Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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), which are not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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%). This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, this is not affected by brigatinib. 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 Weak Interaction

Brigatinib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfentanil is metabolised by CYP3A4 and concentrations may decrease due to induction by brigatinib. Coadministration should be monitored as effectiveness of alfentanil may be reduced. No a priori dose adjustment is required, but alfentanil dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfuzosin is metabolised by CYP3A, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of alfuzosin may be reduced. No a priori dose adjustment is required, but alfuzosin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

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 a substrate of P-gp, and concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for aliskiren toxicity. No a priori dose adjustment is required.

Description:

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No Interaction Expected

Brigatinib

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, which are not affected by brigatinib. Allopurinol is also an inhibitor of xanthine oxidase, which does not affect brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4, and 1A2. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of alosetron may be reduced. No a priori dose adjustment is required, but alosetron dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alprazolam is mainly metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of alprazolam may be reduced. No a priori dose adjustment is required .

Description:

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No Interaction Expected

Brigatinib

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.

Description:

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Potential Weak Interaction

Brigatinib

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ambrisentan is metabolised by glucuronidation via UGT1A3, UGT1A9, and UGT2B7 and to a lesser extent by CYP3A4 and CYP2C19. Moreover, ambrisentan is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on ambrisentan concentrations is unknown. Coadministration should be monitored for ambrisentan efficacy and toxicity. No a priori dose adjustment is required.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

Amiloride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. This is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amiodarone is metabolised by CYP3A4 and CYP2C8 and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of amiodarone may be reduced. No a priori dose adjustment is required, but amiodarone dose may need to be increased when treatment appears to be subtherapeutic. Additionally, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate), and P-gp (strong). Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by desethylamiodarone, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required. Brigatinib is a substrate of P-gp. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors will have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by amiodarone is not expected. 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

Brigatinib

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) and concentrations may increase due to OCT1 inhibition by brigatinib. Coadministration should be monitored for amisulpride toxicity. No a priori dose adjustment is required.

Description:

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No Interaction Expected

Brigatinib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, which are not affected by brigatinib. A small proportion is metabolised by CYPs 3A4, 1A2 and 2C9. Therefore, a clinically relevant effect on lidocaine concentrations or efficacy due to CYP3A4 induction by brigatinib is not expected.

Description:

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Potential Weak Interaction

Brigatinib

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amlodipine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of amlodipine may be reduced. No a priori dose adjustment is required, but amlodipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

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. Brigatinib does not interfere with this metabolic or elimination pathway. However, the European SmPC 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

Brigatinib

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. Ampicillin excretion is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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.

Description:

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Do Not Coadminister

Brigatinib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contra-indicated. Apixaban is a substrate of P-gp and BCRP. Apixaban concentrations may increase due to P-gp and BCRP inhibition by brigatinib. Apixaban is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9, and 2C19. Thus, concentrations may also decrease due to CYP3A4 induction by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on apixaban concentrations is unknown. Coadministration of apixaban with brigatinib is contra-indicated.

Description:

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Potential Weak Interaction

Brigatinib

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of aprepitant may be reduced. No a priori dose adjustment is required, but aprepitant dose may need to be increased when treatment appears to be subtherapeutic. During treatment, aprepitant is a moderate inhibitor of CYP3A4. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by aprepitant. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity. Moreover, after treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9, and UGT. Concentrations of brigatinib may decrease due to weak induction of CYP3A4 by aprepitant, but this is unlikely to be clinically significant.

Description:

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Potential Weak Interaction

Brigatinib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of aripiprazole may be reduced. No a priori dose adjustment is required, but aripiprazole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Asenapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of asenapine may be reduced. No a priori dose adjustment is required, but asenapine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Astemizole is metabolised by CYPs 2D6, 2J2, and 3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of astemizole may be reduced. No a priori dose adjustment is required, but astemizole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Atorvastatin is metabolised by CYP3A4, and is a substrate of P-gp and OATP1B1. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on atorvastatin concentrations is unknown. Coadministration should be monitored for atorvastatin efficacy and toxicity. No a priori dose adjustment is required.

Description:

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No Interaction Expected

Brigatinib

Azathioprine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azathioprine is converted to 6-mercaptopurine which is metabolised analogously to natural purines by xanthine oxidase. This is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Azithromycin concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for azithromycin toxicity. No a priori dose adjustment is required. Azithromycin is also an inhibitor of P-gp and brigatinib is a substrate of P-gp. However, the clinical relevance of P-gp inhibition by azithromycin is unknown. Moreover, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors will have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by azithromycin is not expected.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Interaction

Brigatinib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Bedaquiline is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as bedaquiline exposure is closely related to efficacy, thus any decrease in exposure may decrease efficacy. If coadministration is unavoidable consider doubling the bedaquiline dose. Bedaquiline has a known QT prolongation risk at higher concentrations, therefore QTc monitoring will be required to help prevent cardiac toxicity when doubling the bedaquiline dose.

Description:

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No Interaction Expected

Brigatinib

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.

Description:

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Potential Weak Interaction

Brigatinib

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bepridil is metabolised by CYP2D6 (major) and CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of bepridil may be reduced. No a priori dose adjustment is required, but bepridil dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Betamethasone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of betamethasone may be reduced. No a priori dose adjustment is required, but betamethasone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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. Brigatinib is unlikely to interact with this metabolic or elimination pathway.

Description:

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Potential Weak Interaction

Brigatinib

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of bisoprolol may be reduced. No a priori dose adjustment is required, but bisoprolol dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Concentrations of brigatinib may decrease due to weak induction of CYP3A4 by bosentan, but this is unlikely to be clinically significant. Coadministration should be monitored as effectiveness of brigatinib may be decreased. No a priori dose adjustment is required.

Description:

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Potential Weak Interaction

Brigatinib

Bromazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of bromazepam may be reduced. No a priori dose adjustment is required.

