Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Interaction

Lorlatinib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for acenocoumarol efficacy.

Description:

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Potential Weak Interaction

Lorlatinib

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs, major UGT1A6). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. A similar effect may occur with coadministration of aspirin. Care should be taken. Monitoring of aspirin efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

Agomelatine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Care should be taken. Monitoring of agomelatine efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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. Although no pharmacokinetic interaction exposure 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

Lorlatinib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Alfentanil undergoes extensive CYP3A4 metabolism. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with alfentanil. Care should be taken. Monitoring of alfentanil efficacy may be required .

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with alfuzosin. Care should be taken. Monitoring of alfuzosin efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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. Additionally, aliskiren is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with aliskiren. Care should be taken. Monitoring of aliskiren efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib. Allopurinol is also an inhibitor of xanthine oxidase, which does not affect lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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 weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Similar effects may occur after coadministration with alosetron. Therefore, Monitoring of alosetron efficacy may be required. Concentrations may also decrease due to induction of CYP1A2 by lorlatinib in vitro, but this is unlikely to be clinically significant. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with alosetron is not expected.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with alprazolam. Care should be taken. Monitoring of alprazolam efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with aluminium hydroxide is not expected.

Description:

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Potential Weak Interaction

Lorlatinib

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ambrisentan is metabolized by glucuronidation via UGT1A3, UGT1A9, and UGT2B7 and to a lesser extent by CYP3A4 and CYP2C19. Moreover, ambrisentan is a substrate of P-gp. Ambrisentan concentrations may decrease due to weak induction of UGT and moderate induction of CYP3A4 and P-gp by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Similar effects may occur after coadministration with ambrisentan. Care should be taken. Monitoring of ambrisentan efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amiodarone is metabolised by CYP3A4 and CYP2C8. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of amiodarone efficacy may be required. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate), and P-gp (strong). Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 and P-gp by desethylamiodarone, but this is unlikely to be clinically significant. 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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No Interaction Expected

Lorlatinib

Amisulpride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily eliminated renally (possibly via OCT). Concentrations may increase due to potential inhibition of OCT by lorlatinib, but this is unlikely to be clinically relevant.

Description:

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Potential Weak Interaction

Lorlatinib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2, and 2C9. Amitriptyline concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of amitriptyline efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with amlodipine. Care should be taken. Monitoring of amlodipine efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 , and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant.

Description:

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Potential Weak Interaction

Lorlatinib

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. Lorlatinib 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

Lorlatinib

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. This is not affected by lorlatinib. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours.

Description:

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No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with antacids are not expected.

Description:

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Do Not Coadminister

Lorlatinib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but coadministration is contraindicated. Apixaban is a substrate of P-gp and BCRP, and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9, and 2C19. Apixaban concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of P-gp and weak induction of CYP2C9 by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with apixaban. Coadministration is therefore contraindicated.

Description:

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Potential Weak Interaction

Lorlatinib

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro, but this is unlikely to be clinically significant. Aprepitant concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of aprepitant efficacy may be required. During treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of lorlatinib may increase due to moderate inhibition of CYP3A4 by aprepitant during treatment. Care should be taken. Monitoring for lorlatinib toxicity may be required.

Description:

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Potential Weak Interaction

Lorlatinib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aripiprazole is metabolised by CYP3A4 and CYP2D6 and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of aripiprazole efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 weak induction of UGT and moderate induction of CYP3A4 by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of asenapine efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of astemizole efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and P-gp by lorlatinib. Concentrations may also increase due to potential OATP1B1 inhibition by lorlatinib, but this effect has only been established in vitro and unlikely to be clinically relevant. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with atorvastatin. Care should be taken. Monitoring of atorvastatin efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to moderate induction of P-gp by lorlatinib. Care should be taken. Monitoring of azithromycin efficacy may be required. Azithromycin is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by azithromycin is unknown and no clinically relevant effect on lorlatinib exposure is expected.

Description:

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No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

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Potential Interaction

Lorlatinib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bedaquiline is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with bedaquiline. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor bedaquiline efficacy.

Description:

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No Interaction Expected

Lorlatinib

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. Concentrations may increase due to potential OAT3 inhibition by lorlatinib, but this is unlikely to be significant. 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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of bepridil efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with betamethasone. Care should be taken. Monitoring of betamethasone efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1, which does not affect lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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, which are not affected by lorlatinib. Absorption from the gastrointestinal tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of bisoprolol efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 lorlatinib may decrease due to weak induction of CYP3A4 by bosentan, but this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration of lorlatinib with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration of lorlatinib with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with bosentan. Care should be taken. Monitoring of bosentan efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of bromazepam efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with budesonide. Care should be taken. Monitoring of budesonide efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

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). Concentrations may decrease due to moderate induction of CYP3A4 and weak induction of UGT by lorlatinib, although the magnitude of the UGT induction effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Similar effects may occur after coadministration with buprenorphine. Care should be taken. Monitoring of buprenorphine efficacy may be required.

