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 microbial flora. Lapatinib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Alendronate is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, alendronate should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfentanil undergoes extensive CYP3A4 metabolism. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. For administration routes other than oral, a clinically relevant interaction is not expected.

Coadministration has not been studied. Alfuzosin is metabolised by CYP3A. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered alfuzosin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45% increase in midazolam AUC. A similar effect may occur with alfuzosin. Care should be taken when orally administered alfuzosin is coadministered with lapatinib. Monitoring for alfuzosin toxicity is recommended.

Coadministration has not been studied. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Lapatinib is an inhibitor of P-gp and may increase concentrations of aliskiren. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with aliskiren. If coadministration appears necessary, monitoring of blood pressure is recommended.

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. Lapatinib not interfere with this metabolic pathway.

Coadministration has not been studied. Aluminium hydroxide is not metabolised. Lapatinib is unlikely to interfere with this pathway. The solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with aluminium hydroxide. If coadministration is clinically necessary, lapatinib should be administered at least 2 hours before or 4 hours after antacids.

Coadministration has not been studied. Ambrisentan is metabolised by glucuronidation via UGTs 1A3, 1A9 and 2B7, and to a lesser extent by CYP3A4 and CYP2C19. Ambrisentan is also a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of orally administered ambrisentan may increase. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with ambrisentan. If coadministration appears necessary, monitoring of blood pressure is recommended.

Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP3A4 and CYP2C8. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with amiodarone. Lapatinib is also an in vitro inhibitor of CYP2C8 at clinically relevant concentrations. Caution should be exercised and a dose reduction of amiodarone should be considered. Monitor closely for amiodarone toxicity. Furthermore, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong) and 2B6 (moderate) and P-gp (strong). Concentrations of lapatinib may alter due to inhibition of CYP3A4, CYP2C19 and P-gp. The clinical relevance of CYP3A4 inhibition is unknown. Selection of an alternate concomitant medicinal product with no or minimal potential to inhibit CYP3A4 should be considered. Since CYP2C19 is only a minor pathway in lapatinib metabolism, no clinically significant interaction is expected. However P-gp inhibition may increase exposure of lapatinib, therefore caution should be exercised. Monitor lapatinib toxicity and lapatinib plasma concentrations, if available. In addition, lapatinib and amiodarone may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring 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 based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily renally eliminated (possibly via OCT). Lapatinib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but is not recommended. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered astemizole may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with astemizole. Care should be taken when orally administered astemizole is coadministered with lapatinib. Monitoring for astemizole toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant effect on astemizole exposure is not expected. Furthermore, lapatinib and astemizole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib also inhibits P-gp and OATP1B1 (in vitro). Concentrations of atorvastatin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur after coadministration with atorvastatin. If coadministration is unavoidable, monitor for atorvastatin toxicity.

Coadministration has not been studied but should be approached with caution. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Lapatinib is an inhibitor of P-gp and may increase concentrations of azithromycin. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC 80%. A similar effect may occur with azithromycin. As the clinical relevance of this interaction is unknown, monitoring for azithromycin toxicity may be required. Azithromycin is also an inhibitor of P-gp, but the clinical relevance of P-gp inhibition by azithromycin is unknown. Lapatinib is not a substrate of P-gp. However, lapatinib and azithromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied but should be approached with caution. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered bepridil may increase. Since CYP3A4 is a minor pathway, a pharmacokinetic interaction is not expected. However, lapatinib and bepridil may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Bisoprolol is also a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of bisoprolol may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with bisoprolol. Monitoring of blood pressure is recommended.

Coadministration has not been studied. Bosentan is a substrate of CYP3A4 and CYP2C9. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic lapatinib. Concentrations of orally administered bosentan may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with bosentan. Care should be taken when orally administered bosentan is coadministered with lapatinib. Monitoring for bosentan toxicity is recommended. Bosentan is also a weak inducer of CYP3A4 and CYP2C9 and may decrease lapatinib exposure. In a phase III study, imatinib (a CYP3A4 substrate) concentrations, on average, decreased by 33% (95% CI 18%, 45%) in the presence of bosentan. Imatinib and lapatinib are both mainly metabolised by CYP3A4 and a similar result may occur with lapatinib. If coadministration is necessary, close monitoring of lapatinib efficacy is required. Monitor lapatinib plasma concentrations, if available.