Description:

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Potential Weak Interaction

Brigatinib

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Budesonide is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of budesonide may be reduced. No a priori dose adjustment is required, but budesonide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Buprenorphine concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of buprenorphine may be reduced. No a priori dose adjustment is required, but buprenorphine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib and does not affect brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Buspirone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of buspirone may be reduced. No a priori dose adjustment is required, but buspirone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Interaction

Brigatinib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Brigatinib is an inducer of CYP3A4 and may decrease concentrations of carbamazepine. Coadministration should be closely monitored as carbamazepine efficacy may be reduced. Moreover, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6, UGT1A1, and P-gp (moderate). Concentrations of brigatinib may increase due to inhibition of CYP2C8 by carbamazepine. After coadministration with gemfibrozil, a strong CYP2C8 inhibitor, brigatinib exposure decreased by only 12%. Therefore, a clinically relevant interaction due to CYP2C8 inhibition by carbamazepine is unlikely. Concentrations of brigatinib may also increase due to inhibition of CYP3A4 by carbamazepine. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

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No Interaction Expected

Brigatinib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4, and 2B7, and metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. This is not affected by brigatinib. Carvedilol is also an inhibitor of P-gp and brigatinib is a substrate of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown. Moreover, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by carvedilol is not expected.

Description:

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No Interaction Expected

Brigatinib

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. Brigatinib is unlikely to interfere with this metabolic pathway.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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 tract. This is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which are not affected by brigatinib. In vitro data indicate that cetirizine is also an inhibitor of OCT2, which does not affect brigatinib.

Description:

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Do Not Coadminister

Brigatinib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Chloramphenicol is predominantly glucuronidated. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong), and CYP2D6 (weak). Concentrations of brigatinib may decrease due to induction of CYP3A4 by chloramphenicol. After coadministration with rifampicin, a strong CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with chloramphenicol. Therefore, coadministration of intravenous chloramphenicol with brigatinib is contraindicated. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Description:

See summary

Potential Weak Interaction

Brigatinib

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chlordiazepoxide is extensively metabolised by CYP3A4 but does not inhibit or induce cytochromes. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of chlordiazepoxide may be reduced. No a priori dose adjustment is required, but chlordiazepoxide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, this is not affected by brigatinib. 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.

Description:

See summary

Potential Interaction

Brigatinib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ciclosporin is a substrate for CYP3A4 and P-gp, and inhibits CYP3A4 and OATP1B1. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on ciclosporin concentrations is unknown. Coadministration should be monitored for ciclosporin efficacy and toxicity. Monitor ciclosporin plasma levels, if available. No a priori dose adjustment is required. Moreover, concentrations of brigatinib may decrease due to induction of CYP3A4 by ciclosporin. Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. If coadministration is unavoidable closely monitor brigatinib efficacy and, if available, brigatinib plasma concentrations.

Description:

See summary

No Interaction Expected

Brigatinib

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, this is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cimetidine is metabolised by CYP P450 enzymes. 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. Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by cimetidine, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. This is not affected by brigatinib. Ciprofloxacin is also metabolised and partially cleared through the bile and intestine. Furthermore, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by ciprofloxacin. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity.

Description:

See summary

Potential Weak Interaction

Brigatinib

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cisapride is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of cisapride may be reduced. No a priori dose adjustment is required, but cisapride dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%), and 3A4 (31%). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of citalopram may be reduced. No a priori dose adjustment is required, but citalopram dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Interaction

Brigatinib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clarithromycin is metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong) and P-gp. Clarithromycin concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of clarithromycin may be reduced. Brigatinib is a substrate of P-gp and BCRP. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors will have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by clarithromycin is not expected. Moreover, concentrations of brigatinib may increase due to inhibition of CYP3A4 by clarithromycin. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clindamycin is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of clindamycin may be reduced. Additionally, in vitro data suggest that clindamycin is a CYP3A4 inhibitor which may increase brigatinib concentrations. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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

Brigatinib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clofazimine is largely excreted unchanged in the faeces. In vitro data suggest that clofazimine is a moderate to strong CYP3A4 inhibitor. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by clofazimine. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clomipramine is metabolised by CYPs 3A4, 1A2, and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Concentrations of clomipramine may decrease and desmethylclomipramine may increase due to CYP3A4 induction by brigatinib. Coadministration should be monitored for efficacy and toxicity of clomipramine. No a priori dose adjustment is required, but clomipramine dose may need to be adjusted when therapy appears ineffective or toxic. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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), this is not affected by brigatinib. Clonidine is also a weak inhibitor of OCT2, which does not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. Therefore, a clinically significant effect on efficacy of clopidogrel or its active metabolite due to CYP3A4 induction of brigatinib is not expected, as this is only a minor pathway. Clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak), and in vitro of CYP2C9 at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Concentrations of brigatinib may increase due to inhibition of CYP2C8 by clopidogrel. After coadministration with gemfibrozil, a strong CYP2C8 inhibitor, brigatinib exposure decreased by only 12%. Therefore, a clinically relevant interaction is unlikely.

Description:

See summary

Potential Weak Interaction

Brigatinib

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Concentrations of nordiazepam may decrease and oxazepam may increase due to CYP3A4 induction by brigatinib. Both exert a therapeutic effect, but their half-lives differ significantly; 36-200 hours for nordiazepam and 4-15 hours for diazepam. Therefore, the therapeutic effect may theoretically be shortened due to CYP3A4 induction by brigatinib, and overall effectiveness may be reduced. Coadministration should be monitored. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Clozapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of clozapine may be reduced. No a priori dose adjustment is required, but clozapine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Codeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Codeine is converted to morphine, an active metabolite with analgesic and opioid properties, via CYP2D6 which is not affected by brigatinib. Morphine is further metabolised by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). This is not affected by brigatinib. Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Codeine concentrations may decrease due to CYP3A4 induction by brigatinib. Additionally, the metabolite morphine is a substrate of P-gp and concentrations may increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on codeine concentrations is unknown. Coadministration should be monitored for codeine efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Colchicine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on colchicine concentrations is unknown. Coadministration should be monitored for colchicine efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Dabigatran is transported via P-gp and is renally excreted. Concentrations may increase due to P-gp inhibition by brigatinib. If coadministration is unavoidable, monitor closely for dabigatran toxicity and, if available, dabigatran plasma concentrations. Administer dabigatran 2 hours before brigatinib in a fasted state to circumvent the intestinal P-gp interaction.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP450 enzymes. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desipramine is metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

Do Not Coadminister

Brigatinib

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Concentrations of etonogestrel may decrease due to CYP3A4 induction by brigatinib. Coadministration is contraindicated as the effectiveness of desogestrel may be reduced leading to contraceptive failure. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking desogestrel with brigatinib should be considered.