Description:

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Potential Weak Interaction

Lorlatinib

Bupropion

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Bupropion is primarily metabolised by CYP2B6 and concentrations will decrease due to weak induction of CYP2B6 by lorlatinib. After coadministration of lorlatinib (150 mg once daily for 15 days) with bupropion (100 mg single dose), the AUC of bupropion decreased by 50%. Care should be taken. Monitoring of bupropion efficacy may be required. Bupropion is also strong inhibitor of CYP2D6, which does not affect lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with buspirone. Care should be taken. Monitoring of buspirone efficacy may be required.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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, this is not affected by lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Do Not Coadminister

Lorlatinib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8 and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Moreover, carbamazepine is an inducer of CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong), CYP1A2 (weak), CYP2B6, P-gp (moderate) and UGT1A1. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by carbamazepine. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. A similar effect may occur after coadministration with carbamazepine. Coadministration is contraindicated.

Description:

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Potential Weak Interaction

Lorlatinib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4, and 2B7, and additionally metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 and weak induction of UGT and CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with carvedilol. Care should be taken. Monitoring of carvedilol efficacy may be required. Carvedilol is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Ceftriaxone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib. In vitro data indicate that cetirizine is also an inhibitor of OCT2, this does not affect lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chloramphenicol is predominantly glucuronidated and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong), and CYP2D6 (weak). Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition by chloramphenicol. Coadministration should be approached with caution. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with chloramphenicol. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%. 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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with chlordiazepoxide. Care should be taken. Monitoring of chlordiazepoxide efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

Chlortalidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciclosporin is a substrate of CYP3A4 and P-gp, and concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with ciclosporin. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for ciclosporin efficacy and ciclosporin plasma concentrations. Furthermore, ciclosporin inhibits CYP3A4 and OATP1B1. Concentrations of lorlatinib may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine is metabolised by CYP450 enzymes. In vitro data indicate that cimetidine inhibits OAT1 and OCT2, but at concentrations much higher than the observed clinical concentrations. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with cimetidine is not expected. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6, and 2C19. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by cimetidine, but this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant. It is also metabolised and partially cleared through the bile and intestine. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to CYP3A4 inhibition by ciprofloxacin. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with cisapride. Care should be taken. Monitoring of cisapride efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of citalopram efficacy may be required.

Description:

See summary

Potential Interaction

Lorlatinib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clarithromycin is metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong) and P-gp. Clarithromycin concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with clarithromycin. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for clarithromycin efficacy. Moreover, lorlatinib is metabolised by CYP3A4 and concentrations may increase due to strong inhibition by clarithromycin. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with clarithromycin. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Clindamycin is metabolised by CYP3A4, and in vitro data suggest that it is a CYP3A4 inhibitor. Concentrations of lorlatinib may increase due to inhibition of CYP3A4 by clindamycin, but this is unlikely to be clinically significant. Concentrations of clindamycin may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with clindamycin. Care should be taken. Monitoring of clindamycin efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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

No Interaction Expected

Lorlatinib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces. In vitro data suggest that clofazimine is a CYP3A4 inhibitor. Concentrations of lorlatinib may increase due to inhibition of CYP3A4 by clofazimine, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 increase due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Moreover, concentrations of clomipramine may decrease and desmethylclomipramine increase due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Overall, the effect of induced metabolism by lorlatinib on clomipramine efficacy or toxicity is unknown. Care should be taken. Monitoring of clomipramine efficacy and toxicity may be required. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6, which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. Clonidine is also a weak inhibitor of OCT2, which does not affect lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6, and 1A2 playing a minor role. Concentrations of clopidogrel may decrease and concentrations of the active metabolite may increase, due to moderate induction of CYP3A4 and weak induction of CYP2B6 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with bupropion, a combined CYP2B6 and CYP3A4 substrate, the AUC of bupropion decreased by 50%. A similar effect may occur after coadministration with clopidogrel. Also, clopidogrel concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor for clopidogrel toxicity. Moreover, clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and in vitro of CYP2C9 at high concentrations, but this does not affect lorlatinib. The clinical relevance of CYP2C9 inhibition is unknown.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. Nordiazepam concentrations may decrease and diazepam concentrations may increase due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of clorazepate efficacy and toxicity may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Moreover, concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of clozapine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Codeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolized by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Concentrations of codeine may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with codeine. Additionally, the metabolite morphine is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with codeine. Care should be taken. Monitoring of codeine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease by moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with colchicine. Care should be taken. Monitoring of colchicine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Dabigatran is transported via P-gp and is renally excreted. Concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with dabigatran. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor dabigatran efficacy and increase the dabigatran dose by 200%.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

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 increase due to weak CYP2C9 induction and may decrease due to moderate induction of CYP3A4 by lorlatinib. The net effect is unknown. Coadministration with lorlatinib could reduce the contraceptive efficacy of desogestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 decrease lorlatinib plasma concentrations. However, the clinical relevance of this interaction is not known. Moreover, the induction of CYP3A4 by dexamethasone has not been established yet. However, dexamethasone is a substrate of CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with dexamethasone. Care should be taken. Monitoring of dexamethasone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with dextropropoxyphene. Care should be taken. Monitoring of dextropropoxyphene efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Additionally, morphine is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with diamorphine. Care should be taken. Monitoring of diamorphine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. Diazepam concentrations may decrease and nordiazepam and temazepam concentrations increase, due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of diazepam toxicity and efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. A similar effect may occur after coadministration with diclofenac. However, no clinically significant effect on diclofenac exposure is expected.

