lormetazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lormetazepam is mainly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A4 and UGT2B7 and may 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

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Lovastatin is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with lovastatin. If coadministration is unavoidable, monitor closely for lovastatin toxicity and consider a dose reduction for lovastatin.

Description:

See summary

Potential Interaction

Crizotinib

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Crizotinib is an inhibitor of CYP3A4 and may increase macitentan concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with macitentan. If coadministration is unavoidable, monitor closely for macitentan toxicity and blood pressure. A dose reduction for macitentan should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Crizotinib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Medroxyprogesterone is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with levonorgestrel. If coadministration is unavoidable, monitor closely for medroxyprogesterone toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Medroxyprogesterone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with levonorgestrel. If coadministration is unavoidable, monitor closely for medroxyprogesterone toxicity.

Description:

See summary

Potential Weak Interaction

Crizotinib

Mefenamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Crizotinib is an in vitro inhibitor of UGT2B7 and UGT1A9 and may increase concentrations of mefenamic acid. The clinical relevance of this interaction is unknown. Monitoring for mefenamic acid toxicity may be required.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Meropenem

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

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%). Crizotinib is unlikely to interfere with this metabolic or elimination pathway. Metamizole is an inducer of CYP3A4 and may decrease crizotinib concentrations. The clinical relevance of this interaction is unknown. A decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, monitor closely for crizotinib efficacy and, if available, crizotinib plasma concentrations. A dose increment for crizotinib may be necessary.

Description:

See summary

Potential Weak Interaction

Crizotinib

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 substrate of OCT1, OCT2, OCT3, MATE1 and MATE2K. Concentrations may increase due to in vitro inhibition of OCT1 and OCT2 by crizotinib. The clinical relevance of this interaction is unknown. Therefore, monitoring for metformin toxicity and blood glucose levels may be required.

Description:

See summary

Potential Interaction

Crizotinib

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Methadone is demethylated by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with methadone. If coadministration is unavoidable, monitor closely for methadone toxicity and consider a dose reduction for methadone. Furthermore, crizotinib and methadone potentially cause QTc interval prolongation. Therefore, close ECG monitoring is also recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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 crizotinib, or to be affected if co-administered with crizotinib.

Description:

See summary

Potential Interaction

Crizotinib

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Methylprednisolone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with methylprednisolone. If coadministration is unavoidable, monitor closely for methylprednisolone toxicity and consider a dose reduction for methylprednisolone.

Description:

See summary

No Interaction Expected

Crizotinib

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 CYP450 system (mainly CYP2D6). Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Crizotinib

Metolazone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Crizotinib

Metoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metoprolol is mainly metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and metoprolol have a potential to induce bradycardia. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

Metronidazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metronidazole is eliminated via glomerular filtration. Crizotinib 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 crizotinib cannot be excluded. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required.

Description:

See summary

Potential Interaction

Crizotinib

Mexiletine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent CYP1A2. Crizotinib does not inhibit or induce CYP2D6 or CYP1A2. However, crizotinib and mexiletine have a potential to induce bradycardia. Therefore, coadministration with mexiletine should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mianserin is metabolised by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase mianserin concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on mianserin exposure is expected. Crizotinib does not inhibit or induce CYP2D6 or CYP1A2.

Description:

See summary

Do Not Coadminister

Crizotinib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Miconazole is extensively metabolized by the liver. Crizotinib is unlikely to interfere with this unspecified metabolic pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Crizotinib concentrations may increase due to CYP3A4 inhibition. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with miconazole, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should also be considered. Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinical relevant interaction is expected.

Description:

See summary

Potential Interaction

Crizotinib

Midazolam (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and should be approached with caution. Midazolam is metabolised by CYP3A4 and concentrations will increase due to inhibition by crizotinib. In advanced cancer patients (n=12) coadministration of midazolam (2 mg single oral dose) and crizotinib (250 mg oral twice daily for 28 days) increased midazolam exposure 3.7-fold compared to midazolam alone. If coadministration is unavoidable, monitor closely for midazolam toxicity and consider a dose reduction for midazolam.