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 play a role. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway, no clinically relevant effect on bromazepam exposure is expected.

Coadministration has not been studied. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. For the oral formulation of buprenorphine, lapatinib may increase concentrations of buprenorphine. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with buprenorphine. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant interaction is not expected. Lapatinib is also an in vitro inhibitor of UGT1A1 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for buprenorphine toxicity may be required.

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. Lapatinib does not interfere with this elimination pathway.

Coadministration should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of carbamazepine may increase, but since carbamazepine is a strong CYP3A4 inducer itself, no clinically relevant effect on carbamazepine exposure is expected. Lapatinib also inhibits CYP2C8 in vitro at clinically relevant concentrations, but since CYP2C8 is a minor pathway, this is unlikely to lead to a clinically relevant effect. However, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of lapatinib may decrease due to induction of CYP3A4 and CYP2C8. In healthy volunteers, coadministration of lapatinib and carbamazepine decreased systemic exposure of lapatinib by approximately 72%. Therefore, coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If patients must be co-treated with carbamazepine, pharmacokinetic studies suggest titrating the dose of lapatinib up by a factor of 3-4 based on tolerability. If carbamazepine is discontinued the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2. Carvedilol is also a substrate of P-gp. Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations. Lapatinib is also an inhibitor of P-gp and may increase concentrations of carvedilol. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with carvedilol. Monitoring of blood pressure is recommended.

Coadministration has not been studied but should be approached with caution. Ciclosporin is a substrate of CYP3A4 and P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Coadministration should be approached with caution. Monitor for ciclosporin toxicity and plasma concentrations, if available. Furthermore, ciclosporin is an inhibitor of CYP3A4 and OATP1B1. Concentrations of lapatinib may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. No a priori dosage adjustment is recommended for lapatinib, but close monitoring is recommended. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Cimetidine is metabolised by CYP450 enzymes. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an in vitro inhibitor of CYP2C8 at clinically relevant concentrations. Concentrations of cimetidine may increase but the clinical significance of CYP3A4 and CYP2C8 inhibition is unknown. Furthermore, in vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Lapatinib does not interact with this pathway. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Concentrations of lapatinib may increase due to inhibition of CYP3A4 and CYP2C19. The solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with cimetidine. A decrease in exposure may lead to a decrease in lapatinib efficacy. If coadministration is unavoidable, monitor lapatinib efficacy and plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. Ciprofloxacin is also metabolised and partially cleared through the bile and intestine. Lapatinib does not interact with this pathway. However, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of lapatinib may increase due to moderate inhibition of CYP3A4. Coadministration should be approached with caution. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for lapatinib toxicity and monitor lapatinib plasma concentrations, if available. Furthermore, lapatinib and ciprofloxacin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Clindamycin is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered clindamycin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with clindamycin. Care should be taken when orally administered clindamycin is coadministered with lapatinib. Monitoring for clindamycin toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), no clinically relevant interaction is expected. Furthermore, in vitro data suggest that clindamycin is a CYP3A4 inhibitor, and may increase concentrations of lapatinib. The clinical relevance of this interaction is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. Monitoring for lapatinib toxicity may be required and, if available, monitor lapatinib plasma concentrations.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces. Lapatinib does not interfere with this elimination pathway. However, in vitro data suggest that clofazimine is a CYP3A4 inhibitor, and may increase concentrations of lapatinib. The clinical relevance of this interaction is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. Monitoring for lapatinib toxicity may be required and, if available, monitor lapatinib plasma concentrations. Furthermore, lapatinib and clofazimine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied but is not recommended. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolised by CYP2D6. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered clomipramine may increase and thus concentrations of desmethylclomipramine may decrease. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with clomipramine. Care should be taken when orally administered clomipramine is coadministered with lapatinib. Monitoring for toxicity is recommended. Furthermore, lapatinib and clomipramine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

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 the form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 but is unlikely to interact with the elimination of lapatinib. Lapatinib does not interfere with this pathway.