Description:

See summary

Potential Interaction

Lorlatinib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp. Concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with digoxin. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for digoxin efficacy and plasma concentrations.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dihydrocodeine undergoes predominantly direct glucuronidation , with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Similar effects may occur after coadministration with dihydrocodeine. Care should be taken. Monitoring of dihydrocodeine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diltiazem is metabolised by CYP3A4 and CYP2D6, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Monitoring of diltiazem efficacy may be required. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp. However, the clinical relevance of P-gp inhibition by diltiazem is unknown. Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition by diltiazem. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9, and 2C19. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Care should be taken. Monitoring of diphenhydramine efficacy may be required. Diphenhydramine is a weak inhibitor of CYP2D6, this does not affect lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of dipyridamole efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of disopyramide efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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%). Concentrations may decrease due to moderate induction of CYP3A4 and in vitro induction of UGT by lorlatinib, but this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with domperidone. Care should be taken. Monitoring of domperidone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

Dopamine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with doxazosin. Care should be taken. Monitoring of doxazosin efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

Doxepin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolised by CYP2D6. Both of these metabolic pathways are not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib. Between 40-60% of an administered dose can be accounted for in the urine.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of dronabinol efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Drospirenone is metabolised to a minor extent via CYP3A4, And concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with drospirenone. Coadministration with lorlatinib could reduce the contraceptive efficacy of drospirenone and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. 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

Lorlatinib

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 and concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with dutasteride. Care should be taken. Monitoring of dutasteride efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4), and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with dydrogesterone. Coadministration with lorlatinib could reduce the contraceptive efficacy of dydrogesterone and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with edoxaban. Care should be taken. Monitoring for edoxaban efficacy and anti-Xa levels, if available, may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of eltrombopag efficacy may be required. Concentrations may also decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 OAT s), Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with erythromycin. Monitor closely for erythromycin efficacy. Moreover, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Although erythromycin is an inhibitor of P-gp, no clinically significant effect on lorlatinib exposure is expected. However, lorlatinib is metabolised by CYP3A4 and concentrations may increase due to moderate inhibition by erythromycin. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of escitalopram efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Esomeprazole

Quality of Evidence: 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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of esomeprazole efficacy may be required. Esomeprazole is also an inhibitor of CYP2C19, but this does not affect lorlatinib. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with esomeprazole is not expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with estazolam. Care should be taken. Monitoring of estazolam efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Estradiol is metabolised by CYP3A4, CYP1A2, and is glucuronidated . Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with estradiol. Coadministration with lorlatinib could reduce the contraceptive efficacy of estradiol and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation, and glucuronidation (UGT1A1). Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with ethinylestradiol. Coadministration with lorlatinib could reduce the contraceptive efficacy of ethinylestradiol and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Etonogestrel is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with etonogestrel. Coadministration with lorlatinib could reduce the contraceptive efficacy of etonogestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Potential Interaction

Lorlatinib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with everolimus. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for everolimus efficacy and plasma concentrations.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. 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

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on ezetimibe exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro. No clinically significant effect on famotidine exposure is expected. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with famotidine is not expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with felodipine. Care should be taken. Monitoring of felodipine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib. In vitro data suggest that fenofibric acid inhibits OAT3, which does not affect lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with fentanyl. Care should be taken. Monitoring of fentanyl efficacy may be required .

Description:

See summary

Potential Weak Interaction

Lorlatinib

Fexofenadine

Quality of Evidence: Low

Summary:

Coadministration has not been studied and care should be taken. Fexofenadine is a substrate of P-gp and concentrations will decrease due to moderate induction of P-gp by lorlatinib. In non-small cell lung cancer patients (n=8), coadministration of lorlatinib (100 mg once daily for 15 days) and fexofenadine (60 mg single dose, day 1), decreased the AUC of fexofenadine by 67%. Care should be taken. Monitoring of fexofenadine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with finasteride. Care should be taken. Monitoring of finasteride efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, which is not affected by lorlatinib. Flucloxacillin is described as a CYP3A4 inducer. However, the mechanism and clinical relevance of this interaction is unknown. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by flucloxacillin. Concomitant use of lorlatinib with rifampicin, a strong CYP3A4 inducer, was associated with severe hepatotoxicity. The effect of the concomitant use of flucloxacillin on lorlatinib exposure or the risk of hepatotoxicity is unknown. Monitoring of lorlatinib efficacy and hepatotoxicity should be considered.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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). Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition by fluconazole. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

No Interaction Expected

Lorlatinib

Flucytosine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of fludrocortisone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with flunitrazepam. Care should be taken. Monitoring of flunitrazepam efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of fluoxetine efficacy may be required. Fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19, which does not affect lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of flurazepam efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with fluticasone. Care should be taken. Monitoring of fluticasone efficacy may be required. Note: A clinically significant interaction is also unlikely with the topical use of fluticasone.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Similar effects may occur after coadministration with fluvastatin. Care should be taken. Monitoring of fluvastatin efficacy may be required. Moreover, fluvastatin potentially inhibits CYP2C9. However, the clinical relevance of CYP2C9 inhibition is unknown and this does not affect lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition by fluvoxamine. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. As multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low .