Description:

See summary

Potential Interaction

Crizotinib

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Description:

See summary

Potential Weak Interaction

Crizotinib

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%). Crizotinib is an in vitro inhibitor of UGT1A1 or UGT2B7 and may increase concentrations of milnacipran. The clinical relevance of this interaction is unknown. Monitoring for milnacipran toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of mirtazapine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with mirtazapine. If coadministration is unavoidable, monitor closely for mirtazapine toxicity and consider a dose reduction for mirtazapine.

Description:

See summary

Potential Interaction

Crizotinib

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Mometasone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with mometasone. If coadministration is unavoidable, monitor closely for mometasone toxicity and consider a dose reduction for mometasone. Note: No clinically relevant interaction are expected with the topical use of mometasone.

Description:

See summary

No Interaction Expected

Crizotinib

Montelukast

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase montelukast concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on montelukast exposure is expected. Crizotinib does not inhibit or induce CYP2C8 or CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Crizotinib is an in vitro inhibitor of UGT2B7 and UGT1A1 and may increase concentrations of morphine. The clinical relevance of this interaction is unknown. Morphine is also a substrate of P-gp and concentrations may further be increased due to in vitro inhibition by crizotinib. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Monitoring for morphine toxicity should be considered. Furthermore, crizotinib and morphine have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Do Not Coadminister

Crizotinib

Moxifloxacin

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Moxifloxacin is predominantly glucuronidated by UGT1A1 and concentrations may increase due to in vitro inhibition by crizotinib. The clinical relevance of this interaction is unknown. Monitoring for moxiflocacin toxicity may be required. Moreover, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as crizotinib. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Weak Interaction

Crizotinib

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Crizotinib is an in vitro inhibitor of UGT1A9 and UGT2B7 and may increase concentrations of mycophenolate. The clinical relevance of this interaction is unknown. Monitoring for mycophenolate toxicity may be required. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3. Crizotinib is not a substrate of OATs. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Naproxen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Crizotinib is an in vitro inhibitor of UGT2B7 and may increase concentrations of naproxen. The clinical relevance of this interaction is unknown. Monitoring for naproxen toxicity may be required.

Description:

See summary

No Interaction Expected

Crizotinib

Nateglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Crizotinib is a moderate inhibitor of CYP3A4 and may increase nateglinide concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on nateglinide exposure is expected. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Nebivolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nebivolol metabolism involves CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and nebivolol have a potential to induce bradycardia. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Do Not Coadminister

Crizotinib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nefazodone is metabolised mainly by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with nefazodone. If coadministration is unavoidable, monitor closely for nefazodone toxicity and consider a dose reduction for nefazodone. Moreover, nefazodone is a strong inhibitor of CYP3A4 and may increase crizotinib concentrations. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with nefazodone, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should be considered.

Description:

See summary

Potential Interaction

Crizotinib

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Nicardipine concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with nicardipine. If coadministration is unavoidable, monitor closely for nicardipine toxicity and blood pressure. A dose reduction for nicardipine should also be considered. Nicardipine is also a weak inhibitor of CYP3A4 and may increase crizotinib concentrations. However, no clinically relevant effect on crizotinib exposure is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nifedipine is metabolised mainly by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with nifedipine. If coadministration is unavoidable, monitor closely for nifedipine toxicity and blood pressure. A dose reduction for nifedipine should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nisoldipine is metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with nisoldipine. If coadministration is unavoidable, monitor closely for nisoldipine toxicity and blood pressure. A dose reduction for nisoldipine should also be considered.

Description:

See summary

Potential Interaction

Crizotinib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nitrendipine is extensively metabolised mainly by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with nitrendipine. If coadministration is unavoidable, monitor closely for nitrendipine toxicity and blood pressure. A dose reduction for nitrendipine should also be considered.

Description:

See summary

Potential Weak Interaction

Crizotinib

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%). Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of nitrofurantoin. The clinical relevance of this interaction is unknown. Monitoring for nitrofurantoin toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Crizotinib is a moderate inhibitor of CYP3A4 and may increase norelgestromin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with norelgestromin. If coadministration is unavoidable, monitor closely for norelgestromin toxicity.

