Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Osimertinib

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Osimertinib does not inhibit or induce CYPs 2C9, 1A2 or 2C19.

Description:

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No Interaction Expected

Osimertinib

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs, major UGT1A6). Osimertinib does not inhibit or induce UGT1A6.

Description:

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No Interaction Expected

Osimertinib

Agomelatine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Osimertinib does not inhibit or induce CYPs 1A2, 2C9 or 2C19.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway. Although no pharmacokinetic interaction is expected, alendronic acid should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronic acid before taking any other oral medicinal product.

Description:

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No Interaction Expected

Osimertinib

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfentanil undergoes extensive CYP3A4 metabolism. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of alfentanil. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with alfentanil. Therefore, no clinically relevant effect on alfentanil exposure is expected.

Description:

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No Interaction Expected

Osimertinib

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfuzosin is metabolised by CYP3A. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of alfuzosin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with alfuzosin. Therefore, no clinically relevant effect on alfuzosin exposure is expected.

Description:

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Potential Weak Interaction

Osimertinib

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. Osimertinib is unlikely to interfere with this metabolic or elimination pathway. Aliskiren is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of aliskiren. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with aliskiren. Monitoring of aliskiren toxicity and blood pressure may be required.

Description:

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No Interaction Expected

Osimertinib

Allopurinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Allopurinol is also an inhibitor of xanthine oxidase. Osimertinib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Osimertinib

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of alosetron. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ulipristal. Therefore, no clinically relevant effect on alosetron exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP1A2.

Description:

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No Interaction Expected

Osimertinib

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alprazolam is mainly metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of alprazolam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with alprazolam. Therefore, no clinically relevant effect on alprazolam exposure is expected.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with aluminium hydroxide. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation caused by aluminium hydroxide.

Description:

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Potential Weak Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of ambrisentan. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on ambrisentan exposure is expected. Osimertinib does not inhibit or induce UGTs 1A3, 1A9 or 2B7 or CYP2C19. Ambrisentan is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of ambrisentan. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with ambrisentan. Monitoring of ambrisentan toxicity and blood pressure may be required.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OCTs.

Description:

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Potential Interaction

Osimertinib

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP3A4 and CYP2C8. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of amiodarone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with amiodarone. Thus, no clinically relevant effect on amiodarone exposure is expected. Osimertinib does not inhibit or induce CYP2C8, 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). Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by desethylamiodarone. After coadministration with itraconazole, a strong CYP3A4 and P-gp inhibitor, osimertinib exposure increased by 24%. A clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected. However, coadministration of osimertinib and amiodarone could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as amiodaraone, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG. 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

Osimertinib

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). Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OCTs.

Description:

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Potential Interaction

Osimertinib

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of amitriptyline. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on amitriptyline exposure is expected. Osimertinib does not inhibit or induce CYPs 2D6, 2C19, 1A2 or 2C9. However, coadministration of osimertinib and amitriptyline could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as amitryptiline, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

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No Interaction Expected

Osimertinib

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amlodipine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of amlodipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with amlodipine. Therefore, no clinically relevant effect on amlodipine exposure is expected.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

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Potential Weak Interaction

Osimertinib

Amphotericin B

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Osimertinib

Ampicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Osimertinib

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 CYP450s. Osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with antacids. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation caused by antacids.

Description:

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Potential Weak Interaction

Osimertinib

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Apixaban is a substrate of P-gp and BCRP and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Osimertinib is an inhibitor of CYP3A4 (in vitro), P-gp and BCRP and may increase concentrations of apixaban. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with apixaban. Therefore, no clinically relevant effect on apixaban exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. Moreover, coadministration of osimertinib and rosuvastatin, a BCRP substrate, increased rosuvastatin AUC by 35%. Similar effects may occur with apixaban. If coadministration is unavoidable, monitoring for apixaban toxicity and anti-Xa activity may be required. Also consider reducing the apixaban dose by 25%

Description:

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No Interaction Expected

Osimertinib

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Osimertinib does not inhibit or induce CYP1A2 or CYP2C19. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of aprepitant. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with aprepitant. Therefore, no clinically relevant effect on aprepitant exposure is expected. During treatment, aprepitant is a moderate inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by aprepitant. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. A clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Osimertinib concentrations may decrease due to weak CYP3A4 induction by aprepitant, butno clinically relevant effect on gefitinib exposure or efficacy is expected.

Description:

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No Interaction Expected

Osimertinib

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of aripiprazole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with aripiprazole. Therefore, no clinically relevant effect on aripiprazole exposure is expected.

Description:

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No Interaction Expected

Osimertinib

Asenapine

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Osimertinib

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of astemizole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with astemizole. Therefore, no clinically relevant effect on astemizole exposure is expected. However, coadministration of osimertinib and astemizole could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as astemizole, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

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Potential Weak Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of atorvastatin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with sirolimus. Therefore, no clinically relevant effect on sirolimus exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with atorvastatin. Monitoring of atorvastatin toxicity may be required.

Description:

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Potential Weak Interaction

Osimertinib

Azathioprine

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Osimertinib

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Osimertinib is an inhibitor of P-gp and may increase concentrations of azithromycin. The clinical relevance of this interaction is unknown. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with azithromycin. Monitoring for azithromycin toxicity may be required. Azithromycin is also an inhibitor of P-gp. Osimertinib is an in vitro substrate of P-gp and concentrations may increase due to inhibition by azithromycin. However, no clinically relevant effect on osimertinib exposure is expected. Furthermore, coadministration of osimertinib and azithromycin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as azithromycin, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

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Potential Interaction

Osimertinib

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bedaquiline is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of bedaquiline. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with bedaquiline. Therefore, no clinically relevant effect on bedaquiline exposure is expected. However, coadministration of osimertinib and bedaquiline could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as bedaquiline, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

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No Interaction Expected

Osimertinib

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Osimertinib

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of bepridil. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on bepridil exposure is expected. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and bepridil could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as bepridil, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

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No Interaction Expected

Osimertinib

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Betamethasone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of betamethasone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with betamethasone. Therefore, no clinically relevant effect on betamethasone exposure is expected.

Description:

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No Interaction Expected

Osimertinib

Bezafibrate

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Osimertinib

Bisacodyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisacodyl is converted to an active metabolite by intestinal and bacterial enzymes. Absorption from the gastrointestinal tract is minimal and the small amount absorbed is excreted in the urine as the glucuronide. Osimertinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

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No Interaction Expected

Osimertinib

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of bisoprolol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with bisoprolol. Therefore, no clinically relevant effect on bisoprolol exposure is expected. Osimertinib does not inhibit or induce CYP2D6 and is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Osimertinib

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of bosentan. No clinically relevant effect on bosentan exposure is expected. Moreover, osimertinib is metabolised by CYP3A4 and concentrations may decrease due to weak CYP3A4 induction by bosentan. However, no clinically relevant effect on osimertinib exposure and efficacy is expected.

Description:

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No Interaction Expected

Osimertinib

Bromazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromazepam undergoes oxidative biotransformation. Interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may also play a role. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of bromazepam. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on bromazepam exposure is expected.