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro, but this is unlikely to be clinically significant. Aprepitant concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of aprepitant efficacy may be required. During treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of lorlatinib may increase due to moderate inhibition of CYP3A4 by aprepitant during treatment. Care should be taken. Monitoring for lorlatinib toxicity may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

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 metabolized by CYP2C9 and to a lesser extent by CYP2C19. Concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Phenytoin is also a strong inducer of CYP3A4, UGT, and P-gp. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by phenytoin. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. Similar effects may occur after coadministration with fosphenytoin. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Lorlatinib

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). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on furosemide exposure is expected. A large proportion of furosemide is also eliminated unchanged renally (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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, which does not affect lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Gemfibrozil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7, and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on gemfibrozil exposure is expected. Moreover, gemfibrozil is an inhibitor of CYP2C8 (strong), OATP1B1, and OAT3, but this does not affect lorlatinib. 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

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Concentrations may decrease due to moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with gestodene. Coadministration with lorlatinib could reduce the contraceptive efficacy of gestodene and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with glibenclamide. Care should be taken. Monitoring of glibenclamide efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Gliclazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Gliclazide is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C19, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Care should be taken. Monitoring of gliclazide efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Glimepiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Glimepiride is mainly metabolised by CYP2C9, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with glimepiride. Care should be taken. Monitoring of glimepiride efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Glipizide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Glipizide is mainly metabolised by CYP2C9, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with glipizide. Care should be taken. Monitoring of glipizide efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with granisetron. Care should be taken. Monitoring of granisetron efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Grapefruit juice is known to inhibit CYP3A4 enzymes. Lorlatinib is metabolised by CYP3A4, and concentrations may increase. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Lorlatinib

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Lorlatinib

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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 lorlatinib. Care should be taken. Monitoring of lorlatinib efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 weak induction of UGT and moderate induction of CYP3A4 by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of haloperidol efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Hydralazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydralazine is metabolised via primary oxidative metabolism and acetylation. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by hydralazine, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with hydrocodone. Care should be taken. Monitoring of hydrocodone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with hydrocortisone. Care should be taken. Monitoring of hydrocortisone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on hydromorphone exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of hydroxyzine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

Ibandronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ibandronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction exposure 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

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on ibuprofen exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Iloperidone is metabolised by CYP3A4 and CYP2D6 and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of iloperidone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Imipramine and desipramine are both metabolised by CYP2D6. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of imipramine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Indapamide is extensively metabolised by CYP450, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of indapamide efficacy may be required. OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

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

Lorlatinib

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

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Irbesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9), and concentrations may decrease due to weak induction of CYP2C9 and UGT by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with irbesartan. Care should be taken. Monitoring of irbesartan efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Isosorbide dinitrate concentrations may decrease and nitric oxide concentrations may increase due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with isosorbide dinitrate. Care should be taken. Monitoring of isosorbide dinitrate toxicity may be required.

Description:

See summary

Potential Interaction

Lorlatinib

Itraconazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be approached with caution. Itraconazole is primarily metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp, and BCRP. Although itraconazole is an inhibitor of P-gp and BCRP, no clinically significant effect on lorlatinib is expected. Lorlatinib is metabolised by CYP3A4, and concentrations will increase due to strong inhibition by itraconazole. In healthy subjects (n=12), coadministration of lorlatinib (100 mg single dose) with itraconazole (200mg once daily for 5 days), increased the AUC of lorlatinib by 42%. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with ivabradine. Care should be taken. Monitoring of ivabradine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ketoconazole is a substrate of CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with ketoconazole. Monitoring of ketoconazole efficacy may be required. Moreover, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. No clinically significant effect of P-gp inhibition on lorlatinib exposure is expected. However, lorlatinib is metabolised by CYP3A4 and concentrations may increase due to strong inhibition by ketoconazole. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with ketoconazole. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Labetalol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7) and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of labetalol efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with lacidipine. Care should be taken. Monitoring of lacidipine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 is not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of lansoprazole efficacy may be required. Also, lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with lansoprazole is not expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with lercanidipine. Care should be taken. Monitoring of lercanidipine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Levonorgestrel mainly is metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with levonorgestrel. Coadministration with lorlatinib could reduce the contraceptive efficacy of levonorgestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Do Not Coadminister

Lorlatinib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with levonorgestrel. Coadministration with lorlatinib could reduce the contraceptive efficacy of levonorgestrel. The Faculty of Sexual and Reproductive Healthcare Clinical Guidance states that the use of copper intrauterine device (Cu-IUD) is the most effective method for emergency contraception in women receiving an enzyme-inducing drug and that women who are not eligible for Cu-IUD should be offered a total of 3 mg levonorgestrel as a single dose for emergency contraception. Note: doubling the standard dose is outside the product license and there is limited evidence in relation to the efficacy.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on levothyroxine exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of lidocaine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Linagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp and concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Care should be taken. Monitoring for linagliptin efficacy may be required. Furthermore, linagliptin is a weak inhibitor of CYP3A4. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by linagliptin, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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, the use of live vaccines for immunisation is contraindicated. However, since lorlatinib is not an immunosuppressant drug, no additional unwanted effects are expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with loperamide. Care should be taken. Monitoring of loperamide efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of loratadine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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, this is unlikely to be affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on lormetazepam exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Losartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations, and concentrations of its active metabolite may increase due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with losartan. Care should be taken. Monitoring of losartan toxicity may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with lovastatin. Care should be taken. Monitoring of lovastatin efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with macitentan. Care should be taken. Monitoring of macitentan efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Maprotiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Maprotiline is mainly metabolised by CYP2D6, which is not affected by lorlatinib. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of maprotiline efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Medroxyprogesterone is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with medroxyprogesterone. Coadministration with lorlatinib could reduce the contraceptive efficacy of medroxyprogesterone and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Do Not Coadminister

Lorlatinib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on mefenamic acid exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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.

