Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP3A4 and CYP2C8, which are not affected by dacomitinib. The major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate) and P-gp (strong). Concentrations of dacomitinib may increase due to inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Additionally, dacomitinib is metabolised by CYP2D6 (~24%), which is moderately inhibited by amiodarone. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265). Dacomitinib is also a substrate of P-gp. Dacomitinib concentrations may increase due to P-gp inhibition, but this effect has only been established in vitro. However, increased exposure to dacomitinib is related to increased toxicity. Dacomitinib is dosed at the maximum tolerated dose, therefore every increase in exposure is considered clinically relevant. Close monitoring for dacomitinib toxicity is recommended. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased concentrations of amitriptyline and/or nortriptyline. Consider a dose reduction by 25% to and closely monitor amitriptyline and nortriptyline plasma concentrations, if available.

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, which is not affected by dacomitinib.

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)). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for asenapine, a significant increase in concentration is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Astemizole is metabolised by CYPs 2D6, 2J2, and 3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on astemizole plasma concentrations is unlikely.

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. This is not affected by dacomitinib. In vitro data indicate that bendroflumethiazide inhibits these renal transporters, but a clinically significant interaction is unlikely in the range of observed clinical concentrations.

Coadministration has not been studied but should be avoided. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with bepridil. Coadministration should be avoided.

Coadministration has not been studied but care should be taken. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased bisoprolol concentrations. Monitoring for bisoprolol toxicity may be required.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on bromazepam plasma concentrations is unlikely.

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. Dacomitinib is metabolised by CYP2D6 (~24%) and concentrations may increase due to inhibition by bupropion. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265). Therefore, no effect of CYP2D6 inhibition by bupropion is expected on dacomitinib exposure.

Coadministration has not been studied but should be approached with caution. Carvedilol undergoes glucuronidation via UGTs 1A1  , 2B4, and 2B7. Carvedilol concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro. Additionally, carvedilol is metabolised via CYP2D6 and to a lesser extent CYP2C9 and CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with carvedilol. Close monitoring for carvedilol toxicity is recommended. Carvedilol is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown. Dacomitinib is a substrate of P-gp. Dacomitinib concentrations may increase due to P-gp inhibition, but this effect has only been established in vitro. However, increased exposure to dacomitinib is related to increased toxicity. Dacomitinib is dosed at the maximum tolerated dose, therefore every increase in exposure is considered clinically relevant. Close monitoring for dacomitinib toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloramphenicol is predominantly glucuronidated. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong) and CYP2D6 (weak). Dacomitinib is metabolised by CYP2D6 (~24%). Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, increased the AUC_0-inf of total active moiety (dacomitinib + PF-05199265) by 6%. This effect was not found to be significant. Concentrations of dacomitinib may increase due to inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a significant interaction.

Coadministration has not been studied but care should be taken. Chlorphenamine is predominantly metabolised in the liver via CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with chlorphenamine. Monitoring for chlorphenamine toxicity may be required.

Coadministration has not been studied but care should be taken. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Monitoring for chlorpromazine toxicity and plasma concentrations, if available, may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine is metabolised by CYP450 enzymes. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6, and 2C19. Concentrations of dacomitinib may increase due to inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Dacomitinib is metabolised by CYP2D6 (~24%) which is inhibited by cimetidine. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on citalopram plasma concentrations is unlikely.

Coadministration has not been studied but care should be taken. Clemastine is predominantly metabolised in the liver via CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with clemastine. Monitoring for clemastine toxicity may be required.

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. This is not affected by dacomitinib.

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. Clomipramine and desmethylclomipramine are metabolised by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of clomipramine and desmethylclomipramine. Monitor closely for toxicity and clomipramine and desmethylclomipramine plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for clozapine, a significant increase in concentration is unlikely.

Coadministration has not been studied but is not recommended. Desipramine is metabolised by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of desipramine. Monitor closely for desipramine toxicity and plasma concentrations, if available.

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). Temazepam is mainly glucuronidated. These metabolic pathways are not affected by dacomitinib.

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. This is not affected by dacomitinib.