Description:

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No Interaction Expected

Osimertinib

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Budesonide is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of budesonide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with budesonide. Therefore, no clinically relevant effect on budesonide exposure is expected.

Description:

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No Interaction Expected

Osimertinib

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of buprenorphine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with buprenorphine. Therefore, no clinically relevant effect on buprenorphine exposure is expected. The clinical relevance of UGT1A1 inhibition is unknown. However, for administration routes other than oral, no clinically relevant effect on buprenorphine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Bupropion

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buspirone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of buspirone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with buspirone. Therefore, no clinically relevant effect on buspirone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Osimertinib

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of carbamazepine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with carbamazepine. Therefore, no clinically relevant effect on carbamazepine exposure is expected. Moreover, carbamazepine is an inducer of CYP2C8 (strong), CYP2C9 (strong), CYP3A4 (strong), CYP1A2 (weak), CYP2B6, P-gp (moderate) and UGT1A1. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by carbamazepine. No clinically relevant effect on osimertinib exposure is expected due to P-gp induction by carbamazepine. Coadministration of osimertinib and rifampicin, a strong CYP3A4 inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with carbamazepine. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as carbamazepine. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

Potential Weak Interaction

Osimertinib

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYP2C9 and CYP1A2. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of carvedilol. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for carvedilol toxicity and blood pressure may be required. Carvedilol is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown. Osimertinib is an in vitro substrate of P-gp and concentrations may increase due to inhibition by carvedilol. However, no clinically relevant effect on osimertinib exposure is expected due to inhibition by carvedilol.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OAT1 or MATE1.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OAT3.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OAT3.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

Cetirizine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine is also an inhibitor of OCT2. Osimertinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloramphenicol is predominantly glucuronidated. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of chloramphenicol. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on chloramphenicol exposure is expected. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong) and CYP2D6 (weak). Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by chloramphenicol. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. 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

No Interaction Expected

Osimertinib

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlordiazepoxide is extensively metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of chlordiazepoxide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with chlordiazepoxide. Therefore, no clinically relevant effect on chlordiazepoxide exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Osimertinib

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Osimertinib does not inhibit or induce CYP2D6 or CYP1A2. However, coadministration of osimertinib and chlorpromazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as chlorpromazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Chlortalidone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Osimertinib

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ciclosporin is a substrate of CYP3A4 and P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of ciclosporin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ciclosporin. Therefore, no clinically relevant effect on ciclosporin exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with ciclosporin. Monitoring of ciclosporin toxicity may be required. Ciclosporin also inhibits CYP3A4 and OATP1B1. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by ciclosporin. After coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Osimertinib is not a substrate of OATP1B1.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of cimetidine. However, as multiple CYP450 enzymes may be involved in metabolism no clinically relevant effect on cimetidine exposure is expected. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Osimertinib is not metabolised by OAT1 or OCT1. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by cimetidine. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with cimetidine. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation caused by cimetidine.

Description:

See summary

Potential Weak Interaction

Osimertinib

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ciprofloxacin is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Osimertinib is unlikely to interfere with this metabolic or elimination pathway. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by ciprofloxacin. After coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. However, coadministration of osimertinib and ciprofloxacin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. If coadministration is unavoidable, monitoring for heart rate and ECG may be required.

Description:

See summary

Do Not Coadminister

Osimertinib

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Cisapride is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of cisapride. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with cisapride. Therefore, no clinically relevant effect on cisapride exposure is expected. However, coadministration of cisapride with other drugs that prolong QTc interval should be avoided. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Coadministration of cisapride and osimertinib should therefore be avoided.

Description:

See summary

Potential Interaction

Osimertinib

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of citalopram. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with citalopram. Therefore, no clinically relevant effect on citalopram exposure is expected. However, coadministration of osimertinib and citalopram could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as citalopram, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clarithromycin is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of clarithromycin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with clarithromycin. Therefore, no clinically relevant effect on clarithromycin exposure is expected. Clarithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by clarithromycin. However, after coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected. However, coadministration of osimertinib and clarithromycin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as clarithromycin, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of clindamycin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with clindamycin. Therefore, no clinically relevant effect on clindamycin exposure is expected. In vitro data suggests that clindamycin is also a CYP3A4 inhibitor. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by clindamycin. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Clobetasol

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clofazimine is largely excreted unchanged in the faeces. Osimertinib is unlikely to interfere with this elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by clofazimine. After coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. However, coadministration of osimertinib and clofazimine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as clofazimine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Osimertinib

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of clomipramine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with clomipramine. Therefore, no clinically relevant effect on clomipramine exposure is expected. Osimertinib does not inhibit or induce CYPs 1A2, 2C19 or 2D6. However, coadministration of osimertinib and clomipramine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as clomipramine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Clonidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in form of the unchanged parent drug (40-60% of the dose). Clonidine is also a weak inhibitor of OCT2. Osimertinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of clopidogrel. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on clopidogrel exposure is expected. Osimertinib does not inhibit or induce CYPs 2C19, 2B6 or 1A2. Clopidogrel is also an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and in vitro of CYP2C9 at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Osimertinib is not metabolised by CYPs 2C8, 2B6 or 2C9.

Description:

See summary

No Interaction Expected

Osimertinib

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of clorazepate. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with clorazepate. Therefore, no clinically relevant effect on clorazepate exposure is expected. Furthermore, oxazepam is mainly glucuronidated. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of oxazepam. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on oxazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

Clozapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase clozapine concentrations. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with clozapine. Therefore, no clinically relevant effect on clozapine exposure is expected. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered. Furthermore, coadministration of osimertinib and clozapine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as clozapine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6. Morphine is further metabolized by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Morphine is also a substrate of P-gp. Osimertinib is an inhibitor of UGT1A1 (in vitro) and P-gp and may increase concentrations of morphine. Since UGT1A1 is a minor metabolic pathway, no clinically relevant effect on morphine exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with morphine. Monitoring for morphine toxicity may be required. Codeine is also converted via CYP3A4 to norcodeine, an inactive metabolite. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of codeine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with codeine. Therefore, no clinically relevant effect on codeine exposure is expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of colchicine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with sirolimus. Therefore, no clinically relevant effect on sirolimus exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with colchicine. Monitoring of colchicine toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

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. Osimertinib is an inhibitor of P-gp and may increase concentations of dabigatran. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with dabigatran. Monitoring for dabigatran toxicity and anti-Xa activity may be required. Administer dabigatran 2 hours before osimertinib in fasted state to circumvent the intestinal P-gp interaction.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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 via multiple CYP450 enzymes. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of dapsone. However, as multiple CYP450 enzymes are involved in metabolism, no clinically relevant effect on dapsone exposure is expected.

Description:

See summary

Potential Interaction

Osimertinib

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Desipramine is metabolised by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and desipramine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as desipramine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of desogestrel. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with desogestrel. Therefore, no clinically relevant effect on desogestrel exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP2C19.