Description:

See summary

Potential Weak Interaction

Crizotinib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Norethindrone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of norethindrone. The clinical relevance of this interaction is unknown. Monitoring for norethinderone toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450s. Crizotinib is an in vitro inducer of CYPs 2C9, 2C8 and 2B6 and may increase concentrations of norgestimate. Although no clinically relevant effect on norgestimate exposure is expected, the addition of a barrier method as a second form of contraception while taking norgestimate in combination with crizotinib should be considered. Crizotinib is also a moderate inhibitor of CYP3A4 and may increase concentrations of norgestimate. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with norgestimate. If coadministration is unavoidable, monitor closely for norgestimate toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolized by CYP3A4 and is glucuronidated to a minor extent. Crizotinib is an inhibitor of CYP3A4 (moderate), UGT1A1 (in vitro) and UGT2B7 (in vitro) and may increase levonorgestrel concentrations. The clinical relevance of UGT1A1 and UGT2B7 inhibition is unknown. However, after coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with norgestrel. If coadministration is unavoidable, monitor closely for levonorgestrel toxicity.

Description:

See summary

Potential Interaction

Crizotinib

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nortriptyline is metabolised mainly by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and nortriptyline have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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

Potential Interaction

Crizotinib

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Crizotinib is unlikely to interfere with this elimination pathway. However, crizotinib and ofloxacin potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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). Crizotinib is an in vitro inhibitor of UGT1A4 and may increase concentrations of olanzapine. The clinical relevance of this interaction is unknown. However, no clinically relevant effect on olanzapine is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Omeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase omeprazole concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on omeprazole exposure is expected. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Crizotinib is not metabolised by CYP1A2 or CYP2C19. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with omeprazole.

Description:

See summary

Potential Interaction

Crizotinib

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Additionally, ondansetron is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase ondansetron concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ondansetron. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for ondansetron toxicity and consider a dose reduction for ondansetron. Furthermore, crizotinib and ondansetron potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Weak Interaction

Crizotinib

Oxazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxazepam is mainly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of oxazepam. The clinical relevance of this interaction is unknown. Monitoring for oxazepam toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Oxcarbazepine is extensively metabolized to the active metabolite monohydroxyderivate (MHD) through cytosolic enzymes. Crizotinib does not interact with this metabolic pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Crizotinib concentrations may decrease due to CYP3A4 induction. The clinical relevance of this interaction is unknown. A decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, monitor closely for crizotinib efficacy and, if available, crizotinib plasma concentrations. A dose increment for crizotinib may also be necessary.

Description:

See summary

Potential Weak Interaction

Crizotinib

Oxprenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxprenolol is largely metabolised via glucuronidation. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of oxprenolol. The clinical relevance of this interaction is unknown. Monitoring for oxprenolol toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase oxycodone concentrations and alter oxymorphone concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with oxycodone. If coadministration is unavoidable, monitor closely for oxycodone toxicity and consider a dose reduction for oxycodone.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4 (moderate) and in vitro of OCT1 and OCT2 and may increase paliperidone concentrations. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on paliperidone exposure is expected. However, the clinical relevance of OCT inhibition is unknown. Therefore, monitoring for paliperidone toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Additionally, palonosetron is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase palonosetron concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with palonosetron. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for palonosetron toxicity and consider a dose reduction for palonosetron.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase pantoprazole concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on pantoprazole exposure is expected. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with pantoprazole.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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) and sulfation and, to a lesser extent, by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Crizotinib is an inhibitor of CYP3A4 (moderate), UGT1A1 (in vitro) and UGT1A9 (in vitro). No clinically relevant effect from CYP3A4 and UGT1A1 inhibition is expected, since these are minor metabolic pathways. The clinical relevance of UGT1A9 inhibition by crizotinib is unknown, therefore no clinically relevant effect on paracetamol exposure is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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. Moreover, paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Crizotinib

Penicillins

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Crizotinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Crizotinib

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of perazine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with perazine. If coadministration is unavoidable, monitor closely for perazine toxicity and consider a dose reduction for perazine.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Perphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Perphenazine is metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and perphenazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase pethidine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on pethidine exposure is expected.