Description:

See summary

Potential Weak Interaction

Brigatinib

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease brigatinib plasma concentrations. However, the clinical relevance of this interaction is not known. Moreover, the induction of CYP3A4 by dexamethasone has not been established yet. Furthermore, dexamethasone is a substrate of CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of dexamethasone may be reduced. No a priori dose adjustment is required, but dexamethasone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dextropropoxyphene is mainly metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of dextropropoxyphene may be reduced. No a priori dose adjustment is required, but dextropropoxyphene dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diamorphine is rapidly metabolised by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). This is not affected by brigatinib. Moreover, morphine is a substrate of P-gp and morphine concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for diamorphine toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Concentrations may alter due to CYP3A4 induction by brigatinib. Net effect on efficacy and toxicity of diazepam is unknown. Coadministration should be monitored. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

Diclofenac

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp, and digoxin concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for digoxin toxicity and digoxin plasma levels, if available. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Therefore, a clinically relevant effect on dihydrocodeine concentrations or efficacy due to CYP3A4 induction by brigatinib is not expected.

Description:

See summary

Potential Interaction

Brigatinib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Diltiazem is metabolised by CYP3A4 and CYP2D6, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of diltiazem may be reduced. No a priori dose adjustment is required, but diltiazem dose may need to be increased when treatment appears to be subtherapeutic. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp. However, the clinical relevance of P-gp inhibition by diltiazem is unknown. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by diltiazem. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity.

Description:

See summary

No Interaction Expected

Brigatinib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9, and 2C19, which is not affected by brigatinib. Moreover, diphenhydramine is a weak inhibitor of CYP2D6, which does not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of disopyramide may be reduced. No a priori dose adjustment is required, but disopyramide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Dolasetron

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Brigatinib

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Domperidone is mainly metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of domperidone may be reduced. No a priori dose adjustment is required, but domperidone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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 to inactive compounds in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase.. 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 brigatinib, or to be affected if co-administered with brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Doxazosin is metabolised mainly by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of doxazosin may be reduced. No a priori dose adjustment is required, but doxazosin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. In addition, doxepin and nordoxepin are metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Dronabinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of dronabinol may be reduced. No a priori dose adjustment is required, but dronabinol dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Interaction

Brigatinib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Drospirenone is metabolised to a minor extent via CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of drospirenone may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking drospirenone with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib. 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

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dutasteride is mainly metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of dutasteride may be reduced. No a priori dose adjustment is required, but dutasteride dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Interaction

Brigatinib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of dydrogesterone may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking dydrogesterone with brigatinib should be considered.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. Concentrations of edoxaban may increase due to P-gp inhibition by brigatinib. Monitoring of edoxaban efficacy and anti-Xa levels is recommended. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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), which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Erythromycin is a substrate of CYP3A4 and P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, erythromycin concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on erythromycin concentrations is unknown. Coadministration should be monitored for erythromycin efficacy and toxicity. No a priori dose adjustment is required. Moreover, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by erythromycin. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity. Brigatinib is a substrate of P-gp. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors will have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by erythromycin is not expected.

Description:

See summary

Potential Weak Interaction

Brigatinib

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%), and 3A4 (35%) to form N-desmethylescitalopram. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of escitalopram may be reduced. No a priori dose adjustment is required, but escitalopram dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Esomeprazole is metabolised by CYP2C19 and CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of esomeprazole may be reduced. No a priori dose adjustment is required, but esomeprazole dose may need to be increased when treatment appears to be subtherapeutic. Esomeprazole is also an inhibitor of CYP2C19, which does not affect brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of estazolam may be reduced. No a priori dose adjustment is required.

Description:

See summary

Potential Interaction

Brigatinib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Estradiol is metabolised by CYP3A4, CYP1A2, and is glucuronidated. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of estradiol may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking estradiol with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

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%). This is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation, and glucuronidation (UGT1A1). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of ethinylestradiol may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking ethinylestradiol with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Etonogestrel is metabolised by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of etonogestrel may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking etonogestrel with brigatinib should be considered.

Description:

See summary

Potential Weak Interaction

Brigatinib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on everolimus concentrations is unknown. Coadministration should be monitored for everolimus efficacy and toxicity. No a priori dose adjustment is required. Monitor everolimus plasma concentrations, if available.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. 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

No Interaction Expected

Brigatinib

Ezetimibe

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ezetimibe is glucuronidated by UGTs 1A1, and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Felodipine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of felodipine may be reduced. No a priori dose adjustment is required, but felodipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which does not affect brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fentanyl undergoes extensive CYP3A4 metabolism, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fentanyl may be reduced. No a priori dose adjustment of fentanyl is required, but fentanyl dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fexofenadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fexofenadine is a substrate of P-gp and concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for fexofenadine toxicity. No a priori dose adjustment is required

Description:

See summary

Potential Weak Interaction

Brigatinib

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Finasteride is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of finasteride may be reduced. No a priori dose adjustment is required, but finasteride dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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

No Interaction Expected

Brigatinib

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. This is not affected by brigatinib. Flucloxacillin is described as a CYP3A4 inducer. Concentrations of brigatinib may decrease due to induction of CYP3A4 by flucloxacillin. However, the mechanism and clinical relevance of this interaction is unknown.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluconazole is cleared primarily by renal excretion and is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate), and 2C19 (strong). Concentrations of brigatinib may increase due to inhibition of CYP3A4 by fluconazole. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. Brigatinib 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. Brigatinib may also induce 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 Weak Interaction