Description:

See summary

Potential Weak Interaction

Osimertinib

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease osimertinib plasma concentrations. The induction of CYP3A4 by dexamethasone has not been established yet therefore a clinically significant interaction with osimertinib cannot be ruled out. Dexamethasone is also a substrate of CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of dexamethasone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with dexamethasone. Therefore, no clinically relevant effect on dexamethasone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dextropropoxyphene is mainly metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of dextropropoxyphene. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with dextropropoxyphene. Therefore, no clinically relevant effect on dextropropoxyphene exposure is expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diamorphine is rapidly metabolised by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Osimertinib is an inhibitor of UGT1A1 (in vitro) and P-gp and may increase concentrations of morphine. Since UGT1A1 is a minor metabolic pathway, no clinically relevant effect on morphine exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with morphine. Monitoring for morphine toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of diazepam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with diazepam. Therefore, no clinically relevant effect on diazepam exposure is expected. Furthermore, temazepam is mainly glucuronidated. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of temazepam. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on diazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce UGT2B7 or CYP2C9.

Description:

See summary

Potential Weak Interaction

Osimertinib

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of digoxin. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with digoxin. Monitoring of digoxin toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of dihydrocodeine. However, since CYP3A4 is a minor metabolic pathway and multiple UGTs are involved in glucuronidation, no clinically relevant effect on dihydrocodeine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diltiazem is metabolised by CYP3A4 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of diltiazem. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with amlodipine. Therefore, no clinically relevant effect on amlodipine exposure is expected. Osimertinib does not inhibit or induce CYP2D6. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp. Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by diltiazem. However, after coadministration with itraconazole, a strong CYP3A4 and P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, no clinically relevant effect on osimertinib exposure due to CYP3A4 or P-gp inhibition is expected.

Description:

See summary

Potential Interaction

Osimertinib

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is a weak inhibitor of CYP2D6. Osimertinib does not interact with this metabolic pathway. However, coadministration of osimertinib and diphenhydramine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as diphenhydramine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of dipyridamole. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for dipyridamole toxicity may be required. For administration routes other than oral, no clinically relevant effect on dipyridamole exposure is expected.

Description:

See summary

Potential Interaction

Osimertinib

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of disopyramide. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on disopyramide exposure is expected. However, coadministration of osimertinib and disopyramide could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as disopyramide, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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%). Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of dolasetron. However, since CYP3A4 is a minor metabolic pathway and multiple UGTs are involved in glucuronidation, no clinically relevant effect on dolasetron exposure is expected. However, coadministration of osimertinib and dolasteron could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as dolasteron, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Domperidone is mainly metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of domperidone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with domperidone. Therefore, no clinically relevant effect on domperidone exposure is expected. However, coadministration of osimertinib and domperidone could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as domperidone, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxazosin is metabolised mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of doxazosin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with doxazosin. Therefore, no clinically relevant effect on doxazosin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2C19 or CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Doxycycline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40-60% of an administered dose can be accounted for in the urine. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Dronabinol

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolised to a minor extent via CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of drospirenone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with drospirenone. Therefore, no clinically relevant effect on drospirenone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The clinical relevance of delayed absorption is considered to be limited.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6 or CYP1A2.

Description:

See summary

No Interaction Expected

Osimertinib

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dutasteride is mainly metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of dutasteride. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with dutasteride. Therefore, no clinically relevant effect on dutasteride exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of dydrogesterone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with dydrogesterone. Therefore, no clinically relevant effect on dydrogesterone exposure is expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of edoxaban. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on edoxaban exposure due to CYP3A4 inhibition is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with edoxaban. Monitoring for edoxaban toxicity and anti-Xa activity may be required.

Description:

See summary

Potential Weak Interaction

Osimertinib

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). Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of eltrombopag. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for eltrombopag toxicity may be required. For administration routes other than oral, no clinically relevant effect on eltrombopag exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Enalapril

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of erythromycin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with erythromycin. Therefore, no clinically relevant effect on erythromycin exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with erythromycin. Monitoring of erythromycin toxicity may be required. Erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by erythromycin. After coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected. Furthermore, coadministration of osimertinib and erythromycin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Coadministration with other QT prolonging drugs, such as erythromycin, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of escitalopram. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with escitalopram. Therefore, no clinically relevant effect on escitalopram exposure is expected. However, coadministration of osimertinib and escitalopram could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as escitalopram, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of esomeprazole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ulipristal. Therefore, no clinically relevant effect on esomeprazole exposure is expected. Esomeprazole is also an inhibitor of CYP2C19. Osimertinib is not metabolised by CYP2C19. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with esomeprazole. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation caused by esomeprazole.

Description:

See summary

No Interaction Expected

Osimertinib

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of estazolam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with estazolam. Therefore, no clinically relevant effect on estazolam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of estradiol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with estradiol. Therefore no clinically relevant effect on estradiol exposure is expected. Furthermore, since multiple UGT enzymes are involved in glucuronidation, no clinically relevant effect on estradiol exposure is expected due to UGT1A1 inhibition.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

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No Interaction Expected

Osimertinib

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of ethinylestradiol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ethinylestradiol. Therefore no clinically relevant effect on ethinylestradiol exposure is expected. Furthermore, since multiple metabolic pathways are involved, no clinically relevant effect on estradiol exposure is expected due to UGT1A1 inhibition.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Osimertinib

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of etonogestrel. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with etonogestrel. Therefore, no clinically relevant effect on etonogestrel exposure is expected.

Description:

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Potential Weak Interaction

Osimertinib

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of everolimus. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with everolimus. Therefore, no clinically relevant effect on everolimus exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with everolimus. Monitoring of everolimus toxicity may be required. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The clinical relevance of delayed absorption is considered to be limited.

Description:

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Potential Weak Interaction

Osimertinib

Ezetimibe

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of ezetimbe. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for ezetimibe toxicity may be required. For administration routes other than oral, no clinically relevant effect on labetalol exposure is expected.

Description:

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No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce OATs. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with famotidine. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation caused by famotidine.

Description:

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No Interaction Expected

Osimertinib

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Felodipine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of felodipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with felodipine. Therefore, no clinically relevant effect on felodipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Fenofibrate

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Osimertinib

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl undergoes extensive CYP3A4 metabolism. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of fentanyl. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with fentanyl. Therefore, no clinically relevant effect on fentanyl exposure is expected.

Description:

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Potential Weak Interaction

Osimertinib

Fexofenadine

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Fexofenadine is a substrate of P-gp. Osimertinib is an inhibitor of P-gp and will increase concentrations of fexofenadine. In non-small cell lung cancer patients (n=24), fexofenadine exposure increased by 56% after coadministration with osimertinib (80 mg single dose) and 27% after coadministration with steady state osimertinib (80 mg). Monitoring for fexofenadine toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Finasteride is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of finasteride. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with finasteride. Therefore, no clinically relevant effect on finasteride exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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:

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Potential Interaction

Osimertinib

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Osimertinib does not inhibit or induce CYP2D6 and is unlikely to interfere with this elimination pathway. However, coadministration of osimertinib and flecainide could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as flecainide, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs. Flucloxacillin is also described as a CYP3A4 inducer. Osimertinib is metabolised by CYP3A4 and concentrations may decrease due to induction by flucloxacillin. The clinical relevance of this interaction is unknown. Since there is no clear relationship between exposure and efficacy of osimertinib, decreased exposure is unlikely to result in decreased efficacy. However, monitoring of osimertinib efficacy and, if available, osimertinib plasma concentrations may be required.