Description:

See summary

No Interaction Expected

Lorlatinib

Meropenem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of the renal transporters OAT3>OAT1. Meropenem concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro and is unlikely to be relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Concentrations of lorlatinib may decrease due to induction of CYP3A4 by metamizole (in vitro), but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

Metformin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine and is substrate of OCT1, OCT2, OCT3, MATE1, and MATE2K. Concentrations may increase due to potential inhibition of OCT1 and MATE1 by lorlatinib, but this effect has only been established in vitro. No clinically significant effect on metformin exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with methadone. Care should be taken. Monitoring of methadone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib, or to be affected if coadministered with lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with methylprednisolone. Care should be taken. Monitoring of methylprednisolone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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), which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Metolazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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). Thus, a clinically relevant interaction with lorlatinib is not expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which are not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mianserin is metabolised by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of mianserin efficacy may be required.

Description:

See summary

Potential Interaction

Lorlatinib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Miconazole is extensively metabolized by the liver. Miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition by miconazole. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with miconazole. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%. Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinically relevant interaction exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Midazolam (oral)

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Midazolam is metabolised by CYP3A4, and concentrations will decrease due to moderate induction of CYP3A4 by lorlatinib. In healthy subjects (n=3), coadministration of midazolam (2 mg single dose, day 1) and lorlatinib (25 mg once daily, day 1-15), decreased the AUC of midazolam by 61%. Care should be taken. Monitoring of midazolam efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Midazolam (parenteral)

Quality of Evidence: Low

Summary:

Coadministration has not been studied but care should be taken. Midazolam is metabolised by CYP3A4, and concentrations decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with oral midazolam, the AUC of midazolam decreased by 61%. A similar effect may occur with parenteral midazolam. Care should be taken. Monitoring of midazolam efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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%). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on milnacipran exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of mirtazapine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with mometasone. Care should be taken. Monitoring of mometasone efficacy may be required. Note: No clinically relevant interactions are expected with the topical use of mometasone.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of montelukast efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. A similar effect may occur after coadministration with morphine. Additionally, morphine is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with morphine. Care should be taken. Monitoring of morphine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Moxifloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Moxifloxacin is predominantly glucuronidated by UGT1A1 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of moxifloxacin efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7, and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of mycophenolate efficacy may be required. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3, but this does not affect lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. However, no clinically significant effect on naproxen exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of nateglinide efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nefazodone is metabolised mainly by CYP3A4 and is also a strong inhibitor of CYP3A4. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with nefazodone. Moreover, lorlatinib is metabolised by CYP3A4 and concentrations may increase due to strong inhibition by nefazodone. Coadministration should be approached with caution. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with nefazodone. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of nicardipine efficacy may be required. Moreover, nicardipine is a weak inhibitor of CYP3A4. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by nicardipine, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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. These are not affected by lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with nifedipine. Care should be taken. Monitoring of nifedipine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nisoldipine is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with nisoldipine According to the label of nisoldipine, coadministration with CYP3A4 inhibitors should be avoided. If coadministration is unavoidable, monitor closely for nisoldipine efficacy.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with nitrendipine. Care should be taken. Monitoring of nitrendipine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of nitrofurantion efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4), and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with norelgestromin. Coadministration with lorlatinib could reduce the contraceptive efficacy of norelgestromin and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Do Not Coadminister

Lorlatinib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Norethindrone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation . Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with norethisterone. Coadministration with lorlatinib could reduce the contraceptive efficacy of norethisterone and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Do Not Coadminister

Lorlatinib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Norgestimate is rapidly deacetylated to the active metabolite, which is further metabolised via CYP450. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with norgestimate. Coadministration with lorlatinib could reduce the contraceptive efficacy of norgestimate and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Do Not Coadminister

Lorlatinib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolized by CYP3A4 and is glucuronidated to a minor extent. Concentrations may decrease due to moderate induction of CYP3A4 and in vitro UGT induction by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with norgestrel. Coadministration with lorlatinib could reduce the contraceptive efficacy of norgestrel and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Olanzapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of olanzapine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with omeprazole. Care should be taken. Monitoring of omeprazole efficacy may be required. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. This does not affect lorlatinib. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with omeprazole is not expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Ondansetron concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro, but this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with ondansetron. Care should be taken. Monitoring of ondansetron efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on oxazepam exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxcarbazepine is extensively metabolized to the active metabolite monohydroxyderivate (MHD) through cytosolic enzymes. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by oxcarbazepine and MHD. After coadministration with modafinil, a moderate CYP3A4 inducer, the AUC of lorlatinib decreased by 23%. Monitoring of lorlatinib efficacy and plasma concentrations (if available) should be considered.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. This is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with oxycodone. Care should be taken. Monitoring of oxycodone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of paliperidone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Palonosetron concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro, but this is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with palonosetron. Care should be taken. Monitoring of palonosetron efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of pantoprazole efficacy may be required. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with pantoprazole is not expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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 is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Paracetamol (Acetaminophen)