Brigatinib

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fludrocortisone may be reduced. No a priori dose adjustment is required, but fludrocortisone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of flunitrazepam may be reduced. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fluoxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluoxetine is mainly metabolised by CYP2D6 and CYP2C9, and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Fluoxetine concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fluoxetine may be reduced. No a priori dose adjustment is required, but fluoxetine dose may need to be increased when treatment appears to be subtherapeutic. Fluoxetine is also a strong inhibitor of CYP2D6 and CYP2C19, which do not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluphenazine is metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Flurazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. The metabolism of flurazepam is most likely CYP-mediated. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of flurazepam may be reduced. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluticasone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fluticasone may be reduced. No a priori dose adjustment is required, but fluticasone dose may need to be increased when treatment appears to be subtherapeutic. Note: A clinically significant interaction is unlikely with the topical use of fluticasone.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluvastatin is mainly metabolised by CYP2C9 (75%), and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fluvastatin may be reduced. No a priori dose adjustment is required, but fluvastatin dose may need to be increased when treatment appears to be subtherapeutic. Fluvastatin potentially inhibits CYP2C9, but this does not affect brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. This is not affected by brigatinib. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate), and CYP2D6 (weak). Concentrations of brigatinib may increase due to inhibition of CYP3A4 by fluvoxamine. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib. As multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low.

Description:

See summary

Potential Weak Interaction

Brigatinib

Fosaprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations of aprepitant may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of fosaprepitant may be reduced. No a priori dose adjustment is required, but fosaprepitant dose may need to be increased when treatment appears to be subtherapeutic. During treatment aprepitant is a moderate inhibitor of CYP3A4. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by aprepitant. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity. Moreover, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9, and UGT. Concentrations of brigatinib may decrease due to weak induction of CYP3A4 by aprepitant, but this is unlikely to be clinically significant.

Description:

See summary

Do Not Coadminister

Brigatinib

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. This is not affected by brigatinib. Phenytoin is also a potent inducer of CYP3A4, UGT, and P-gp. Concentrations of brigatinib may decrease due to induction of CYP3A4 by fosphenytoin. After coadministration with rifampicin, a strong P-gp and CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with fosphenytoin, therefore coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

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). This is not affected by brigatinib. 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, this does not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Gemfibrozil

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7, which is not affected by brigatinib. Gemfibrozil is an inhibitor of CYP2C8 (strong), OATP1B1, and OAT3. Concentrations of brigatinib will increase due to inhibition of CYP2C8 by gemfibrozil. In healthy subjects (n=20), coadministration of brigatinib (90mg single dose, day 1 and 21) with gemfibrozil (600mg twice daily, days 17-25) brigatinib exposure decreased by only 12%. Therefore, a clinically relevant interaction is unlikely. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9, but in vivo data showed no clinically relevant effect on CYP2C9.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of gestodene may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking gestodene with brigatinib should be considered.

Description:

See summary

Potential Weak Interaction

Brigatinib

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of glibenclamide may be reduced. No a priori dose adjustment is required, but glibenclamide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on granisetron concentrations is unknown. Coadministration should be monitored for granisetron efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Do Not Coadminister

Brigatinib

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Grapefruit juice is known to inhibit CYP3A4 enzymes. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. A similar effect may occur with grapefruit juice, therefore coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Do Not Coadminister

Brigatinib

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolised by CYPs, such as brigatinib. Therefore, coadministration is contraindicated.

Description:

See summary

Potential Weak Interaction

Brigatinib

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction, as well as oxidative metabolism (CYP3A4 and CYP2D6). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of haloperidol may be reduced. No a priori dose adjustment is required, but haloperidol dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

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, this is not affected by brigatinib. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by hydralazine, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. 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.

Description:

See summary

Potential Weak Interaction

Brigatinib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocodone is metabolised by CYP2D6 to hydromorphone, which is not affected by brigatinib. However, hydrocodone is metabolised by CYP3A4 to norhydrocodone, and concentrations may decrease due to CYP3A4 induction by brigatinib. Both metabolites have analgesic effects. Therefore, the net effect on hydrocodone efficacy is unknown. Coadministration should be monitored, and hydrocodone dose lowered when toxicity occurs or increased when brigatinib appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocortisone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of hydrocortisone may be reduced. No a priori dose adjustment is required, but hydrocortisone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Hydrocortisone (topical)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

Hydromorphone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys, this is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of hydroxyzine may be reduced. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, this is not affected by brigatinib. 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

No Interaction Expected

Brigatinib

Ibuprofen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Iloperidone is metabolised by CYP3A4 and CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of iloperidone may be reduced. No a priori dose adjustment is required, but iloperidone dose may need to be increased when treatment appears to be subtherapeutic

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Imipramine is metabolised by CYPs 3A4, 2C19, and 1A2 to desipramine. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of imipramine may be reduced. No a priori dose adjustment is required, but imipramine dose may need to be increased when treatment appears to be subtherapeutic. Imipramine and desipramine are both metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Indapamide is extensively metabolised by CYP450s, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of indapamide may be reduced. No a priori dose adjustment is required, but indapamide dose may need to be increased when treatment appears to be subtherapeutic. 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.