Description:

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Potential Interaction

Osimertinib

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluconazole is cleared primarily by renal excretion. Osimertinib is unlikely to interfere with this elimination pathway. Fluconazole is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by fluconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. However, coadministration of osimertinib and fluconazole could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as fluconazole, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

Flucytosine

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Osimertinib

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of fludrocortisone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with fludrocortisone. Therefore, no clinically relevant effect on fludrocortisone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of flunitrazepam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with flunitrazepam. Therefore, no clinically relevant effect on flunitrazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Fluoxetine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluphenazine is metabolised by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and fluphenazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as fluphenazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Flurazepam

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 flurazepam is most likely CYP-mediated. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of flurazepam. However, since multiple CYPs may be involved in metabolism, no clinically relevant effect on flurazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of fluticasone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with fluticasone. Therefore, no clinically relevant effect on fluticasone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Fluvastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Osimertinib does not inhibit or induce CYP2D6 or CYP1A2. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by fluvoxamine. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of formoterol. However, as multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low. Osimertinib does not inhibit or induce CYPs 2D6, 2C19, 2C9, and 2A6.

Description:

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No Interaction Expected

Osimertinib

Fosaprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Osimertinib does not interact with this metabolic pathway. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of aprepitant. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with aprepitant. Therefore, no clinically relevant effect on aprepitant exposure is expected. Osimertinib does not inhibit or induce CYP1A2 or CYP2C19. During treatment aprepitant is a moderate inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by aprepitant. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Osimertinib concentrations may decrease due to weak CYP3A4 induction by aprepitant. However, no clinically relevant effect on gefitinib exposure or efficacy is expected.

Description:

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Potential Interaction

Osimertinib

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Osimertinib does not interact with this metabolic pathway. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Osimertinib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by fosphenytoin. Coadministration of osimertinib and rifampicin, a strong CYP3A4 and P-gp inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with fosphenytoin. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as fosphenytoin. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

No Interaction Expected

Osimertinib

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). Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of furosemide. However, since UGT1A1 is a minor metabolic pathway, no clinically relevant effect on furosemide exposure is expected. A large proportion of furosemide is also eliminated unchanged renally (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. In vitro data indicate that furosemide is also an inhibitor of the renal transporters OAT1/OAT3. Osimertinib does not inhibit or induce and is not a substrate of OATs.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Gemfibrozil

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of gestodene. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with gestodene. Therefore, no clinically relevant effect on gestodene exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP2C19.

Description:

See summary

No Interaction Expected

Osimertinib

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of glibenclamide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with glibenclamide. Therefore, no clinically relevant effect on glibenclamide exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Gliclazide

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Glimepiride

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Glipizide

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of granisetron. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with granisetron. Therefore, no clinically relevant effect on granisetron exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with granisetron. Monitoring of granisetron toxicity may be required. Furthermore, coadministration of osimertinib and granisetron could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as granisetron, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Grapefruit juice is known to inhibit CYP3A4 enzymes. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibtion by grapefruit juice. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Griseofulvin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of haloperidol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with haloperidol. Therefore, no clinically relevant effect on haloperidol exposure is expected. However, coadministration of osimertinib and haloperidol could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as haloperidol, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by hydralazine. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Hydrocodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of hydromorphone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with hydrocodone. Therefore, no clinically relevant effect on hydrocodone exposure is expected. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocortisone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of hydrocortisone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with hydrocortisone. Therefore, no clinically relevant effect on hydrocortisone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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

Osimertinib

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. Osimertinib does not inhibit or induce UGT2B7.

Description:

See summary

Potential Weak Interaction

Osimertinib

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of hydroxyzine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with hydroxyzine. Therefore, no clinically relevant effect on hydroxyzine exposure is expected. However, coadministration of osimertinib and hydroxyzine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as hydroxyzine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of ibuprofen. However, since UGTs are a minor metabolic pathway, no clinically relevant effect on ibuprofen exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP2C8.

Description:

See summary

Potential Interaction

Osimertinib

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Iloperidone is metabolised by CYP3A4 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of iloperidone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with iloperidone. Therefore, no clinically relevant effect on iloperidone exposure is expected. However, coadministration of osimertinib and iloperidone could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as iloperidone, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of imipramine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with imipramine. Therefore, no clinically relevant effect on imipramine exposure is expected. However, coadministration of osimertinib and imipramine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as imipramine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Indapamide is extensively metabolised by CYP450s. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of indapamide. As multiple CYP450s may be involved in metabolism no clinically relevant effect on indapamide exposure is expected. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Osimertinib does not inhibit or induce OATs. However, coadministration of osimertinib and indapamide could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as indapamide, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Insulin

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Osimertinib

Interferon alpha

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Osimertinib

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Irbesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of benazepril. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on benazepril exposure is expected. Osimertinib does inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

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

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of isosorbide dinitrate. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with isosorbide dinitrate. Therefore, no clinically relevant effect on isosorbide dinitrate exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Itraconazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Itraconazole is primarily metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of itraconazole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with itraconazole. Therefore, no clinically relevant effect on itraconazole exposure is expected. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Osimertinib is metabolised by CYP3A4 and concentrations will increase due to inhibition by itraconazole. In non-small cell lung cancer patients (n=39), coadministration of itraconazole (200 mg twice daily) and osimertinib (80 mg single dose), increased osimertinib exposure increased by 24%. This is not clinically relevant.

Description:

See summary

Potential Interaction

Osimertinib

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ivabradine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of ivabradine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ivabradine. Therefore, no clinically relevant effect on ivabradine exposure is expected. However, coadministration of osimertinib and ivabradine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as ivabradine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ketoconazole is a substrate of CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of ketoconazole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ketoconazole. Therefore, no clinically relevant effect on ketoconazole exposure is expected. Ketoconazole is also an inhibitor of CYP3A4 (strong) and P-gp. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may increase due to inhibition by ketoconazole. However, after coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected. However, coadministration of osimertinib and ketoconazole could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as ketoconazole, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

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). Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of labetalol. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for labetalol toxicity and blood pressure may be required. For administration routes other than oral, no clinically relevant effect on labetalol exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lacidipine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of lacidipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with lacidipine. Therefore, no clinically relevant effect on lacidipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of lansoprazole. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on lansoprazole exposure is expected. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with lansoprazole. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation.

Description:

See summary

No Interaction Expected

Osimertinib

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lercanidipine is mainly metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of lercanidipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with lercanidipine. Therefore, no clinically relevant effect on lercanidipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

Potential Interaction

Osimertinib

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OCTs. However, coadministration of osimertinib and levofloxacin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as levofloxacin, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levomepromazine is metabolised by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and levomepromazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as levomepromazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of levonorgestrel. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with levonorgestrel. Therefore no clinically relevant effect on levonorgestrel exposure is expected. Furthermore, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on levonorgestrel exposure is expected due to UGT1A1 inhibition.