Description:

See summary

No Interaction Expected

Crizotinib

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 acetylation. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Do Not Coadminister

Crizotinib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenobarbital is metabolized by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Crizotinib does not inhibit or induce these CYPs. Phenobarbital is a strong inducer of CYP3A4, CYP2C9, CYP2C8 and UGTs. Crizotinib concentrations may decrease due to CYP3A4 induction. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with phenobarbital. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

Potential Interaction

Crizotinib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase phenprocoumon concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with phenprocoumon. If coadministration is unavoidable, monitor closely for phenprocoumon toxicity and consider a dose reduction for phenprocoumon. Furthermore, one case report describes an increased PT and INR after coadministration of crizotinib and warfarin. A similar effect may occur after coadministration with phenprocoumon. The clinical relevance of this interaction is unknown. Monitoring for INR/PT may also be required.

Description:

See summary

Do Not Coadminister

Crizotinib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Crizotinib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Crizotinib is an in vitro substrate of P-gp and concentrations may decrease due to induction by carbamazepine. However, the clinical relevance of this interaction is unknown. Crizotinib concentrations may also decrease due to CYP3A4 induction. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with phenytoin. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP4F2.

Description:

See summary

Do Not Coadminister

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of pimozide. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with pimozide. Moreover, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as crizotinib. Therefore, coadministration is contraindicated.

Description:

See summary

Potential Interaction

Crizotinib

Pindolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Crizotinib does not inhibit or induce CYP2D6 and is unlikely to interfere with this elimination pathway. However, crizotinib and pindolol have a potential to induce bradycardia. Therefore, coadministration with should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

Pioglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase pioglitazone concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on pioglitazone exposure is expected. Crizotinib does not inhibit or induce CYPs 2C8, 1A2 or 2C9.

Description:

See summary

Potential Interaction

Crizotinib

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and pipotiazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT2B7 and may increase concentrations of pitavastatin. The clinical relevance of this interaction is unknown. Monitoring for pitavastatin toxicity may be required. Pitavastatin is also a substrate of OATP1B1. Crizotinib does not inhibit or induce OATP1B1.

Description:

See summary

Do Not Coadminister

Crizotinib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Crizotinib is an in vitro inhibitor of UGT1A1, UGT2B7 and P-gp and may increase concentrations of posaconazole. The clinical relevance of UGT inhibition and of the local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract are unknown. Therefore, close monitoring for posaconazole toxicity is recommended. Posaconazole is also a strong inhibitor of CYP3A4 and may increase crizotinib concentrations. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with posaconazole, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should also be considered. Furthermore, crizotinib and posaconazole potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of prasugrel. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with prasugrel. If coadministration is unavoidable, monitor closely for prasugrel toxicity and thrombocytes aggregation test. A dose reduction for prasugrel should also be considered. Furthermore, crizotinib and prasugrel have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

Pravastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Prednisolone undergoes hepatic metabolism via CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with prednisolone. If coadministration is unavoidable, monitor closely for prednisolone toxicity and consider a dose reduction for prednisolone.

Description:

See summary

Potential Interaction

Crizotinib

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with prednisone. If coadministration is unavoidable, monitor closely for prednisone toxicity and consider a dose reduction for prednisone.

Description:

See summary

No Interaction Expected

Crizotinib

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). Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Crizotinib

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Crizotinib does not inhibit or induce CYP2D6 or CYP2C19. However, crizotinib and prochlorperazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Promethazine is metabolised by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and promethazine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase propafenone concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on propafenone exposure is expected. Crizotinib and propafenone have a potential to induce bradycardia. Therefore, coadministration with propafenone should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

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). Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of propranolol. The clinical relevance of this interaction is unknown. Monitoring for propranolol toxicity may be required.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizontinib is unlikely to interfere with this elimination pathway. Prucalopride is also a substrate of P-gp. Crizotinib is in vitro an inhibitor of P-gp and may increase concentrations of prucaloopride. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for prucalopride toxicity should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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 Interaction

Crizotinib

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Quetiapine is primarily metabolised by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with quetiapine. If coadministration is unavoidable, monitor closely for quetiapine toxicity and consider a dose reduction for quetiapine.