Coadministration has not been studied but should be avoided. Diltiazem is metabolised by CYP3A4 and CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased diltiazem plasma concentrations. Coadministration should be avoided. If coadministration cannot be avoided, monitor closely for diltiazem toxicity. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp. However, the clinical relevance of P-gp inhibition by diltiazem is unknown. Dacomitinib is a substrate of P-gp. Dacomitinib concentrations may increase due to P-gp inhibition, but this effect has only been established in vitro. Increased exposure to dacomitinib is related to increased toxicity. Dacomitinib is dosed at the maximum tolerated dose, therefore every increase in exposure is considered clinically relevant. Close monitoring for dacomitinib toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9, and 2C19. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on diphenhydramine plasma concentrations is unlikely. Moreover, diphenhydramine is a weak inhibitor of CYP2D6. Dacomitinib is metabolised by CYP2D6 (~24%). Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC0-inf of total active moiety (dacomitinib + PF-05199265).

Coadministration has not been studied but care should be taken. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro. Monitoring for dipyridamole toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on dolasetron plasma concentrations is unlikely.

Coadministration has not been studied but is not recommended. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. Doxepin and nordoxepin are metabolised by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of doxepin and nordoxepin. Monitor closely for toxicity and doxepin and nordoxepin plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Duloxetine is metabolised by CYP2D6 and CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of duloxetine. Monitor closely for duloxetine toxicity and plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%), and 3A4 (35%) to form N-desmethylescitalopram. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on citalopram plasma concentrations is unlikely.

Coadministration has not been studied but is contraindicated. Esomeprazole is metabolised by CYP2C19 and CYP3A4, which are not affected by dacomitinib. Esomeprazole is also an inhibitor of CYP2C19 which does not affect dacomitinib. The bioavailability of dacomitinib is pH-dependent, thus an increase in gastric pH by esomeprazole may reduce its bioavailability. Coadministration of rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29% in vivo. This may result in reduced activity of dacomitinib. Therefore, coadministration should be avoided. If coadministration is clinically necessary, dacomitinib should be administered when acid secretion is least inhibited, which is just before a new dose of esomeprazole. Dacomitinib may be administered concomitantly with an acidic beverage like cola, to overcome the decreased bioavailability. However, this has not been assessed in a clinical study.

Coadministration has not been studied but care should be taken. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro. Monitoring for ethinylestradiol toxicity may be required.

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. Concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro. Monitoring for ezetimibe toxicity may be required.

Coadministration has not been studied but should be approached with caution. Famotidine is excreted via OAT1/OAT3. The bioavailability of dacomitinib is pH-dependent, thus an increase in gastric pH by famotidine reduces its bioavailability. Coadministration rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29%. This may result in reduced activity of dacomitinib. Therefore, coadministration is not recommended. If coadministration is necessary, dacomitinib should be administered when acid secretion is least inhibited, which is 2 hours before a new dose of famotidine and at least 10 hours after the last dose of famotidine. Monitor dacomitinib plasma concentrations, if available.

Coadministration has not been studied but should be avoided. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with flecainide. Coadministration should be avoided.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect of CYP2D6 inhibition by dacomitinib on fluoxetine exposure is unlikely. Additionally, fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. Dacomitinib is metabolised by CYP2D6 (~24%). Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265).

Coadministration has not been studied but is not recommended. Fluphenazine is metabolised by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with fluphenazine. Closely monitor fluphenazine toxicity and plasma concentrations, if available.

Coadministration has not been studied but care should be taken. The metabolism of flurazepam is most likely CYP-mediated. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Monitoring for flurazepam efficacy may be required.

Coadministration has not been studied but is not recommended. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of fluvoxamine. Monitor closely for fluvoxamine toxicity and plasma concentrations, if available. Additionally, fluvoxamine is an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate), and CYP2D6 (weak). Concentrations of dacomitinib may increase due to moderate inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Dacomitinib is also metabolised by CYP2D6 (~24%) which is weakly inhibited by fluvoxamine. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265).

Coadministration has not been studied but care should be taken. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased haloperidol concentrations. Monitoring for haloperidol toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydralazine is metabolised via primary oxidative metabolism and acetylation. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Dacomitinib is metabolised by CYP2D6 (~24%) and CYP3A4 (~6%). Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265). Since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected.

Coadministration has not been studied but should be approached with caution. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration with dacomitinib may decrease plasma concentrations of hydromorphone and thereby reduce the analgesic effect. Close monitoring of hydrocodone efficacy is recommended.

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

Coadministration has not been studied but should be avoided. Iloperidone is metabolised by CYP3A4 and CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with iloperidone. Coadministration should be avoided. If coadministration cannot be avoided, decrease the dose by 50% and monitor closely for toxicity.