Description:

See summary

No Interaction Expected

Brigatinib

Insulin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

Interferon alpha

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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), which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Concentrations of isosorbide dinitrate may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of isosorbide dinitrate may be reduced. No a priori dose adjustment is required, but dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Interaction

Brigatinib

Itraconazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be approached with caution. Itraconazole is primarily metabolised by CYP3A4 and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of itraconazole may be reduced. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp, and BCRP. Brigatinib is a substrate of P-gp and BCRP. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp/BCRP inhibitors have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp/BCRP inhibition by itraconazole is not expected. However, concentrations of brigatinib will increase due to inhibition of CYP3A4 by itraconazole. In healthy subjects (n=20), coadministration of brigatinib (90 mg single dose, day 1 and 21) with itraconazole (200 mg twice daily, days 17-25) increased brigatinib exposure by 101%. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

Potential Weak Interaction

Brigatinib

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ivabradine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of ivabradine may be reduced. No a priori dose adjustment is required, but ivabradine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ketoconazole is a substrate for CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of ketoconazole may be reduced. Moreover, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Brigatinib is a substrate of P-gp and BCRP. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp/BCRP inhibitors have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp/BCRP inhibition by ketoconazole is not expected. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by ketoconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

No Interaction Expected

Brigatinib

Labetalol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7), which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lacidipine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of lacidipine may be reduced. No a priori dose adjustment is required, but lacidipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of lansoprazole may be reduced. No a priori dose adjustment is required, but lansoprazole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lercanidipine is mainly metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of lercanidipine may be reduced. No a priori dose adjustment is required, but lercanidipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levomepromazine is metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Levonorgestrel mainly is metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of levonorgestrel may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking levonorgestrel with brigatinib should be considered.

Description:

See summary

Potential Interaction

Brigatinib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of drospirenone may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking levonorgestrel with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

Levothyroxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation, this is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with only a minor contribution from CYP3A4. Therefore, a clinically relevant effect on lidocaine concentrations or efficacy due to CYP3A4 induction by brigatinib is not expected.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, linagliptin is also a substrate for P-gp and concentrations may increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on linagliptin concentrations is unknown. Coadministration should be monitored for linagliptin efficacy and toxicity. No a priori dose adjustment is required. Linagliptin is also a weak inhibitor of CYP3A4 and concentrations of brigatinib may increase, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Lithium

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

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 brigatinib is not an immunosuppressant drug, no additional unwanted effects are expected.

Description:

See summary

Potential Weak Interaction

Brigatinib

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Loperamide is mainly metabolised by CYP3A4 and CYP2C8, and is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on loperamide concentrations is unknown. Coadministration should be monitored for loperamide efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of loratadine may be reduced. No a priori dose adjustment is required, but loratadine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Lormetazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lovastatin is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of lovastatin may be reduced. No a priori dose adjustment is required, but lovastatin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9, and 2C8, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of macitentan may be reduced. No a priori dose adjustment is required, but macitentan dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Medroxyprogesterone is metabolised by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of medroxyprogesterone may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking medroxyprogesterone with brigatinib should be considered.

Description:

See summary

Potential Interaction

Brigatinib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Brigatinib

Mefenamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Do Not Coadminister

Brigatinib

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract, which is not affected by brigatinib. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Metamizole is also an inducer of CYP3A4. The level of induction is unknown. Concentrations of brigatinib may decrease due to induction of CYP3A4 by metamizole. After coadministration with rifampicin, a strong CYP3A4 inducer, brigatinib exposure decreased by 80%. Moreover, moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. Therefore, coadministration of metamizole with brigatinib is contraindicated.

Description:

See summary

Potential Weak Interaction

Brigatinib

Metformin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metformin is mainly eliminated unchanged in the urine and is a substrate for OCT1, OCT2, OCT3, MATE1, and MATE2K. Concentrations may increase due to OCT1 inhibition by brigatinib. Coadministration should be monitored for metformin toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Methadone is demethylated by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of methadone may be reduced. No a priori dose adjustment is required, but methadone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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 brigatinib, or to be affected if coadministered with brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Methylprednisolone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of methylprednisolone may be reduced. No a priori dose adjustment is required, but methylprednisolone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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). This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. 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.

Description:

See summary

No Interaction Expected

Brigatinib

Metoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoprolol is mainly metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Metronidazole

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

Mexiletine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent CYP1A2. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mianserin is metabolised by CYP2D6 and CYP1A2, and to a lesser extent by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of mianserin may be reduced. No a priori dose adjustment is required, but the mianserin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Interaction

Brigatinib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Miconazole is extensively metabolised by the liver. Moreover, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of brigatinib may increase due to inhibition of CYP3A4 by miconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg). Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinically relevant interaction is expected.

Description:

See summary

Potential Weak Interaction

Brigatinib

Midazolam (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Midazolam is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of midazolam may be reduced. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Brigatinib

Milnacipran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Mirtazapine concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of mirtazapine may be reduced. No a priori dose adjustment is required, but mirtazapine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mometasone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of mometasone may be reduced. No a priori dose adjustment is required, but mometasone dose may need to be increased when treatment appears to be subtherapeutic. Note: No clinically relevant interaction is expected with the topical use of mometasone.

Description:

See summary

Potential Weak Interaction

Brigatinib

Montelukast

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of montelukast may be reduced. No a priori dose adjustment is required, but montelukast dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). This is not affected by brigatinib. However, morphine is a substrate of P-gp and morphine concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for morphine toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

Moxifloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7, which are not affected by brigatinib. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3, this does not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Naproxen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Nateglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of nateglinide may be reduced. No a priori dose adjustment is required, but nateglinide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Nebivolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nebivolol metabolism involves CYP2D6, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nefazodone is metabolised mainly by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of nefazodone may be reduced. No a priori dose adjustment is required, but nefazodone dose may need to be increased when treatment appears to be subtherapeutic. Moreover, nefazodone is a strong inhibitor of CYP3A4 and therefore, concentrations of brigatinib may increase. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

Potential Weak Interaction

Brigatinib

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of nicardipine may be reduced. No a priori dose adjustment is required, but nicardipine dose may need to be increased when treatment appears to be subtherapeutic. Moreover, nicardipine is a weak inhibitor of CYP3A4. Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by nicardipine, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nifedipine is metabolised mainly by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of nifedipine may be reduced. No a priori dose adjustment is required, but nifedipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nisoldipine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of nisoldipine may be reduced.