Description:

See summary

No Interaction Expected

Osimertinib

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of levothyroxine. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on levothyroxine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of lidocaine. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on lidocaine exposure is expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of linagliptin. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on linagliptin exposure is expected. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with linagliptin. Therefore, monitoring of linagliptin toxicity and blood glucose levels may be required. Linagliptin is also a weak inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by linagliptin. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition by linagliptin is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate, therefore, no pharmacokinetic interaction is expected. However, coadministration of osimertinib and lithium could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as lithium, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Live vaccines

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolised by CYP3A4 and CYP2C8, and is a substrate of P-gp. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of loperamide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ulipristal. Therefore, no clinically relevant effect on esomeprazole exposure is expected due to CYP3A4 inhibition. Furthermore, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. However, since loperamide has a very broad therapeutic index, no clinically relevant effect on loperamide exposure is expected due to P-gp inhibition.

Description:

See summary

No Interaction Expected

Osimertinib

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of loratadine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with loratadine. Therefore, no clinically relevant effect on loratadine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of lormetazepam. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on lormetazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Losartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Osimertinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lovastatin is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of lovastatin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with lovastatin. Therefore, no clinically relevant effect on lovastatin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of macitentan. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with macitentan. Therefore, no clinically relevant effect on macitentan exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Maprotiline

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of medroxyprogesterone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with medroxyprogesterone. Therefore, no clinically relevant effect on medroxyprogesterone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Meropenem

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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%). Osimertinib is unlikely to interfere with this metabolic or elimination pathway. Metamizole is also an inducer of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may decrease due to CYP3A4 induction by metamizole. However, no clinically significant effect on osimertinib exposure and efficacy is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OCTs or MATEs.

Description:

See summary

Potential Interaction

Osimertinib

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Methadone is demethylated by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of methadone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with methadone. Therefore, no clinically relevant effect on methadone exposure is expected. However, coadministration of osimertinib and methadone could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as methadone, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylprednisolone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of methylprednisolone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with methylprednisolone. Therefore, no clinically relevant effect on methylprednisolone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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). Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Metolazone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). The mechanism of this interaction with CYP3A has not yet been identified therefore an interaction with Osimertinib which is metabolised by CYP3A4 cannot be excluded. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Mexiletine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mianserin is metabolised by CYP2D6 and CYP1A2, and to a lesser extent by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of mianserin. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on mianserin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Miconazole is extensively metabolized by the liver. Osimertinib is unlikely to interfere with this unspecified metabolic pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by miconazole. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Osimertinib is not metabolised by CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

Midazolam (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Midazolam is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of midazolam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with midazolam. Therefore, no clinically relevant effect on midazolam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of mirtazapine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with mirtazapine. Therefore, no clinically relevant effect on mirtazapine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mometasone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of mometasone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with mometasone. Therefore, no clinically relevant effect on mometasone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Montelukast

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Weak Interaction

Osimertinib

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Osimertinib is an inhibitor of UGT1A1 (in vitro) and P-gp and may increase concentrations of morphine. Since UGT1A1 is a minor metabolic pathway, no clinically relevant effect on morphine exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with morphine. Monitoring for morphine toxicity may be required.

Description:

See summary

Potential Interaction

Osimertinib

Moxifloxacin

Quality of Evidence: Low

Summary:

Coadministration has not been studied but care should be taken. Moxifloxacin is predominantly glucuronidated by UGT1A1. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of moxifloxacin. Although no clinically relevant interaction is expected, the clinical relevance of intestinal UGT1A1 inhibition is unknown. Monitoring for moxifloxacin toxicity may be required. For administration routes other than oral, no clinically relevant effect on moxifloxacin exposure is expected. However, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. If coadministration is unavoidable, use with caution, including close ECG monitoring.

Description:

See summary

Potential Weak Interaction

Osimertinib

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3. Osimertinib does not interact with this metabolic pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce UGT2B7, CYP2C9 or CYP1A2.

Description:

See summary

No Interaction Expected

Osimertinib

Nateglinide

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nefazodone is metabolised mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of nefazodone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with nefazodone. Therefore, no clinically relevant effect on nefazodone exposure is expected. Nefazodone is also a strong inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by nefazodone. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of nicardipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with nicardipine. Therefore, no clinically relevant effect on nicardipine exposure is expected. Osimertinib does not inhibit or induce CYP2D6 or CYP2C8. Nicardipine is also a weak inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by nicardipine. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nifedipine is metabolised mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of nifedipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with nifedipine. Therefore, no clinically relevant effect on nifedipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nisoldipine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of nisoldipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with nisoldipine. Therefore, no clinically relevant effect on nisoldipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrendipine is extensively metabolised mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of nitrendipine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with nitrendipine. Therefore, no clinically relevant effect on nitrendipine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Osimertinib is unlikely to interfere with this elimination pathway. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of nitrofurantoin. However, as multiple UGT enzymes are involved in glucuronidation, no clinically relevant effect on nitrofurantoin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of norelgestromin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with norelgestromin. Therefore, no clinically relevant effect on norelgestromin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Osimertinib is unlikely to interfere with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of norgestimate. However, as multiple CYP450s may be involved in metabolism, no clinically relevant effect on norgestimate exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of levonorgestrel. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with levonorgestrel. Therefore no clinically relevant effect on levonorgestrel exposure is expected. Furthermore, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on levonorgestrel exposure is expected due to UGT1A1 inhibition.

Description:

See summary

Potential Interaction

Osimertinib

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nortriptyline is metabolised mainly by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and nortriptyline could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as nortriptyline, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Nystatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Systemic absorption of nystatin from oral or topical dosage forms is not significant, therefore no drug interactions are expected.

Description:

See summary

Potential Interaction

Osimertinib

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Osimertinib is unlikely to interfere with this elimination pathway. However, coadministration of osimertinib and ofloxacin could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as ofloxacin, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Olanzapine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Omeprazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of omeprazole. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on omeprazole exposure is expected. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Osimertinib is not metabolised by these CYPs. Furthermore, after coadministration with omeprazole osimertinib exposure increased by 7%. Active metabolites were unaffected. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation.

Description:

See summary

Potential Interaction

Osimertinib

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of ondansetron. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ondansetron. Therefore no clinically relevant effect is expected on ondansetron exposure. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with ondansetron. Monitoring of ondansetron toxicity may be required. Furthermore, coadministration of osimertinib and ondansetron could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as ondansetron, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of oxazepam. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on oxazepam exposure is expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib does not interact with this metabolic pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Osimertinib is metabolised by CYP3A4 and concentrations may decrease due to moderate induction by oxcarbazepine and MHD. The clinical relevance of this interaction is unknown. Since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. However, monitoring of osimertinib efficacy and, if available, osimertinib plasma concentrations may be required.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of oxprenolol. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on oxprenolol exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of oxycodone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with oxycodone. Therefore, no clinically relevant effect on oxycodone exposure is expected. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Paliperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of paliperidone. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on paliperidone exposure is expected. Osimertinib does not inhibit or induce OCTs or CYP2D6.