Coadministration has not been studied but is not recommended. Imipramine is metabolised by CYPs 3A4, 2C19, and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of imipramine and desipramine. Monitor closely for toxicity and imipramine and desipramine plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9), which is not affected by dacomitinib.

Coadministration has not been studied but is contraindicated. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. This is not affected by dacomitinib. The bioavailability of dacomitinib is pH-dependent thus any increase in gastric pH by lansoprazole may reduce its bioavailability. Coadministration of rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29% in vivo. This may result in reduced activity of dacomitinib. Therefore, coadministration should be avoided. If coadministration is clinically necessary, dacomitinib should be administered when acid secretion is least inhibited, which is just before a new dose of lansoprazole. Dacomitinib may be administered concomitantly with an acidic beverage like cola, to overcome the decreased bioavailability. However, this has not been assessed in a clinical study.

Coadministration has not been studied but should be avoided. Levomepromazine is metabolised by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with levomepromazine. Coadministration should be avoided.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, because loratadine is mainly metabolised by CYP3A4, a significant increase in exposure is unlikely.

Coadministration has not been studied but is not recommended. Maprotiline is mainly metabolised by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of maprotiline. Monitor closely for maprotiline toxicity and plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Metoclopramide is partially metabolised by CYP450 system (mainly CYP2D6). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with metoclopramide. A dose reduction of 50% for metoclopramide is advised. Additionally, closely monitor for metoclopramide toxicity, including ECG and extrapyramidal symptoms.

Coadministration has not been studied but should be avoided. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with mexiletine. Coadministration should be avoided.

Coadministration has not been studied but should be approached with caution. Mianserin is metabolised by CYP2D6 and CYP1A2, and to a lesser extent by CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to increased plasma concentrations of mianserin. Monitor closely for mianserin toxicity and plasma concentrations, if available.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on mirtazapine plasma concentrations is unlikely.

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro. Additionally, morphine is a substrate of P-gp and concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. Monitoring for morphine toxicity (e.g., respiratory depression) may be required.

Coadministration has not been studied but should be approached with caution. Nebivolol metabolism involves CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with nebivolol. Close monitoring for nebivolol toxicity is recommended.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for nicardipine, a significant increase in concentration is unlikely. Additionally, nicardipine is a weak inhibitor of CYP3A4. Concentrations of dacomitinib may increase due to inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on norgestimate plasma concentrations is unlikely.

Coadministration has not been studied but is not recommended. Nortriptyline is metabolised mainly by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with nortriptyline. Closely monitor nortriptyline toxicity and plasma concentrations, if available.

Coadministration has not been studied but care should be taken. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the alternative metabolic pathways available, a significant effect on olanzapine plasma concentrations is less likely. Monitoring for olanzapine toxicity and plasma concentrations, if available, may be required.

Coadministration has not been studied but is contraindicated. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4.This is not affected by dacomitinib. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19, which does not affect dacomitinib. The bioavailability of dacomitinib is pH-dependent thus any increase in gastric pH by omeprazole may reduce its bioavailability. Coadministration of rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29% in vivo. This may result in reduced activity of dacomitinib. Therefore, coadministration should be avoided. If coadministration is clinically necessary, dacomitinib should be administered when acid secretion is least inhibited, which is just before a new dose of omeprazole. Dacomitinib may be administered concomitantly with an acidic beverage like cola, to overcome the decreased bioavailability. However, this has not been assessed in a clinical study.

Coadministration has not been studied but care should be taken. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the minor role of CYP2D6 in ondansetron metabolism, a significant effect on ondansetron concentrations is unlikely. Ondansetron is also a substrate of P-gp and concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. Monitoring for ondansetron toxicity may be required.

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

Coadministration has not been studied but is not recommended. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration with dacomitinib may decrease plasma concentrations of oxymorphone, which is 14 times more potent than oxycodone, and thereby reduce the analgesic effect. Close monitoring of oxycodone efficacy and toxicity is recommended.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for paliperidone, a significant increase in concentration is unlikely.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, due to the minor role of CYP2D6 in palonosetron metabolism, a significant effect on palonosetron concentrations is unlikely. Palonosetron is also a substrate of P-gp and concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. Monitoring for palonosetron toxicity may be required.