Description:

See summary

Potential Weak Interaction

Brigatinib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of nitrendipine may be reduced. No a priori dose adjustment is required, but nitrendipine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). This is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of norelgestromin may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking norelgestromin with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethindrone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. This is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of norgestimate may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking norgestimate with brigatinib should be considered.

Description:

See summary

Potential Interaction

Brigatinib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of norgestrel may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking norgestrel with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nortriptyline is metabolised mainly by CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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

No Interaction Expected

Brigatinib

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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). This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Omeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of omeprazole may be reduced. No a priori dose adjustment is required, but omeprazole dose may need to be increased when treatment appears to be subtherapeutic. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19, which does not affect brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2D6. Additionally, ondansetron is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on ondansetron concentrations is unknown. Coadministration should be monitored for ondansetron efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

Oxazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated, which is not affected by brigatinib.

Description:

See summary

Do Not Coadminister

Brigatinib

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cytosolic enzymes, which are not affected by brigatinib. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Concentrations of brigatinib may decrease due to induction of CYP3A4 by oxcarbazepine. Moderate CYP3A inducers may decrease the AUC of brigatinib by approximately 50% based on simulations from a physiologically-based pharmacokinetic model. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

Oxprenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolised via glucuronidation, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Noroxycodone is 14x more potent than oxycodone and noroxycodone concentrations may increase due to CYP3A4 induction by brigatinib. Coadministration should be monitored as toxicity of oxycodone may be increased.

Description:

See summary

Potential Weak Interaction

Brigatinib

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, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of paliperidone may be reduced. No a priori dose adjustment is required, but paliperidone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Palonosetron is metabolised mainly by CYP3A4, and to a lesser extent by CYP2D6 and CYP1A2. Additionally, palonosetron is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on palonosetron concentrations is unknown. Coadministration should be monitored for palonosetron efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, this is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6, and 2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of pantoprazole may be reduced. No a priori dose adjustment is required, but pantoprazole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib. Paracetamol is also, to a lesser extent, metabolised by oxidation (CYPs 2E1 (major), 1A2, 3A4, and 2D6). Therefore, a clinically relevant effect on paracetamol concentrations or efficacy due to CYP3A4 induction by brigatinib is not expected, as it is only a minor pathway.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. Paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9, which do not affect brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

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). This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Perazine is mainly metabolised by CYPs 1A2, 3A4, and 2C19, and to a lesser extent by CYPs 2C9, 2D6, and 2E1, with oxidation via FMO3. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of perazine may be reduced. No a priori dose adjustment is required, but perazine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib. Elimination occurs predominantly via the urine.

Description:

See summary

No Interaction Expected

Brigatinib

Perphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perphenazine is metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Pethidine concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of pethidine may be reduced. No a priori dose adjustment is required, but pethidine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Do Not Coadminister

Brigatinib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenobarbital is metabolised by CYP2C19 and 2C9 (major pathway) and to a lesser extent by CYP2E1. This is not affected by brigatinib. Phenobarbital is a strong inducer of CYP3A4, CYP2C9, CYP2C8, and UGTs. Concentrations of brigatinib may decrease due to induction of CYP3A4 by phenobarbital. After coadministration with rifampicin, a strong CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with phenobarbital, therefore coadministration is contraindicated.

Description:

See summary

Potential Weak Interaction

Brigatinib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored for efficacy (INR/PT) as effectiveness of phenprocoumon may be reduced. No a priori dose adjustment is required, but phenprocoumon dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Do Not Coadminister

Brigatinib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. This is not affected by brigatinib. Phenytoin is a strong inducer of CYP3A4, UGT, and P-gp. Concentrations of brigatinib may decrease due to induction of CYP3A4 by phenytoin. After coadministration with rifampicin, a strong P-gp and CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with phenytoin, therefore coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Pimozide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of pimozide may be reduced. No a priori dose adjustment is required, but pimozide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Pindolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Pioglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2, and 2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of pioglitazone may be reduced. No a priori dose adjustment is required, but pioglitazone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Pipotiazine

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 pipotiazine has not been well described but may involve CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Pitavastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. This is not affected by brigatinib. Moreover, pitavastatin is a substrate of OATP1B1, which is also not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for posaconazole toxicity. No a priori dose adjustment is required. Moreover, posaconazole is a strong inhibitor of CYP3A4. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by posaconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

No Interaction Expected

Brigatinib

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.

Description:

See summary

Potential Interaction

Brigatinib

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. Prasugrel concentrations may decrease, and concentrations of its active metabolite may increase due to CYP3A4 induction by brigatinib. Coadministration is not recommended prasugrel toxicity may be increased.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisolone undergoes hepatic metabolism via CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of prednisolone may be reduced. No a priori dose adjustment is required, but prednisolone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of prednisone may be reduced. No a priori dose adjustment is required, but prednisone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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), which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Promethazine is metabolised by CYP2D6, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Therefore, a clinically relevant effect on lidocaine concentrations or efficacy due to CYP3A4 induction by brigatinib is not expected, as CYP3A4 is only a minor pathway.

Description:

See summary

No Interaction Expected

Brigatinib

Propranolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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). This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. Additionally, prucalopride is a substrate of P-gp, and concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for prucalopride toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Pyridoxine (Vitamin B6)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Brigatinib

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quetiapine is primarily metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of quetiapine may be reduced. No a priori dose adjustment is required, but quetiapine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak), and P-gp (moderate). Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by quinidine, but this is unlikely to be clinically significant. As brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors will have a relevant effect on brigatinib exposure. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9, and CYP2E1. Concentrations may decrease due to CYP3A4 induction by brigatinib. Additionally, quinidine is a substrate of P-gp and concentrations may increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on quinidine concentrations is unknown. Coadministration should be monitored for quinidine efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of rabeprazole may be reduced. No a priori dose adjustment is required, but rabeprazole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on ranolazine concentrations is unknown. Coadministration should be monitored for ranolazine efficacy and toxicity. No a priori dose adjustment is required. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4, and CYP2D6. Brigatinib is a substrate of P-gp. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by ranolazine is not expected. However, concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by ranolazine, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Reboxetine is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of reboxetine may be reduced. No a priori dose adjustment is required, but reboxetine dose may need to be increased when treatment appears to be subtherapeutic. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4, but in vivo data showed no inhibitory effect on CYP3A4.