Description:

See summary

Potential Weak Interaction

Osimertinib

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also substrate of P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of palonosetron. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on palonosetron exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with palonosetron. Monitoring of palonosetron toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of pantoprazole. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on pantoprazole exposure is expected. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with pantoprazole. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Paracetamol (Acetaminophen)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15) and sulfation and, to a lesser extent, by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of paracetamol. However, since CYP3A4 and UGT1A1 are minor metabolic pathways, no clinically relevant effect on paracetamol exposure is expected. Osimertinib does not inhibit or induce UGTs 1A9, 1A6 or 2B15 or CYPs 2E1, 1A2 or 2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Paroxetine is also an inhibitor of CYP2D6 (strong) and CYP2C9. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

Potential Weak Interaction

Osimertinib

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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). Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

No Interaction Expected

Osimertinib

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of perazine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with perazine. Therefore, no clinically relevant effect on perazine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Interaction

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and perphenazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as perphenazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Phenelzine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Phenobarbital is metabolized by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Osimertinib does not inhibit or induce these CYPs 2C19, 2C9 or 2E1. Phenobarbital is a strong inducer of CYP3A4, CYP2C9, CYP2C8 and UGTs. Osimertinib is metabolised by CYP3A4 and concentrations may decrease due to induction by phenobarbital. Coadministration of osimertinib and rifampicin, a strong CYP3A4 inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with phenobarbital. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as phenobarbital. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

No Interaction Expected

Osimertinib

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of phenprocoumon After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with phenprocoumon. Therefore, no clinically relevant effect on phenprocoumon exposure is expected.

Description:

See summary

Potential Interaction

Osimertinib

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Osimertinib does not inhibit or induce CYP2C9 or CYP2C19. Phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by fosphenytoin. Coadministration of osimertinib and rifampicin, a strong CYP3A4 and P-gp inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with fosphenytoin. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as fosphenytoin. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP4F2.

Description:

See summary

Do Not Coadminister

Osimertinib

Pimozide

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of pimozide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with pimozide. Therefore, no clinically relevant effect on pimozide exposure is expected. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

Pioglitazone

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and pipotiazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as pipotiazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

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 UGT1A3 and UGT2B7 with minimal metabolism by CYP2C9 and CYP2C8. Pitavastatin is a substrate of OATP1B1. Osimertinib does not inhibit or induce, UGT1A3, UGT2B7, CYP2C9, CTP2C8 or OATP1B1.

Description:

See summary

Potential Interaction

Osimertinib

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Osimertinib is an in vitro inhibitor of UGT1A1 and P-gp and may increase concentrations of posaconazole. Since multiple UGTs are involved in glucuronidation, no clinically relevant effect on posaconazole exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with posaconazole. Monitoring for posaconazole toxicity may be required. Posaconazole is also a strong inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by posaconazole. After coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. However, coadministration of osimertinib and posaconazole could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as posaconazole, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Potassium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Potassium is eliminated renally. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of prasugrel. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with prasugrel. Therefore, no clinically relevant effect on prasugrel exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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 CYP450 enzymes and is a substrate of OATP1B1. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of pravastatin. However, as CYP450s are a minor metabolic pathway a clinically relevant effect on pravastatin exposure is not expected. Osimertinib does not inhibit or induce OATP1B1.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisolone undergoes hepatic metabolism via CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of prednisolone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with prednisolone. Therefore, no clinically relevant effect on prednisolone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Osimertinib does not interact with this metabolic pathway. Prednisolone is then metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of prednisone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with prednisone. Therefore, no clinically relevant effect on prednisone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

Potential Interaction

Osimertinib

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Osimertinib does not inhibit or induce CYP2D6 or CYP2C19. However, coadministration of osimertinib and prochlorperazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as prochlorperazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Interaction

Osimertinib

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Promethazine is metabolised by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. However, coadministration of osimertinib and promethazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as promethazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of propafenone. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on propafenone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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). Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of propranolol. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on propranolol exposure is expected. Osimertinib does not inhibit or induce CYPs 2D6, 1A2 or 2C19.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is unlikely to interfere with this metabolic or elimination pathway. Prucalopride is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of prucalopride. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with prucalopride. Monitoring for prucalopride toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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

No Interaction Expected

Osimertinib

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of quetiapine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with quetiapine. Therefore, no clinically relevant effect on quetiapine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

Potential Interaction

Osimertinib

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of quinidine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with quinidine. Therefore, no clinically relevant effect on quinidine exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP2E1. Quinidine is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of quinidine. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with quinidine. Monitoring for quinidine toxicity may be required. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may increase due to inhibition by quinidine. After coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. Furthermore, coadministration of osimertinib and quinidine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Coadministration with other QT prolonging drugs, such as quinidine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of rabeprazole. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on rabeprazole exposure is expected. Osimertinib does not inhibit or induce CYP2C19. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with rabeprazole. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this metabolic pathway

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce OATs. Furthermore, osimertinib exposure increased by 7% after coadministration with the proton-pump inhibitor omeprazole. Active metabolites were unaffected. A similar effect may occur after coadministration with ranitidine. Therefore, no clinically relevant effect on osimertinib exposure is expected due to pH elevation.

Description:

See summary

Potential Interaction

Osimertinib

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of ranolazine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ranolazine. Therefore, no clinically relevant effect on ranolazine exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with ranolazine. Monitoring of ranolazine toxicity and blood pressure may be required. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Osimertinib is metabolized by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by ranolazine. After coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected. Furthermore, coadministration of osimertinib and ranolazine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as ranolazine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG

Description:

See summary

No Interaction Expected

Osimertinib

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Reboxetine is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of reboxetine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with reboxetine. Therefore, no clinically relevant effect on reboxetine exposure is expected. Furthermore, in vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of repaglinide. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with repaglinide. Therefore, no clinically relevant effect on repaglinide exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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

Potential Interaction

Osimertinib

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Rifabutin is metabolised by CYP3A and via deacetylation. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of rifabutin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with rifabutin. Therefore, no clinically relevant effect on rifabutin exposure is expected. Rifabutin is also a strong CYP3A4 and P-gp inducer. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by rifabutin. Coadministration of osimertinib and rifampicin, a strong CYP3A4 inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with rifabutin. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as rifabutin. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

Potential Interaction

Osimertinib

Rifampicin

Quality of Evidence: Moderate

Summary:

Coadministration has been studied and is not recommended. Rifampicin is metabolised via deacetylation. Osimertinib does not interact with this metabolic pathway. Rifampicin is also a strong CYP3A4 and P-gp inducer. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations will decrease due to induction by rifampicin. In non-small cell lung cancer patients (n=41), coadministration of osimertinib (80 mg once daily) and rifampicin (600 mg once daily) decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with rifampicin. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

Potential Interaction

Osimertinib

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Rifapentine is metabolised via deacetylation. Osimertinib does not interact with this metabolic pathway. Rifapentine is also a strong CYP3A4, CYP2C8 and P-gp inducer. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by rifapentine. Coadministration of osimertinib and rifampicin, a strong CYP3A4 inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with rifapentine. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as rifapentine. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of risperidone. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on risperidone exposure is expected. Osimertinib does not inhibit or induce CYP2D6. Risperidone is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of risperidone. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with risperidone. Monitoring for risperidone toxicity may be required.