Coadministration has not been studied but is contraindicated. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6, and 2C9. Dacomitinib is a strong inhibitor of CYP2D6. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 constitutes a minor metabolic pathway of pantoprazole, no significant increase in concentration is expected. The bioavailability of dacomitinib is pH-dependent thus any increase in gastric pH by pantoprazole may reduce its bioavailability. Coadministration of rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29% in vivo. This may result in reduced activity of dacomitinib. Therefore, coadministration should be avoided. If coadministration is clinically necessary, dacomitinib should be administered when acid secretion is least inhibited, which is just before a new dose of pantoprazole. Dacomitinib may be administered concomitantly with an acidic beverage like cola, to overcome the decreased bioavailability. However, this has not been assessed in a clinical study.

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). While dacomitinib is a strong inhibitor of CYP2D6, this is unlikely to alter paracetamol metabolism significantly. However, concentrations may increase due to potential inhibition of UGT1A1 by dacomitinib, but this effect has only been established in vitro and is unlikely to be clinically significant.

Coadministration has been studied and is not recommended. Paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9. In healthy patients (n=14), coadministration of dacomitinib (45 mg single dose, day 4) with paroxetine (30 mg once daily for 10 days) did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265). However, paroxetine is mainly metabolised by CYP2D6, which is also strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with paroxetine. Closely monitor paroxetine toxicity and plasma concentrations, if available.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for perazine, a significant increase in concentration is unlikely.

Coadministration has not been studied but should be avoided. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. As the metabolism of periciazine has not been well characterized, coadministration should be avoided.

Coadministration has not been studied but should be approached with caution. Perphenazine is metabolised by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with perphenazine. Monitor closely for perphenazine toxicity and consider a dose reduction.

Coadministration has not been studied but should be avoided. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with pimozide. Coadministration should be avoided. If coadministration cannot be avoided, decrease the pimozide dose and monitor closely for toxicity.

Coadministration has not been studied but care should be taken. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. Coadministration may lead to elevated pindolol concentrations. Monitoring for pindolol toxicity may be required.

Coadministration has not been studied but should be avoided. The metabolism of pipotiazine has not been well described but may involve CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. As the metabolism of pipotiazine has not been well characterized, coadministration should be avoided.

Coadministration has not been studied but should be approached with caution. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with prochlorperazine. Close monitoring for prochlorperazine toxicity is recommended.

Coadministration has not been studied but care should be taken. Promethazine is metabolised by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with promethazine. Monitoring for promethazine toxicity may be required.

Coadministration has not been studied but should be avoided. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with propafenone. Coadministration should be avoided.

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). CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes one of several metabolic pathways for propranolol, a significant increase in concentration is unlikely.

Coadministration has not been studied but should be approached with caution. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1, which are not affected by dacomitinib. Quinidine is a substrate of P-gp and concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. Monitoring for quinidine toxicity may be required, including ECG-monitoring. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Dacomitinib is metabolised by CYP2D6 (~24%) and concentrations may increase due to inhibition by quinidine. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265). Concentrations of dacomitinib may also increase due to inhibition of CYP3A4 by quinidine. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Additionally, dacomitinib is a substrate of P-gp. Concentrations of dacomitinib may increase due to P-gp inhibition by quinidine, but this effect has only been established in vitro. However, increased exposure to dacomitinib is related to increased toxicity. Dacomitinib is dosed at the maximum tolerated dose, therefore every increase in exposure is considered clinically relevant. Close monitoring for dacomitinib toxicity is recommended.

Coadministration has been studied and is contraindicated. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4, which are not affected by dacomitinib. The bioavailability of dacomitinib is pH-dependent thus any increase in gastric pH by rabeprazole may reduce its bioavailability. In healthy males (n=24), coadministration of dacomitinib (45 mg single dose, day 1) with rabeprazole (40mg once daily, day -5 to 1) decreased the AUC_inf of dacomitinib by 29%. This may result in reduced activity of dacomitinib. Therefore, coadministration should be avoided. If coadministration is clinically necessary, dacomitinib should be administered when acid secretion is least inhibited, which is just before a new dose of rabeprazole. Dacomitinib may be administered concomitantly with an acidic beverage like cola, to overcome the decreased bioavailability. However, this has not been assessed in a clinical study.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. This is not affected by dacomitinib.