Description:

See summary

Potential Weak Interaction

Brigatinib

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of repaglinide may be reduced. No a priori dose adjustment is required, but repaglinide dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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

Brigatinib

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifabutin is metabolised by CYP3A4 and via deacetylation. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of rifabutin may be reduced. Rifabutin is also a strong CYP3A4 and P-gp inducer. Concentrations of brigatinib may decrease due to induction of CYP3A4 by rifabutin. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, brigatinib exposure decreased by 80%. A similar effect may occur with rifabutin, therefore coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Brigatinib

Rifampicin

Quality of Evidence: Low

Summary:

Coadministration has been studied and is contraindicated. Rifampicin is metabolised via deacetylation and is also a strong CYP3A4 and P-gp inducer. Concentrations of brigatinib will decrease due to induction of CYP3A4 by rifampicin. In healthy subjects (n=20), coadministration of brigatinib (180 mg single dose, day 1 and 23) with rifampicin (600 mg once daily, days 17-27) decreased brigatinib exposure by 80%. Coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Brigatinib

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Rifapentine is metabolised via deacetylation and is also a strong CYP3A4, CYP2C8, and P-gp inducer. Concentrations of brigatinib may increase due to inhibition of CYP2C8 by rifapentine. After coadministration with gemfibrozil, a strong CYP2C8 inhibitor, brigatinib exposure decreased by only 12%. Therefore, a clinically relevant interaction due to CYP2C8 induction is unlikely. However, concentrations of brigatinib may decrease due to induction of CYP3A4 by rifapentine. After coadministration with rifampicin, a strong CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with rifapentine, therefore coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

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, and concentrations may decrease due to CYP3A4 induction by brigatinib. Furthermore, risperidone is a substrate of P-gp, and risperidone concentrations may increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on risperidone concentrations is unknown. Coadministration should be monitored for sitagliptin efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Do Not Coadminister

Brigatinib

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. Concentrations may decrease due to CYP3A4 induction by brigatinib. Moreover, rivaroxaban is substrate for P-gp and BCRP. Thus, concentrations may also increase due to P-gp and BCRP inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on rivaroxaban concentrations is unknown. Coadministration of rivaroxaban with brigatinib is contra-indicated.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is substrate for BCRP, and rosuvastatin concentrations may increase due to BCRP inhibition by brigatinib. Coadministration should be monitored for rosuvastatin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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, this is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, and systemic concentrations may decrease due to CYP3A4 induction by brigatinib. However, since the systemic exposure of salmeterol is low, no clinically relevant interaction is expected.

Description:

See summary

Potential Weak Interaction

Brigatinib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on saxagliptin concentrations is unknown. Coadministration should be monitored for saxagliptin efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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

Potential Weak Interaction

Brigatinib

Sertindole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sertindole is metabolised by CYP2D6 and CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of sertindole may be reduced. No a priori dose adjustment is required, but sertindole dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Sertraline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6, and 3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of sertraline may be reduced. No a priori dose adjustment is required, but sertraline dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of sildenafil may be reduced. No a priori dose adjustment is required, but sildenafil dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4. Moreover, simvastatin is a substrate for BCRP, and the active metabolite is a substrate of OATP1B1. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to BCRP inhibition by brigatinib. The net effect of CYP3A4 induction and BCRP inhibition on simvastatin concentrations is unknown. Coadministration should be monitored for simvastatin efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sirolimus is metabolised by CYP3A4 and is substrate of P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on sirolimus concentrations is unknown. Coadministration should be monitored for sirolimus efficacy and toxicity. No a priori dose adjustment is required. Monitor sirolimus plasma concentrations, if available.

Description:

See summary

Potential Weak Interaction

Brigatinib

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. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on sitagliptin concentrations is unknown. Coadministration should be monitored for sitagliptin efficacy and toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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.

Description:

See summary

No Interaction Expected

Brigatinib

Sotalol

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which are not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

Do Not Coadminister

Brigatinib

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. Concentrations of brigatinib may decrease due to induction of CYP3A4 by St John’s Wort. After coadministration with rifampicin, a strong P-gp and CYP3A4 inducer, brigatinib exposure decreased by 80%. A similar effect may occur with St John’s Wort, therefore coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Sulpiride

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Brigatinib

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 decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of tacrolimus may be reduced. Monitor tacrolimus plasma concentrations, if available. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced mild inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by tacrolimus, but this is unlikely to be clinically significant. Coadministration should be monitored as toxicity of brigatinib may be increased. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tadalafil is metabolised by CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of tadalafil may be reduced. No a priori dose adjustment is required, but tadalafil dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of tamsulosin may be reduced. No a priori dose adjustment is required, but tamsulosin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as effectiveness of telithromycin may be reduced. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. However, the clinical relevance of P-gp inhibition is unknown. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by telithromycin. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

Temazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

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 CYP2C8 and CYP2C19, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of terbinafine may be reduced. Terbinafine is also a moderate-strong inhibitor of CYP2D6, which does not affect brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Testosterone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of testosterone may be reduced. No a priori dose adjustment is required, but testosterone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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

Potential Weak Interaction

Brigatinib

Thioridazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of thioridazine may be reduced. No a priori dose adjustment is required, but thioridazine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tiapride is excreted largely unchanged in urine, which is not affected by brigatinib.