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15) and sulfation and, to a lesser extent, by oxidation (CYPs 2E1 (major), 1A2, 3A4, and 2D6). Concentrations will decrease due to weak induction of UGT by lorlatinib. In non-small cell lung cancer patients (n=8), coadministration of lorlatinib (100 mg once daily for 15 days) and paracetamol (100 mg single dose, day 1), decreased the AUC of paracetamol by 45%. However, no clinically significant effect on paracetamol exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. Moreover, paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9, which do not affect lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of perazine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

Perindopril

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT and CYP2B6, and moderate induction of CYP3A4 by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with bupropion, a combined CYP2B6 and CYP3A4 substrate, the AUC of bupropion decreased by 50%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with pethidine. Care should be taken. Monitoring of pethidine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenobarbital is metabolized by CYP2C19 and 2C9 (major pathway) and to a lesser extent by CYP2E1. Concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Phenobarbital is also a strong inducer of CYP3A4, CYP2C9, CYP2C8, and UGTs. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by phenobarbital. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. Similar effects may occur after coadministration with phenobarbital. Coadministration is contraindicated.

Description:

See summary

Potential Interaction

Lorlatinib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Concentrations may decrease due to moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with phenprocoumon. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor phenprocoumon efficacy.

Description:

See summary

Do Not Coadminister

Lorlatinib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Phenytoin is also a strong inducer of CYP3A4, UGT and P-gp. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by phenytoin. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. Similar effects may occur after coadministration with fosphenytoin. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of pimozide efficacy may be required .

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Thus, care should be taken. Monitoring of pioglitazone efficacy may be required. Concentrations may also decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Moreover, pitavastatin is a substrate of OATP1B1 . Concentrations may decrease due to weak induction of UGT and CYP2C9 by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. This is unlikely to be clinically significant. Concentrations may also increase due to potential OATP1B1 inhibition by lorlatinib, but this effect has only been established in vitro and is unlikely to be clinically relevant.

Description:

See summary

Potential Interaction

Lorlatinib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Concentrations may decrease due to weak induction of UGT and moderate induction of P-gp by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with posaconazole. Monitor closely for posaconazole efficacy. Moreover, posaconazole is a strong inhibitor of CYP3A4. Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition by posaconazole. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with posaconazole. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6, and to a lesser extent by CYP2C9 and CYP2C19. Concentrations of prasugrel may decrease and concentrations of its active metabolite may increase due to moderate induction of CYP3A4 and weak induction of CYP2B6 and CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with bupropion, a combined CYP2B6 and CYP3A4 substrate, the AUC of bupropion decreased by 50%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with prasugrel. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor prasugrel efficacy.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may increase due to potential OATP1B1 inhibition by lorlatinib, but this effect has only been established in vitro and is unlikely to be clinically relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with prednisolone. Care should be taken. Monitoring of prednisolone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with prednisone. Care should be taken. Monitoring of prednisone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 are not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of propafenone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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). Concentrations may decrease due to induction of CYP1A2 by lorlatinib and UGT in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with prucalopride. Care should be taken. Monitoring of prucalopride efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with quetiapine. Care should be taken. Monitoring of quetiapine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with quinidine. Moreover, quinidine is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with quinidine. Care should be taken. Monitoring of quinidine efficacy may be required. Furthermore, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak), and P-gp (moderate). Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by quinidine, but this is unlikely to be clinically significant. Although quinidine is an inhibitor of P-gp, no clinically significant effect on lorlatinib exposure is expected .

Description:

See summary

Potential Weak Interaction

Lorlatinib

Rabeprazole

Quality of Evidence: 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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of rabeprazole efficacy may be required. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with rabeprazole is not expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown and unlikely to be clinically relevant.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may increase due to potential inhibition of OAT3 by lorlatinib, but this effect has only been established in vitro. No clinically significant effect on ranitidine exposure is expected. Lorlatinib exposure could be pH-dependent. However, concomitant use with rabeprazole, a proton pump inhibitor, did not have a significant effect on lorlatinib exposure. Thus, a clinically relevant interaction with ranitidine is not expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ranolazine is primarily metabolized by CYP3A4, to a lesser extent by CYP2D6, and is a substrate of P-gp. Concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with ranolazine. Care should be taken. Monitoring of ranolazine efficacy may be required. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4, and CYP2D6. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 and P-gp by ranolazine, but this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with reboxetine. Care should be taken. Monitoring of reboxetine efficacy may be required. 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

Lorlatinib

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 moderate induction of CYP3A4 and increase due to potential OATP1B1 inhibition by lorlatinib, however OATP1B1 inhibition has only been established in vitro. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of repaglinide efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on retinol exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with rifabutin. Rifabutin is also a strong CYP3A4 and P-gp inducer. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by rifabutin. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. A similar effect may occur after coadministration with rifabutin. Coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Lorlatinib

Rifampicin

Quality of Evidence: Low

Summary:

Coadministration has been studied and is contraindicated. Rifampicin is metabolised via deacetylation and is a strong CYP3A4 and P-gp inducer. Lorlatinib is metabolised by CYP3A4, and concentrations will decrease due to induction by rifampicin. In healthy subjects (n=12), after coadministration of lorlatinib (100 mg single dose) with rifampicin (600 mg once daily for 12 days) the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. Coadministration is contraindicated.