Description:

See summary

Do Not Coadminister

Osimertinib

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is contra-indicated. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of rivaroxaban. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with rivaroxaban. Therefore, no clinically relevant effect on rivaroxaban exposure is expected. Rivaroxaban is also a substrate of P-gp and BCRP. Osimertinib is an inhibitor of P-gp and BCRP and may increase concentrations of rivaroxaban. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. Moreover, coadministration of osimertinib and rosuvastatin, a BCRP substrate, increased rosuvastatin AUC by 35%. Similar effects may occur with rivaroxaban and as any increase in exposure to rivaroxaban increases toxicity, coadministration is contra-indicated.

Description:

See summary

No Interaction Expected

Osimertinib

Rosiglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Osimertinib does not inhibit or induce CYP2C8 or CYP2C9.

Description:

See summary

Potential Weak Interaction

Osimertinib

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and care should be taken. Rosuvastatin is largely excreted unchanged via the faeces via OATP1B1 and is substrate of BCRP. In non-small cell lung cancer patients (n=44), coadministration of rosuvastatin (20 mg, day 1 and 32) with osimertinib (80 mg once daily, days 4-34), increased rosuvastatin exposure by 35% due to BCRP inhibition by osimertinib. Monitoring for rosuvastatin toxicity may be required.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of salmeterol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with salmeterol. Therefore, no clinically relevant effect on salmeterol exposure is expected. Furthermore, the systemic exposure of salmeterol is low.

Description:

See summary

Potential Weak Interaction

Osimertinib

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of saxagliptin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with saxagliptin. Therefore, no clinically relevant effect on saxagliptin exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with saxagliptin. Monitoring of saxagliptin toxicity and blood glucose levels may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Senna

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Senna glycosides are hydrolysed by colonic bacteria in the intestinal tract and the active anthraquinones liberated into the colon. Excretion occurs in the urine and the faeces and also in other secretions. No clinically significant interactions are known.

Description:

See summary

Do Not Coadminister

Osimertinib

Sertindole

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of sertindole. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with sertindole. Therefore, no clinically relevant effect on sertindole exposure is expected. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec.

Description:

See summary

No Interaction Expected

Osimertinib

Sertraline

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of sildenafil. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with sildenafil. Therefore, no clinically relevant effect on sildenafil exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Simvastatin is metabolised by CYP3A4. Simvastatin is also substrate of BCRP and the active metabolite is a substrate of OATP1B1. Osimertinib is an inhibitor of CYP3A4 (in vitro) and BCRP, and may increase concentrations of simvastatin. In non-small cell lung cancer patients (n=49), coadministration of simvastatin (40 mg, day 1 and 31) with osimertinib (80 mg once daily, days 3-32) did not have a clinically relevant effect on simvastatin exposure.

Description:

See summary

Potential Weak Interaction

Osimertinib

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sirolimus is metabolised by CYP3A4 and is substrate of P-gp. Osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of sirolimus. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with sirolimus. Therefore, no clinically relevant effect on sirolimus exposure is expected. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with sirolimus. Monitoring of sirolimus toxicity may be required. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATS. However, osimertinib is an in vitro inhibitor of CYP3A4 and P-gp and may increase concentrations of sitagliptin. Since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on sitagliptin exposure is expected. Furthermore, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with sitagliptin. Monitoring of sitagliptin toxicity and blood glucose levels may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Sodium nitroprusside

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Osimertinib

Sotalol

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be approached with caution. Sotalol is excreted unchanged via renal elimination. Osimertinib is unlikely to interfere with this elimination pathway. The product labels for sotalol advise extreme caution if given with other drugs that can potentially prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

Potential Interaction

Osimertinib

St John's Wort

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. St John’s wort is a P-gp and CYP3A4 inducer. Osimertinib is metabolised by CYP3A4 and is a substrate of P-gp and concentrations may decrease due to induction by St. John’s wort. Coadministration of osimertinib and rifampicin, a strong CYP3A4 inducer, decreased the steady-state AUC of osimertinib by 78%. The AUC of the active metabolite, AZ5104, decreased by 82%, whereas the AUC of the active metabolite, AZ7550, increased by 30%. A similar effect may occur after coadministration with St John’s wort. A decrease in exposure could lead to decreased efficacy. However, since there is no clear relationship between exposure and efficacy of osimertinib, a decreased exposure is unlikely to result in decreased efficacy. Although this relationship is lacking, the FDA product label recommends doubling the dose of osimertinib prior to initiation of treatment with a strong CYP3A4 inducer, such as St John’s wort. It is unknown whether a dose increment of osimertinib will sufficiently compensate for the loss of exposure. Closely monitor osimertinib efficacy and, if available, osimertinib plasma concentrations.

Description:

See summary

No Interaction Expected

Osimertinib

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Sulfadiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Osimertinib does not inhibit or induce CYP2C9.

Description:

See summary

Potential Interaction

Osimertinib

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Osimertinib is unlikely to interfere with this elimination pathway. However, coadministration of osimertinib and sulpiride could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as sulpiride, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic interaction is unlikely. Tacrolimus is metabolised mainly by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of tacrolimus. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with tacrolimus. Therefore, no clinically relevant effect on tacrolimus exposure is expected. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Therefore, no clinically relevant effect on osimertinib exposure is expected due to CYP3A4 inhibition. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See summary

No Interaction Expected

Osimertinib

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tadalafil is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of tadalafil. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with tadalafil. Therefore, no clinically relevant effect on tadalafil exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of tamsulosin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with tamsulosin. Therefore, no clinically relevant effect on tamsulosin exposure is expected. Osimertinib does no inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of telithromycin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with telithromycin. Therefore, no clinically relevant effect on telithromycin exposure is expected. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by telithromycin. However, after coadministration with itraconazole, a strong CYP3A4 and P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 or P-gp inhibition is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

Telmisartan

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of temazepam. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on temazepam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of terbinafine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with terbinafine. Therefore, no clinically relevant effect on terbinafine exposure is expected. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Osimertinib is not metabolised by CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of testosterone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with testosterone. Therefore, no clinically relevant effect on testosterone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP1A2.

Description:

See summary

No Interaction Expected

Osimertinib

Thiamine (Vitamin B1)

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Do Not Coadminister

Osimertinib

Thioridazine

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of thioridazine. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on thioridazine exposure is expected. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec.

Description:

See summary

Potential Interaction

Osimertinib

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tiapride is excreted largely unchanged in urine. Osimertinib is unlikely to interfere with this elimination pathway. However, coadministration of osimertinib and tiapride could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as tiapride, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

Potential Weak Interaction

Osimertinib

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ticagrelor is a substrate of CYP3A4 and P-gp. Osimertinib is an inhibitor of CYP3A4 (in vitro) and P-gp and may increase concentrations of ticagrelor. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ticagrelor. Therefore, no clinically relevant effect on ticagrelor exposure is expected due to CYP3A4 inhibition. However, coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with ticagrelor. Monitoring of ticagrelor toxicity and thrombocytes aggregation test may be required. Ticagrelor is also a weak inhibitor of CYP3A4. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by ticagrelor. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to weak CYP3A4 inhibition by ticagrelor is not expected.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Tolbutamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C8 and CYP2C19. Osimertinib does not inhibit or induce these CYPs 2C9, 2C8 or 2C19.