Description:

See summary

No Interaction Expected

Crizotinib

Quinapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quinapril is de-esterified to the active metabolite quinaprilat which is eliminated primarily by renal excretion via OAT3. Crizotinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Crizotinib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase quinidine concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with quinidine. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for quinidine toxicity and consider a dose reduction for quinidine. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Crizotinib concentrations may increase due to CYP3A4 and P-gp inhibition. No clinically relevant effect from CYP3A4 inhibition is expected. However, the clinical relevance of P-gp inhibition is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and quinidine have a potential to induce bradycardia and potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase rabeprazole concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on rabeprazole exposure is expected. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with rabeprazole.

Description:

See summary

No Interaction Expected

Crizotinib

Ramipril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Crizotinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Ranitidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Crizotinib does not inhibit or induce OATs. Furthermore, although the aqueous solubility of crizotinib is pH dependent, no clinically significant effect of gastric pH increasing drugs on crizotinib exposure is expected. Crizotinib exposure decreased by only 10% after coadministration with the proton-pump inhibitor esomeprazole. A similar effect may occur after coadministration with ranitidine.

Description:

See summary

Potential Interaction

Crizotinib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase ranolazine concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ranolazine. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for ranolazine toxicity and blood pressure. A dose reduction for ranolazine should also be considered. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Crizotinib concentrations may increase due to CYP3A4 and P-gp inhibition by ranolazine. However, no clinically relevant effect from CYP3A4 inhibition is expected. The clinical relevance of P-gp inhibition is unknown. Monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and ranolazine have a potential to induce bradycardia and potentially cause QTc interval prolongation. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Reboxetine is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with reboxetine. If coadministration is unavoidable, monitor closely for reboxetine toxicity and consider a dose reduction for reboxetine. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. Crizotinib is metabolised by CYP3A4 but no clinically relevant effect on exposure due to inhibition by reboxetine is expected.

Description:

See summary

Potential Interaction

Crizotinib

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Crizotinib does not inhibit or induce CYP2C8 or OATP1B1. However, crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of repaglinide. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with repaglinide. If coadministration is unavoidable, monitor closely for repaglinide toxicity, blood glucose levels and consider a dose reduction for repaglinide should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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

Crizotinib

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifabutin is metabolised by CYP3A and via deacetylation. Rifabutin concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with rifabutin. Rifabutin is also a strong CYP3A4 and P-gp inducer and may decrease crizotinib exposure. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with rifabutin. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Crizotinib

Rifampicin

Quality of Evidence: Moderate

Summary:

Coadministration has been studied and is contraindicated. Rifampicin is metabolised via deacetylation. Crizotinib does not interact with this metabolic pathway. Rifampicin is also a strong CYP3A4 and P-gp inducer and will decrease crizotinib exposure. In healthy subjects (n=15), coadministration of crizotinib (250 mg single dose) and rifampicin (600 mg single dose) caused crizotinib exposure to decrease by 84-94%. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Crizotinib

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifapentine is metabolised via deacetylation. Crizotinib does not interact with this metabolic pathway. Rifapentine is also a strong CYP3A4, CYP2C8 and P-gp inducer. Rifapentine may decrease crizotinib exposure due to CYP3A4 and P-gp induction. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with rifapentine. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib can sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase risperidone concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on risperidone exposure is expected due to CYP3A4 inhibition. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for risperidone toxicity may be required. For administration routes other than oral, no clinically relevant interaction is expected.

Description:

See summary

Do Not Coadminister

Crizotinib

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contra-indicated. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Moreover, rivaroxaban is substrate of P-gp and BCRP. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase rivaroxaban concentrations. Any increase in exposure of rivaroxaban increases toxicity, therefore coadministration is conta-indicated.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C8 or CYP2C9.

Description:

See summary

No Interaction Expected

Crizotinib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is substrate of BCRP. Crizotinib does not inhibit or induce OATP1B1 or BCRP.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase salmeterol concentrations. However, the systemic exposure of salmeterol is low, therefore, no clinically relevant effect on salmeterol exposure is expected.

Description:

See summary

Potential Interaction

Crizotinib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase saxagliptin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with saxagliptin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for saxagliptin toxicity, blood glucose levels and consider a dose reduction for saxagliptin.