Description:

See summary

Do Not Coadminister

Lorlatinib

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. Lorlatinib is metabolised by CYP3A4, and concentrations may decrease due to induction by rifapentine. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. A similar effect may occur after coadministration with rifapentine. Coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Furthermore, risperidone is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with risperidone. Care should be taken. Monitoring of risperidone efficacy may be required.

Description:

See summary

Potential Interaction

Lorlatinib

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2, and hydrolytic enzymes) and partly eliminated unchanged in urine. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Moreover, rivaroxaban is substrate of P-gp and BCRP and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with rivaroxaban. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor rivaroxaban efficacy.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Rosiglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. Care should be taken. Monitoring of rosiglitazone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is substrate of BCRP. Concentrations may decrease due to inhibition of BCRP by lorlatinib (gastrointestinal tract), however, this is unlikely to be of clinical significance. Concentrations may also increase due to potential OATP1B1 inhibition by lorlatinib, but this effect has only been established in vitro and is unlikely to be clinically relevant. No effect on lorlatinib exposure is expected.

Description:

See summary

No Interaction Expected

Lorlatinib

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, which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. However, the systemic exposure of salmeterol is low, therefore a clinically significant interaction is unlikely.

Description:

See summary

No Interaction Expected

Lorlatinib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration of saxagliptin with rifampicin, a strong CYP3A4 and P-gp inducer, the AUC of saxagliptin decreased by 76%. However, dipeptidyl peptidase-4 (DPP-4) inhibition was unchanged. Thus, although the pharmacokinetics of saxagliptin may alter when coadministered with lorlatinib, the pharmacodynamic properties of saxagliptin are expected to remain unchanged.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of sertindole efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 and concentrations may decrease due to moderate induction of CYP3A4 and weak induction of CYP2B6 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with bupropion, a combined CYP2B6 and CYP3A4 substrate, the AUC of bupropion decreased by 50%. Care should be taken. Monitoring of sertraline efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with sildenafil. Care should be taken. Monitoring of sildenafil efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with simvastatin. Care should be taken. Monitoring of simvastatin efficacy may be required. Simvastatin is also a substrate of BCRP and the active metabolite is a substrate of OATP1B1 . Concentrations may decrease due to inhibition of BCRP (gastrointestinal tract) and OATP1B1, however, this is unlikely to be of clinical significance. No effect on lorlatinib exposure is expected.

Description:

See summary

Potential Interaction

Lorlatinib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Sirolimus is metabolised by CYP3A4 and is substrate of P-gp. Concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Similar effects may occur after coadministration with sirolimus. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for sirolimus efficacy and plasma concentrations.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 and P-gp by lorlatinib and increase due to potential OAT3 inhibition by lorlatinib, however OAT3 inhibition has only been established in vitro. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. Care should be taken. Monitoring of sitagliptin efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase, which is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Do Not Coadminister

Lorlatinib

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. Lorlatinib concentrations may decrease due to induction by St John’s Wort. After coadministration with rifampicin, a strong CYP3A4 inducer, the AUC of lorlatinib decreased by 85%. Moreover, concomitant use of lorlatinib with rifampicin was associated with severe hepatotoxicity. A similar effect may occur after coadministration with St John’s Wort. Therefore, coadministration is contraindicated.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Sulfadiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with sulfadiazine. Care should be taken. Monitoring for sulfadiazine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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. This is not affected by lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tacrolimus is metabolised mainly by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with tacrolimus. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for tacrolimus efficacy and plasma concentrations. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Concentrations of lorlatinib may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with tadalafil. Care should be taken. Monitoring of tadalafil efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with tamsulosin. Care should be taken. Monitoring of tamsulosin efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Interaction

Lorlatinib

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Monitoring of telithromycin efficacy may be required. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. However, the clinical relevance of P-gp inhibition is unknown. Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition by telithromycin. Coadministration should be approached with caution. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with telithromycin. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Telmisartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Telmisartan is mainly glucuronidated by UGT1A3 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYPs 1A2, 2D6, and 3A4 substrate), the AUC of paracetamol decreased by 45%. Care should be taken. Monitoring of telmisartan efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 and concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown. No clinically significant effect on temazepam exposure is expected.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4, and to a lesser extent CYP2C8 and CYP2C19. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Concentrations may also decrease due to weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with terbinafine. Care should be taken. Monitoring of terbinafine efficacy may be required. Terbinafine is also a moderate-strong inhibitor of CYP2D6, which does not affect lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with testosterone. Care should be taken. Monitoring of testosterone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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. Concentrations may decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of thioridazine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Interaction

Lorlatinib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ticagrelor is a substrate and of CYP3A4 and P-gp and concentrations may decrease due to moderate induction of CYP3A4 and P-gp by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with ticagrelor. If coadministration is unavoidable, closely monitor ticagrelor efficacy. Ticagrelor is also a weak inhibitor of CYP3A4. Concentrations of lorlatinib may increase due to weak inhibition of CYP3A4 by ticagrelor, but this is unlikely to be clinically significant.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib. Note: the systemic absorption of timolol after ocular administration is low. Therefore, a clinically relevant interaction via CYP2D6 is unlikely.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

Tolbutamide

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Concentrations will decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration of lorlatinib (100 mg once daily for 15 days) with tolbutamide (500 mg single dose), the AUC of tolbutamide decreased by 43%. Care should be taken. Monitoring of tolbutamide efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with tolterodine. Care should be taken. Monitoring of tolterodine efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. However, no clinically significant effect on furosemide exposure is expected. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with tramadol. Care should be taken. Monitoring of tramadol efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with trazodone. Monitoring of trazodone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with triamcinolone. Care should be taken. Monitoring of triamcinolone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with triazolam. Care should be taken. Monitoring of triazolam efficacy may be required.