Coadministration has not been studied. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered clopidogrel may increase and thus concentrations of the active metabolite may decrease. Care should be taken when orally administered clopidogrel is coadministered with lapatinib. Monitoring for both clopidogrel toxicity and efficacy is recommended. Furthermore, clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Since CYP2C8 is a minor pathway in lapatinib metabolism, a clinically relevant effect on lapatinib exposure is not expected.

Coadministration has not been studied. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered clorazepate may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with clorazepate. Furthermore, oxazepam is mainly glucuronidated. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. The clinical relevance of UGT inhibition is unknown. Care should be taken when orally administered clorazepate is coadministered with lapatinib. Monitoring for clorazepate and oxazepam toxicity is recommended.

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. Lapatinib does not interact with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of colchicine may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Furthermore, coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with colchicine. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for colchicine toxicity.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly renally excreted via glomerular filtration. Lapatinib does not interact with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Dabigatran is a substrate of P-gp and is renally excreted. Lapatinib is an inhibitor of P-gp and may increase concentrations of dabigatran. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur with dabigatran. Therefore, caution should be exercised and a dose reduction of dabigatran should be considered. Monitoring of dabigatran toxicity and ecarine clotting time or diluted thrombin time is recommended, if available.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Desipramine is metabolised by CYP2D6. Lapatinib does not inhibit or induce CYP2D6. However, lapatinib and desipramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration should be approached with caution. Dexamethasone is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered dexamethasone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with dexamethasone. Care should be taken when orally administered dexamethasone is coadministered with lapatinib. Monitoring for dexamethasone toxicity may be required. For administration routes other than oral (e.g. i.v. drugs), no clinically relevant interaction is expected. Furthermore, dexamethasone is a known weak inducer of CYP3A4 and may decrease lapatinib plasma concentrations. The clinical relevance of this interaction is unknown as the induction of CYP3A4 by dexamethasone has yet to be established. In patients, coadministration of lapatinib and dexamethasone increased the risk of developing hepatotoxicity by around 5 times, compared to lapatinib alone. If coadministration is unavoidable, closely monitor lapatinib efficacy and symptoms of hepatotoxicity. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Dextropropoxyphene is mainly metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of dextropropoxyphene may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with dextropropoxyphene. Care should be taken when orally administered dextropropoxyphene is coadministered with lapatinib. Monitoring for dextropropoxyphene toxicity is recommended.

Coadministration has not been studied. 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. Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations, and may increase morphine concentrations. A clinically relevant interaction is unlikely as UGT1A1 is only a minor pathway in morphine metabolism. However, lapatinib is also an inhibitor of P-gp. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur with morphine. Monitoring for morphine toxicity is recommended.

Coadministration has not been studied. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered diazepam may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with diazepam. Furthermore, temazepam is mainly glucuronidated. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. The clinical relevance of this interaction is unknown. Care should be taken when orally administered diazepam is coadministered with lapatinib. Monitoring for diazepam and temazepam toxicity is recommended.

Coadministration should be approached with caution. Digoxin is renally eliminated via OATP4C1 and P-gp. Lapatinib is an inhibitor of P-gp and may increase digoxin concentrations. Coadministration of lapatinib and digoxin increased digoxin AUC by 80%. It is recommended that the lowest possible dose of digoxin should initially be given to patients on lapatinib. The digoxin dose should be carefully titrated to obtain the desired clinical effect while assessing the overall clinical state of the patient. Monitor digoxin concentrations, if available.

Coadministration has not been studied. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for dihydrocodeine toxicity may be required. Furthermore, lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is only a minor pathway in dihydrocodeine metabolism, a clinically relevant effect due to CYP3A4 inhibtion is not expected.

Coadministration has not been studied but is not recommended. Domperidone is mainly metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered domperidone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with domperidone. If coadministration is unavoidable, monitoring for domperidone toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), no clinically relevant effect on domperidone exposure is expected. However, lapatinib and domperidone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

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 the disposition of lapatinib, or to be affected if coadministered with lapatinib.

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. Lapatinib does not interact with this elimination pathway.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: 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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of drospirenone may increase. However, since CYP3A4 is a minor pathway, no clinically relevant interaction is expected.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of dydrogesterone may increase. The clinical relevance of this interaction is unknown. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with dydrogesterone. Care should be taken when orally administered dydrogesterone is coadministered with lapatinib. Monitoring for dydrogesterone toxicity may be required.