Description:

See summary

No Interaction Expected

Crizotinib

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

Crizotinib

Sertindole

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of sertindole. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with sertindole. Moreover, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as crizotinib. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

Sertraline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Crizotinib is a moderate inhibitor of CYP3A4 and may increase sertraline concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on sertraline exposure is expected. Crizotinib does not inhibit or induce CYPs 2C9, 2C19 or 2D6.

Description:

See summary

Potential Interaction

Crizotinib

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Crizotinib is an inhibitor of CYP3A4 and may increase sildenafil concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with sildenafil. If coadministration is unavoidable, monitor closely for sildenafil toxicity and blood pressure. A dose reduction for sildenafil should also be considered.

Description:

See summary

Potential Interaction

Crizotinib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Simvastatin is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with simvastatin. If coadministration is unavoidable, monitor closely for simvastatin toxicity and consider a dose reduction for simvastatin. Simvastatin is also a substrate of BCRP and the active metabolite is a substrate of OATP1B1. Crizotinib does not inhibit or induce BCRP or OATP1B1.

Description:

See summary

Potential Interaction

Crizotinib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Sirolimus is metabolised by CYP3A4 and is substrate of P-gp. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase sirolimus concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with sirolimus. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for sirolimus toxicity. Monitor sirolimus plasma concentrations, if available, and adjust dose accordingly. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase sitagliptin concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on sitagliptin exposure is expected due to CYP3A4 inhibition. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for sitagliptin toxicity and blood glucose levels should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Sotalol

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be approached with caution. Sotalol is excreted unchanged via renal elimination. Crizotinib is unlikely to interfere with this elimination pathway. The product labels for sotalol advise extreme caution if given with other drugs that potentially prolong the QT interval, such as crizotinib. Crizotinib and sotalol also have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for ECG, heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this unspecified metabolic pathway.

Description:

See summary

Do Not Coadminister

Crizotinib

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 crizotinib concentrations. After coadministration with rifampicin, a strong CYP3A4 inducer, crizotinib exposure decreased by 84-94%. A similar effect may occur after coadministration with St John’s Wort. A decrease in exposure can lead to decreased efficacy. It is unknown whether a dose increment for crizotinib sufficiently compensate for the loss of exposure. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Crizotinib

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

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Crizotinib is unlikely to interfere with this elimination pathway. However, crizotinib and sulpiride potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tacrolimus is metabolised mainly by CYP3A4 and concentrations may increase due to inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with tacrolimus. If coadministration is unavoidable, monitor closely for tacrolimus toxicity. Monitor tacrolimus plasma concentrations, if available, and adjust dose accordingly. 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 crizotinib exposure is expected. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

Potential Interaction

Crizotinib

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tadalafil is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib, After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with tadalafil. If coadministration is unavoidable, monitor closely for tadalafil toxicity and consider a dose reduction for tadalafil.

Description:

See summary

Potential Interaction

Crizotinib

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Crizotinib is an inhibitor of CYP3A4 and may increase tamsulosin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with tamsulosin. If coadministration is unavoidable, monitor closely for tamsulosin toxicity and consider a dose reduction for tamsulosin.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Do Not Coadminister

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase telithromycin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with telithromycin. If coadministration is unavoidable, monitor closely for telithromycin toxicity and consider a dose reduction for telithromycin. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp and may increase crizotinib concentrations. The clinical relevance of P-gp inhibition is unknown. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with telithromycin, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce UGT1A3.

Description:

See summary

Potential Weak Interaction

Crizotinib

Temazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Temazepam is mainly glucuronidated. Crizotinib is an in vitro inhibitor of UGT1A4 and UGT2B7 and may increase concentrations of temazepam. The clinical relevance of this interaction is unknown. Monitoring for temazepam toxicity may be required.

Description:

See summary

Potential Interaction

Crizotinib

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Crizotinib is a moderate inhibitor of CYP3A4 and may increase concentrations of terbinafine. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with terbinafine. If coadministration is unavoidable, monitor closely for terbinafine toxicity and consider a dose reduction for terbinafine. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Crizotinib is not metabolised by CYP2D6.

Description:

See summary

Potential Interaction

Crizotinib

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Testosterone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with testosterone. If coadministration is unavoidable, monitor closely for testosterone toxicity and consider a dose reduction for testosterone.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP1A2.