Coadministration has not been studied but should be approached with caution. Ranitidine is excreted via OAT1/OAT3, which is not affected by dacomitinib. The bioavailability of dacomitinib is pH-dependent thus any increase in gastric pH by ranitidine reduces its bioavailability. Coadministration rabeprazole with a single dose of dacomitinib decreased the AUC_inf of dacomitinib by 29%. This may result in reduced activity of dacomitinib. Therefore, coadministration is not recommended. If coadministration is necessary, dacomitinib should be administered when acid secretion is least inhibited, which is 2 hours before a new dose of ranitidine and at least 10 hours after the last dose of ranitidine. Monitor dacomitinib plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 constitutes a minor metabolic pathway for ranolazine, a significant effect on ranolazine plasma concentrations is unlikely. Ranolazine is also a substrate of P-gp. Ranolazine concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. Monitoring for ranolazine toxicity may be required. Moreover, ranolazine is a weak inhibitor of P-gp, CYP3A4, and CYP2D6. Concentrations of dacomitinib may increase due to inhibition of CYP3A4. However, since CYP3A4 only contributes to dacomitinib metabolism to a small degree (~6%), no relevant effect of CYP3A4 inhibition on dacomitinib exposure is expected. Dacomitinib is metabolised by CYP2D6 (~24%) which is inhibited by ranolazine. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC0-inf of total active moiety (dacomitinib + PF-05199265). Dacomitinib is a substrate of P-gp. Dacomitinib concentrations may increase due to P-gp inhibition, but this effect has only been established in vitro. Increased exposure to dacomitinib is related to increased toxicity. Dacomitinib is dosed at the maximum tolerated dose, therefore every increase in exposure is considered clinically relevant. Close monitoring for dacomitinib toxicity is recommended.

Coadministration has not been studied but is not recommended. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with risperidone. Monitor closely for risperidone toxicity and plasma concentrations, if available. Risperidone is also a substrate of P-gp. Risperidone concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. This further emphasises the need for close monitoring for risperidone toxicity and plasma concentrations.

Coadministration has not been studied but should be avoided. Sertindole is metabolised by CYP2D6 and CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with pimozide. Coadministration should be avoided. If coadministration cannot be avoided, decrease the sertindole dose and monitor closely for toxicity.

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. Dacomitinib strongly inhibits CYP2D6. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, since sertraline is mainly metabolised by CYP2B6, no significant effect of CYP2D6 inhibition by dacomitinib on sertraline exposure is expected.

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. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 only constitutes a minor metabolic pathway for tamsulosin metabolism, a significant effect on tamsulosin exposure is unlikely.

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

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 CYP2C8 and CYP2C19. This is not affected by dacomitinib. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Coadministration of dacomitinib with paroxetine, a strong CYP2D6 inhibitor, did not have a relevant effect on the AUC_0-inf of total active moiety (dacomitinib + PF-05199265).

Coadministration has not been studied but should be avoided. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with thioridazine. Coadministration should be avoided.

Coadministration has not been studied but is not recommended. Timolol is predominantly metabolised in the liver by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with timolol. Close monitoring for timolol toxicity is recommended. Note: the systemic absorption of timolol after ocular administration is low. Therefore, a clinically relevant interaction via CYP2D6 is unlikely.

Coadministration has not been studied but should be avoided. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with tolterodine. Coadministration should be avoided. If coadministration cannot be avoided, closely monitor for tolterodine toxicity.

Coadministration has not been studied but is not recommended. Trimipramine is metabolised mainly by CYP2D6, which is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with trimipramine. Closely monitor trimipramine toxicity and plasma concentrations, if available.

Coadministration has not been studied but should be avoided. Tropisetron is metabolised mainly by CYP2D6. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with tropisetron. Coadministration should be avoided. If coadministration cannot be avoided, decrease the tropisetron dose and monitor closely for toxicity. Additionally, tropisetron is a substrate of P-gp and concentrations may increase due to potential inhibition of P-gp by dacomitinib, but this effect has only been established in vitro. This further emphasises the need for tropisetron toxicity monitoring.

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 CYP1A2 and CYP2D6. Dacomitinib is a strong inhibitor of CYP2D6. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. However, as CYP2D6 constitutes a minor metabolic pathway of ulipristal, no significant increase in concentration is expected.

Coadministration has not been studied but is not recommended. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19, and 2C9. CYP2D6 is strongly inhibited by dacomitinib. Coadministration of dacomitinib and dextromethorphan, a probe CYP2D6 substrate, increased the Cmax and AUC_0-inf of dextromethorphan by 973% and 362%, respectively. A similar effect may occur after coadministration with venlafaxine. Closely monitor venlafaxine toxicity and plasma concentrations, if available.

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. None of these metabolic pathways are affected by dacomitinib.