Description:

See summary

Potential Interaction

Brigatinib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ticagrelor is a substrate and inhibitor of CYP3A4 and P-gp. Concentrations may decrease due to CYP3A4 induction by brigatinib. However, concentrations may also increase due to P-gp inhibition by brigatinib. The net effect of CYP3A4 induction and P-gp inhibition on ticagrelor concentrations is unknown. Coadministration should be closely monitored for ticagrelor efficacy and toxicity. No a priori dose adjustment is required. Additionally, concentrations of brigatinib may increase due to weak inhibition of CYP3A4 by ticagrelor, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Brigatinib

Timolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Timolol is predominantly metabolised in the liver by CYP2D6, which is not affected by brigatinib. 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

Brigatinib

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, which is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tolterodine is primarily metabolised by CYP2D6, with CYP3A4 playing a minor role. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of tamsulosin may be reduced. No a priori dose adjustment is required, but tamsulosin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. This is not affected by brigatinib.

Description:

See summary

Potential Weak Interaction

Brigatinib

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of tramadol may be reduced. No a priori dose adjustment is required, but tramadol dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trandolapril is hydrolysed to trandolaprilat, this is not affected by brigatinib.

Description:

See summary

No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Trazodone is primarily metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of trazodone may be reduced. No a priori dose adjustment is required, but trazodone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triamcinolone is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of triamcinolone may be reduced. No a priori dose adjustment is required, but triamcinolone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Weak Interaction

Brigatinib

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Triazolam is metabolised by CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of triazolam may be reduced. No a priori dose adjustment is required.

Description:

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Potential Interaction

Brigatinib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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). Concentrations of trimethoprim may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of trimethoprim may be reduced. Sulfamethoxazole is metabolised by CYP2C9, which is not affected by brigatinib. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Concentrations of brigatinib may increase due to inhibition of CYP2C8 by trimethoprim. After coadministration with gemfibrozil, a strong CYP2C8 inhibitor, brigatinib exposure decreased by only 12%. Therefore, a clinically relevant decrease of brigatinib exposure due to trimethoprim is unlikely. Sulfamethoxazole is a weak inhibitor of CYP2C9, which does not affect brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tropisetron is metabolised mainly by CYP2D6, which is not affected by brigatinib. However, tropisetron is a substrate of P-gp and concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for tropisetron toxicity. No a priori dose adjustment is required.

Description:

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Potential Interaction

Brigatinib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent CYP1A2 and CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of ulipristal may be reduced. If coadministration is unavoidable the addition of a barrier method as a second form of contraception while taking ulipristal with brigatinib should be considered.

Description:

See summary

No Interaction Expected

Brigatinib

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valproic acid is primarily metabolised by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). This is not affected by brigatinib. To a lesser extent (10%) valproic acid is metabolised by CYP2C9 and CYP2C19. In addition, valproic acid is an inhibitor of CYP2C9, which does not affect brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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No Interaction Expected

Brigatinib

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, which is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19, and 2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of venlafaxine may be reduced. No a priori dose adjustment is required, but venlafaxine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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Potential Interaction

Brigatinib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, and 2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of verapamil may be reduced. Verapamil is also an inhibitor of P-gp (strong). Brigatinib is a substrate of P-gp. However, as brigatinib exhibits high solubility and permeability, it is not expected that comedication with P-gp inhibitors have a relevant effect on brigatinib exposure. Therefore, a clinically relevant effect on brigatinib exposure due to P-gp inhibition by brigatinib is not expected. Concentrations of brigatinib may increase due to inhibition of CYP3A4 (moderate) by verapamil. Moderate CYP3A inhibitors may increase the AUC of brigatinib by approximately 40% based on simulations from a physiologically-based pharmacokinetic model. No a priori dose adjustment is required. Monitoring for brigatinib toxicity is warranted, since increased brigatinib exposure is associated with increased toxicity.

Description:

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Potential Weak Interaction

Brigatinib

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. Concentrations may increase due to P-gp inhibition by brigatinib. Coadministration should be monitored for vildagliptin toxicity. No a priori dose adjustment is required.

Description:

See summary

No Interaction Expected

Brigatinib

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:

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Potential Interaction

Brigatinib

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Voriconazole is metabolised by CYP2C19 (major pathway) and to a lesser extent by CYP3A4 and CYP2C9. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration is not recommended as the effectiveness of voriconazole may be reduced. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19, and 2B6. Concentrations of brigatinib may increase due to inhibition of CYP3A4 by voriconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, brigatinib exposure increased by 101%, which is associated with increased toxicity. Coadministration should be avoided. If coadministration is unavoidable, the dose of brigatinib should be reduced by approximately 50% (i.e., from 180 mg to 90 mg, or from 90 mg to 60 mg).

Description:

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Potential Weak Interaction

Brigatinib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. S-warfarin (more potent) is metabolised by CYP2C9, which is not affected by brigatinib. However, R-warfarin is primarily metabolised by CYP1A2 and CYP3A4, and concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored for efficacy (INR/PT) as effectiveness of warfarin may be reduced. No a priori dose adjustment is required, but warfarin dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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%), this is not affected by brigatinib. 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.

Description:

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Potential Weak Interaction

Brigatinib

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent CYP3A4. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of zaleplon may be reduced. No a priori dose adjustment is required.

Description:

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Potential Weak Interaction

Brigatinib

Ziprasidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of ziprasidone may be reduced. No a priori dose adjustment is required, but ziprasidone dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

No Interaction Expected

Brigatinib

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. This is not affected by brigatinib.

Description:

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Potential Weak Interaction

Brigatinib

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9, CYP2C19, CYP2D6, and CYP1A2. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of zolpidem may be reduced. No a priori dose adjustment is required.

Description:

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Potential Weak Interaction

Brigatinib

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of zopiclone may be reduced. No a priori dose adjustment is required.

Description:

See summary

Potential Weak Interaction

Brigatinib

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of zotepine may be reduced. No a priori dose adjustment is required, but zotepine dose may need to be increased when treatment appears to be subtherapeutic.

Description:

See summary

Potential Weak Interaction

Brigatinib

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Concentrations may decrease due to CYP3A4 induction by brigatinib. Coadministration should be monitored as effectiveness of zuclopenthixol may be reduced. No a priori dose adjustment is required, but zuclopenthixol dose may need to be increased when treatment appears to be subtherapeutic.

Description:

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