Coadministration has not been studied but should be approached with caution. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Lapatinib is an in vitro inhibitor of UGT1A1 and CYP2C8 at clinically relevant concentrations. The clinical relevance of this interaction is unknown. Caution should be exercised and a dose reduction of eltrombopag should be considered. Monitor closely for eltrombopag toxicity.

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. Lapatinib does not interact with this metabolic pathway.

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. Lapatinib does not interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of erythromycin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with erythromycin. Therefore, caution should be exercised and a dose reduction of erythromycin should be considered. Monitor for erythromycin toxicity. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp, and may increase concentrations of lapatinib. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for lapatinib toxicity. Monitor lapatinib plasma concentrations, if available. Lapatinib and erythromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of estradiol may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with estradiol. Furthermore, lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations, but the clinical significance of UGT inhibition is unknown. Care should be taken when estradiol is coadministered with lapatinib. Monitoring for estradiol toxicity may be required.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations, but the clinical relevance of UGT inhibition is unknown. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of ethinylestradiol may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with ethinylestradiol. Care should be taken when ethinylestradiol is coadministered with lapatinib. Monitoring for ethinylestradiol toxicity may be required.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. However, since etonogestrel is not orally administered, a clinically relevant interaction is unlikely.

Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of everolimus may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Furthermore, lapatinib is an inhibitor of P-gp. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur after coadministration with everolimus. However, in patients coadministration of lapatinib and everolimus resulted in a 25% increase in everolimus exposure. The exposure of lapatinib was unchanged. Coadministration was well tolerated.

Coadministration has not been studied. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for ezetimibe toxicity may be required.

Coadministration has not been studied. Famotidine is excreted via OAT1/OAT3. Lapatinib does not inhibit or induce OAT1/OAT3. However, the solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with famotidine. A decrease in exposure may lead to a decrease in lapatinib efficacy. If coadministration is unavoidable, monitor lapatinib efficacy and lapatinib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl undergoes extensive CYP3A4 metabolism. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. However, since fentanyl is not orally administered, a clinically relevant interaction is not expected.

Coadministration has not been studied. Fexofenadine is a substrate of P-gp. Lapatinib is an inhibitor of P-gp and may increase concentrations of fexofenadine. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur with fexofenadine. Monitoring for fexofenadine toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. Lapatinib does not interact with this metabolic pathway. However, lapatinib and flecainide may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Lapatinib does not interact with this metabolic pathway. Flucloxacillin has been described as a CYP3A4 inducer and may decrease concentrations of lapatinib. However, the mechanism and clinical relevance of this interaction is unknown. No a priori dose adjustment for lapatinib is recommended. However, monitoring for decreased lapatinib efficacy and, if available, lapatinib plasma concentrations may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered fluoxetine may increase and thus concentrations of norfluoxetine may decrease. Since CYP3A4 is a minor pathway, no clinically relevant effect on fluoxetine exposure is expected. Furthermore, fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. Concentrations of lapatinib may increase due to CYP2C19 inhibition. Since CYP2C19 is only a minor pathway in lapatinib metabolism, a clinically significant interaction is unlikely.

Coadministration has not been studied. The metabolism of flurazepam is most likely CYP-mediated. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an in vitro inhibitor of CYP2C8 at clinically relevant concentrations. The clinical relevance of this interaction is unknown. Care should be taken when flurazepam is coadministered with lapatinib. Monitoring for flurazepam toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Fluticasone is not orally administered and no clinically relevant interaction is expected.

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%). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib also inhibits CYP2C8 in vitro at clinically relevant concentrations. Since CYP3A4 and CYP2C8 are minor pathways, no clinically relevant interaction is expected. Furthermore, fluvastatin potentially inhibits CYP2C9. Lapatinib is not metabolised by CYP2C9.

Coadministration has not been studied but should be approached with caution. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Lapatinib 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). Concentrations of lapatinib may increase due to inhibition of CYPs 3A4, 2C8 and 2C19. Coadministration should be approached with caution. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for lapatinib toxicity. Monitor lapatinib plasma concentrations, if available.