Description:

See summary

Potential Interaction

Osimertinib

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of tolterodine. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on tolterodine exposure is expected. Osimertinib does not inhibit or induce CYP2D6. Moreover, coadministration of osimertinib and tolterodine could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as tolterodine, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

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. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Osimertinib does not inhibit or induce CYP2C9 or OATs.

Description:

See summary

No Interaction Expected

Osimertinib

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Osimertinib is an in vitro inhibitor CYP3A4 and may increase concentrations of tramadol. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with tramadol. Therefore, no clinically relevant effect on tramadol exposure is expected. Osimertinib does not inhibit or induce CYP2B6 or CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not interact with this metabolic pathway.

Description:

See summary

Potential Interaction

Osimertinib

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Trazodone is primarily metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of trazodone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with trazodone. Therefore, no clinically relevant effect on trazodone exposure is expected. However, coadministration of osimertinib and trazodone could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as trazodone, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Triamcinolone is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of triamcinolone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with triamcinolone. Therefore, no clinically relevant effect on triamcinolone exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Triazolam is metabolised by CYP3A4. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of triazolam. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with triazolam. Therefore, no clinically relevant effect on triazolam exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP enzymes (in vitro data suggest CYP3A4, CYP1A2 and CYP2C9). Sulfamethoxazole is metabolised by CYP2C9. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is a weak inhibitor of CYP2C9. Osimertinib is unlikely to interfere with this metabolic or elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib does not inhibit or induce CYP2D6.

Description:

See summary

Potential Interaction

Osimertinib

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tropisetron is metabolised mainly by CYP2D6. Osimertinib does not inhibit or induce CYP2D6. Tropisetron is also a substrate of P-gp. Osimertinib is an inhibitor of P-gp and may increase concentrations of tropisetron. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with tropisetron. Monitoring of tropisetron toxicity may be required. Furthermore, coadministration of osimertinib and tropisetron could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as tropisetron, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of ulipristal. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with ulipristal. Therefore, no clinically relevant effect on ulipristal exposure is expected. Osimertinib does not inhibit or induce CYP1A2 or CYP2D6.

Description:

See summary

No Interaction Expected

Osimertinib

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valproic acid is primarily metabolized by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolized by CYP2C9 and CYP2C19. Osimertinib is an in vitro inhibitor of UGT1A1 and may increase concentrations of valproic acid. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect on valproic acid exposure is expected. Osimertinib does not inhibit or induce CYP2C9 or CYP2C19. Valproic acid is also an inhibitor of CYP2C9. Osimertinib is not metabolised by CYP2C9.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Venlafaxine

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

No Interaction Expected

Osimertinib

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of verapamil. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with verapamil. Therefore, no clinically relevant effect on verapamil exposure is expected. Osimertinib does not inhibit or induce CYPs 1A2, 2C8 or 2C9. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong). Osimertinib is metabolised by CYP3A4 and is an in vitro substrate of P-gp and concentrations may increase due to inhibition by verapamil. However, after coadministration with itraconazole, a strong CYP3A4 and a P-gp inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 and P-gp inhibition is not expected.

Description:

See summary

Potential Weak Interaction

Osimertinib

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. Osimertinib is an inhibitor of P-gp and may increase concentrations of vildagliptin. Coadministration of osimertinib and fexofenadine, a P-gp substrate, increased the AUC of fexofenadine by 56% after a single dose of osimertinib and 27% after multiple doses of osimertinib. A similar effect may occur with vildagliptin. Monitoring of vildagliptin toxicity and blood pressure may be required.

Description:

See summary

No Interaction Expected

Osimertinib

Vitamin E

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Potential Interaction

Osimertinib

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. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of voriconazole. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on voriconazole exposure is expected. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Osimertinib is metabolised by CYP3A4 and concentrations may increase due to inhibition by voriconazole. However, after coadministration with itraconazole, a strong CYP3A4 inhibitor, osimertinib exposure increased by 24%. Therefore, a clinically relevant effect on osimertinib exposure due to CYP3A4 inhibition is not expected. However, coadministration of osimertinib and voriconazole could potentially cause QTc interval prolongation. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec. Therefore, coadministration with other QT prolonging drugs, such as voriconazole, should be approached with caution. If coadministration is unavoidable, closely monitor heart rate and ECG.

Description:

See summary

No Interaction Expected

Osimertinib

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of warfarin. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with warfarin. Therefore, no clinically relevant effect on warfarin exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Osimertinib is unlikely to interfere with this elimination pathway and does not inhibit or induce OATs.

Description:

See summary

No Interaction Expected

Osimertinib

Zaleplon

Quality of Evidence: Very Low

Summary:

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

Description:

See summary

Do Not Coadminister

Osimertinib

Ziprasidone

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of ziprasidone. However, since CYP3A4 is a minor metabolic pathway, no clinically relevant effect on ziprasidone exposure is expected. However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval, such as osimertinib. A pharmacokinetic/pharmacodynamic analysis suggested a concentration-dependent QTc interval prolongation of 14 msec (upper bound of two-sided 90% CI: 16 msec) at a dose of osimertinib 80 mg. Of the 1142 patients treated with osimertinib in clinical trials, 0.9% were found to have a QTc > 500 msec, and 3.6% of patients had an increase from baseline QTc > 60 msec.

Description:

See summary

No Interaction Expected

Osimertinib

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. Osimertinib is unlikely to interfere with this elimination pathway.

Description:

See summary

No Interaction Expected

Osimertinib

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 1A2. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of zolpidem. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with zolpidem. Therefore, no clinically relevant effect on zolpidem exposure is expected. Osimertinib does not inhibit or induce CYPs 2C9, 2C19, 2D6 or 1A2.

Description:

See summary

No Interaction Expected

Osimertinib

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of zopiclone. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with zopiclone. Therefore, no clinically relevant effect on zopiclone exposure is expected. Osimertinib does not inhibit or induce CYP2C8.

Description:

See summary

No Interaction Expected

Osimertinib

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Osimertinib is an in vitro inhibitor of CYP3A4 and may increase concentrations of zotepine. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with zotepine. Therefore, no clinically relevant effect on zotepine exposure is expected.

Description:

See summary

No Interaction Expected

Osimertinib

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Osimertinib is an in vitro inhibitor of CYP3A4 and UGT1A1 and may increase concentrations of zuclopenthixol. However, since multiple UGTs are involved in glucuronidation, no clinically relevant effect from UGT inhibition is expected. After coadministration with simvastatin, a CYP3A4 substrate, osimertinib did not have a clinically relevant effect on simvastatin exposure. A similar effect may occur after coadministration with zuclopenthixol. Therefore, no clinically relevant effect on zuclopenthixol exposure is expected due to CYP3A4 inhibition.

Description:

See summary