Description:

See summary

No Interaction Expected

Crizotinib

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

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase thioridazine concentrations. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on thioridazine exposure is expected. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as crizotinib.

Description:

See summary

Potential Interaction

Crizotinib

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tiapride is excreted largely unchanged in urine. Crizotinib is unlikely to interfere with this elimination pathway. However, crizotinib and tiapride potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ticagrelor is a substrate and of CYP3A4 and P-gp. Ticagrelor is also a weak inhibitor of CYP3A4. Crizotinib is an inhibitor of CYP3A4 (moderate) and P-gp (in vitro) and may increase ticagrelor concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ticagrelor. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. If coadministration is unavoidable, monitor closely for ticagrelor toxicity and consider a dose reduction for ticagrelor. Furthermore, crizotinib and ticagrelor have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Interaction

Crizotinib

Timolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Timolol is predominantly metabolised in the liver by CYP2D6. Crizotinib does not inhibit or induce CYP2D6. However, crizotinib and timolol have a potential to induce bradycardia. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment. Note: the systemic absorption of timolol after ocular administration is low. Therefore, a clinically relevant interaction via CYP2D6 is unlikely.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYPs 2C9, 2C8 or 2C19.

Description:

See summary

Potential Interaction

Crizotinib

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Crizotinib is a moderate inhibitor of CYP3A4 and may increase tolterodine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on tolterodine exposure is expected. However, crizotinib and tolterodine potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

No Interaction Expected

Crizotinib

Torasemide

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Crizotinib

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Crizotinib is a moderate inhibitor of CYP3A4 and may increase tramadol concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with tramadol. If coadministration is unavoidable, monitor closely for tramadol toxicity and consider a dose reduction for tramadol.

Description:

See summary

Potential Interaction

Crizotinib

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Trandolapril is hydrolysed to trandolaprilat. Crizotinib does not interact with this metabolic pathway. However, crizotinib and trandolapril have a potential to induce bradycardia. Therefore, coadministration with trandolapril should be approached with caution. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Crizotinib

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Trazodone is primarily metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with trazodone. If coadministration is unavoidable, monitor closely for trazodone toxicity and consider a dose reduction for trazodone. Furthermore, crizotinib and trazodone potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Triamcinolone is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with triamcinolone. If coadministration is unavoidable, monitor closely for triamcinolone toxicity and consider a dose reduction for triamcinolone.

Description:

See summary

Potential Interaction

Crizotinib

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Triazolam is metabolised by CYP3A4 and concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with triazolam. If coadministration is unavoidable, monitor closely for triazolam toxicity and consider a dose reduction for triazolam.

Description:

See summary

No Interaction Expected

Crizotinib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 CYP3A4, CYP1A2 and CYP2C9). Crizotinib is a moderate inhibitor of CYP3A4 and may increase trimethoprim concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on trimethroprim exposure is expected. Sulfamethoxazole is metabolised by CYP2C9. Crizotinib does not inhibit or induce CYP2C9. 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. Crizotinib is not a substrate of these CYPs, OCT2 or MATE1.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Crizotinib

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tropisetron is metabolised mainly by CYP2D6. Additionally, tropisetron is a substrate of P-gp. Crizotinib is an in vitro inhibitor of P-gp and may increase concentrations of tropisetron. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. For administration routes other than oral, no clinically relevant interaction is expected. However, crizotinib and tropisetron potentially cause QTc interval prolongation. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent CYP1A2 and CYP2D6. Crizotinib is an inhibitor of CYP3A4 and may increase ulipristal concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with ulipristal. If coadministration is unavoidable, monitor closely for uliupristal toxicity.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is an in vitro inhibitor of UGT1A1 and UGT2B7 and may increase concentrations of valproic acid. The clinical relevance of this interaction is unknown. Monitoring for valproic acid toxicity may be required. Valproic acid is also an inhibitor of CYP2C9. Crizotinib is not metabolised by CYP2C9.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Crizotinib

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Crizotinib is a moderate inhibitor of CYP3A4 and may increase venlafaxine concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on venlafaxine exposure is expected. Crizotinib does not inhibit or induce CYP2C19 or CYP2C9.