Description:

See summary

Potential Interaction

Lorlatinib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with trimethoprim. Both sulfamethoxazole and trimethoprim are metabolised by CYP2C9, and concentrations of both may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with sulfamethoxazole and trimethoprim. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor trimethoprim/sulfamethoxazole efficacy and closely monitor trimethoprim/sulfamethoxazole plasma concentrations, if available. Finally, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is also a weak inhibitor of CYP2C9. This does not affect lorlatinib clearance or metabolism.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 lorlatinib. Additionally, tropisetron is a substrate of P-gp and concentrations may decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with tropisetron. Care should be taken. Monitoring of tropisetron efficacy may be required.

Description:

See summary

Do Not Coadminister

Lorlatinib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contraindicated. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with ulipristal. Coadministration with lorlatinib could reduce the contraceptive efficacy of ulipristal and therefore a reliable method of barrier contraception must be used in addition to hormonal contraceptives.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Valproic acid is primarily metabolized by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolized by CYP2C9 and CYP2C19. Concentrations may decrease due to weak induction of CYP2C9 and UGT by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration of lorlatinib with paracetamol (a UGT, SULT, and CYP1A2, 2D6 and 3A4 substrate), the AUC of paracetamol decreased by 45%. A similar effect may occur after coadministration with valproic acid. Care should be taken. Monitor valproic acid efficacy and valproic acid concentrations, if available. In addition, valproic acid is an inhibitor of CYP2C9, which does not affect lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of venlafaxine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, and 2C9. Concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Monitoring of verapamil efficacy may be required. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong). Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to moderate inhibition by verapamil. Care should be taken. If coadministration is unavoidable, monitor for lorlatinib toxicity.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 decrease due to moderate induction of P-gp by lorlatinib. After coadministration with fexofenadine, a sensitive P-gp substrate, the AUC of fexofenadine decreased by 67%. A similar effect may occur after coadministration with vildagliptin. Care should be taken. Monitoring of vildagliptin efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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

Lorlatinib

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Voriconazole is metabolised by CYP2C19 (major pathway) and to a lesser extent by CYP3A4 and CYP2C9. Concentrations may decrease due to weak induction of CYP2C9 and moderate induction of CYP3A4 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. A similar effect may occur after coadministration with voriconazole. Monitoring of voriconazole efficacy may be required. Moreover, voriconazole is a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19, and 2B6. Lorlatinib is metabolised by CYP3A4, and concentrations may increase due to strong inhibition by voriconazole. After coadministration with itraconazole, a strong inhibitor of CYP3A4, the AUC of lorlatinib increased by 42%. A similar effect may occur after coadministration with voriconazole. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for lorlatinib toxicity and reduce lorlatinib dose by 25%.

Description:

See summary

Potential Interaction

Lorlatinib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. R-warfarin Concentrations may also decrease due to induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Moreover, S-warfarin (more potent) is a substrate of CYP2C9, and concentrations may decrease due to weak induction of CYP2C9 by lorlatinib. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with warfarin. Coadministration should be approached with caution. If coadministration is unavoidable, closely monitor warfarin efficacy.

Description:

See summary

No Interaction Expected

Lorlatinib

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%). Concentrations may decrease due to weak induction of UGT by lorlatinib, although the magnitude of this effect is unknown and unlikely to be clinically relevant. OAT1/3 are the major transporters of loop and thiazide diuretics. Systemic concentrations may increase due to potential inhibition of OAT3 by lorlatinib, although the magnitude of this effect is unknown and is unlikely to be relevant. 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

Lorlatinib

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of zaleplon efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of ziprasidone efficacy may be required.

Description:

See summary

No Interaction Expected

Lorlatinib

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 lorlatinib.

Description:

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Potential Weak Interaction

Lorlatinib

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 induction of CYP1A2 by lorlatinib in vitro. However, this is unlikely to be clinically significant. Moreover, concentrations may decrease due to moderate induction of CYP3A4 and weak induction of CYP2C9 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. After coadministration with tolbutamide, a sensitive CYP2C9 substrate, the AUC of tolbutamide decreased by 43%. A similar effect may occur after coadministration with zolpidem. Care should be taken. Monitoring of zolpidem efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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, and concentrations may decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of zopiclone efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 induction of CYP1A2 by lorlatinib in vitro. This is unlikely to be clinically significant. Concentrations may also decrease due to moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of zotepine efficacy may be required.

Description:

See summary

Potential Weak Interaction

Lorlatinib

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 moderate induction of CYP3A4 by lorlatinib. After coadministration with midazolam, a sensitive CYP3A4 substrate, the AUC of midazolam decreased by 61%. Care should be taken. Monitoring of zuclopenthixol efficacy may be required.

Description:

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