Description:

See summary

Potential Interaction

Crizotinib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Verapamil concentrations may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with verapamil. If coadministration is unavoidable, monitor closely for verapamil toxicity and blood pressure. A dose reduction for verapamil should also be considered. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong) and may increase crizotinib concentrations. Physiologically-based pharmacokinetic simulations with crizotinib and diltiazem, a moderate CYP3A4 inhibitor, increased crizotinib exposure by only 1.1-fold. A similar effect may occur after coadministration with verapamil. However, the clinical relevance of this interaction is unknown. Therefore, monitoring for crizotinib toxicity and, if available, crizotinib plasma concentrations may be required. Furthermore, crizotinib and verapamil have a potential to induce bradycardia. If coadministration is unavoidable, monitor closely for heart rate and blood pressure. The full effect of crizotinib on reduction of heart rate may not develop until several weeks after the start of treatment.

Description:

See summary

Potential Weak Interaction

Crizotinib

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. Crizotinib is in vitro an inhibitor of P-gp and may increase concentrations of vildagliptin. The local effect of crizotinib on P-gp inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for vildagliptin toxicity should be considered.

Description:

See summary

No Interaction Expected

Crizotinib

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

Crizotinib

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. Crizotinib is a moderate inhibitor of CYP3A4 and may increase voriconazole concentrations. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on voriconazole exposure is expected. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Crizotinib concentrations may increase due to CYP3A4 inhibition by voriconazole. After coadministration with ketoconazole and itraconazole, two strong CYP3A4 inhibitors, crizotinib exposure increased approximately 3.2-fold and 1.6-fold respectively. Similar effects may occur after coadministration with voriconazole, therefore coadministration should be avoided. If coadministration is unavoidable, monitor closely for crizotinib toxicity and, if available, crizotinib plasma concentrations. A dose reduction up to 50% for crizotinib should also be considered. Furthermore, crizotinib and voriconazole potentially cause QTc interval prolongation. If coadministration is unavoidable, close ECG monitoring is recommended.

Description:

See summary

Potential Interaction

Crizotinib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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. Crizotinib is an inhibitor of CYP3A4 (moderate) and may increase warfarin concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with warfarin. The clinical relevance of an increased INR/PT is unknown. If coadministration is unavoidable, monitor closely for warfarin toxicity and INR/PT. A dose reduction for warfarin should also be considered.

Description:

See summary

No Interaction Expected

Crizotinib

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Crizotinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

No Interaction Expected

Crizotinib

Zaleplon

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Do Not Coadminister

Crizotinib

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). Crizotinib is a moderate inhibitor of CYP3A4 and may increase ziprasidone concentrations. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on ziprasidone exposure is expected. However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval, such as crizotinib.

Description:

See summary

No Interaction Expected

Crizotinib

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. Crizotinib is unlikely to interfere with this elimination pathway.

Description:

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Potential Interaction

Crizotinib

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9, CYP2C19, CYP2D6 and CYP1A2. Concentrations of zolpidem may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with zolpidem. If coadministration is unavoidable, monitor closely for zolpidem toxicity and consider a dose reduction for zolpidem.

Description:

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Potential Interaction

Crizotinib

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Concentrations of zopiclone may increase due to CYP3A4 inhibition by crizotinib. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with zopiclone. If coadministration is unavoidable, monitor closely for zopiclone toxicity and consider a dose reduction for zopiclone.

Description:

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Potential Interaction

Crizotinib

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Crizotinib is an inhibitor of CYP3A4 and may increase zotepine concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with zotepine. If coadministration is unavoidable, monitor closely for zotepine toxicity and consider a dose reduction for zotepine.

Description:

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Potential Interaction

Crizotinib

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Crizotinib is an inhibitor of CYP3A4 (moderate), UGT1A1 (in vitro) and UGT2B7 (in vitro) and may increase zuclopenthixol concentrations. After coadministration of crizotinib with a single dose of midazolam, a sensitive CYP3A4 substrate, the midazolam AUC increased 3.7-fold. A similar effect may occur after coadministration with zuclopenthixol. The clinical relevance of UGT1A1 and UGT2B7 inhibition is unknown. If coadministration is unavoidable, monitor closely for zuclopenthixol toxicity and consider a dose reduction for zuclopenthixol.

Description:

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