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 predominantly renally eliminated. Lapatinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation. As multiple CYP450 and UGT enzymes catalyse the transformation, the potential for a pharmacokinetic interaction with lapatinib is low.

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Lapatinib does not interact with this pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of aprepitant may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with aprepitant. Care should be taken when orally administered aprepitant is coadministered with lapatinib. Monitoring for aprepitant toxicity is recommended. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase lapatinib concentrations. Coadministration should be approached with caution. After treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of aprepitant may decrease due to CYP3A4 induction, but a clinically relevant effect due to CYP3A4 induction is not expected.

Coadministration has not been studied but should be avoided. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Lapatinib does not interact with this pathway. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Lapatinib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of lapatinib may decrease due to CYP3A4 and P-gp induction. In healthy volunteers, coadministration of lapatinib and carbamazepine, a potent CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with fosphenytoin. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If patients must be co-treated with fosphenytoin, pharmacokinetic studies suggest titrating the dose of lapatinib up by a factor of 3-4 based on tolerability. If fosphenytoin is discontinued the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

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). A large proportion of furosemide is also renally eliminated unchanged (via OATs). Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations and may increase concentrations of furosemide. Since UGT1A1 is a minor pathway, no clinically relevant effect on furosemide exposure is expected. Furthermore, in vitro data indicate that furosemide is an inhibitor of OAT1/OAT3. Lapatinib is not transported by OATs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7. Lapatinib does not inhibit or induce UGT2B7. Furthermore, gemfibrozil is 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. Although lapatinib is metabolised by CYP2C8 to a minor extent, a clinically significant interaction is not expected.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of gestodene may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with gestodene. Care should be taken when orally administered gestodene is coadministered with lapatinib. Monitoring for gestodene toxicity may be required. For administration routes other than oral (e.g. transdermal drugs), no clinically relevant interaction is expected.

Coadministration has not been studied but is not recommended. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered granisetron may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with granisetron. If unavoidable, care should be taken when orally administered granisetron is coadministered with lapatinib. Monitoring for granisetron toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), no clinically relevant effect on granisetron exposure is expected. However, lapatinib and granisetron may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied but should be avoided. In an animal study, short-term use of green tea resulted in a decreased lapatinib AUC of 74%. Long-term administration of green tea resulted in a decreased lapatinib AUC of 22%. As the clinical relevance of this interaction is unknown, coadministration should be avoided.

Coadministration has not been studied but is not recommended. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4 and 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered haloperidol may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with haloperidol. If coadministration is unavoidable, care should be taken when orally administered haloperidol is coadministered with lapatinib. Monitoring for haloperidol toxicity is recommended. For administration routes other than oral (e.g. i.m. drugs), no clinically relevant effect on haloperidol exposure is expected. Lapatinib and haloperidol may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

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. Lapatinib does not interact with this metabolic pathway.

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. Although in vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6, it is not expected that this will lead to a clinically relevant interaction with lapatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised but is cleared by the kidneys via OAT1. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant concentrations. 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. Significant interactions are not expected with lapatinib.

Coadministration has not been studied. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered hydrocodone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with hydrocodone. Care should be taken when orally administered hydrocodone is coadministered with lapatinib and monitoring for hydrocodone toxicity should be recommended. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered hydroxyzine may increase, but since CYP3A4 is a minor pathway, no clinically relevant effect on hydroxyzine exposure is expected. However, lapatinib and hydroxyzine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring 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. Lapatinib is an in vitro inhibitor of CYP2C8, UGT2B17 and UGT1A1 at clinically relevant concentrations. However, since both CYP2C8 and glucuronidation are minor pathways, no clinically relevant effect on lapatinib exposure is expected.

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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered imipramine may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with imipramine. Care should be taken when orally administered imipramine is coadministered with lapatinib. Monitoring for imipramine toxicity is recommended. Furthermore, lapatinib and imipramine may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied but is not recommended. Indapamide is extensively metabolised by CYP450. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered indapamide may increase. Lapatinib is also an in vitro inhibitor of CYP2C8 at clinically relevant concentrations. The clinical relevance of this interaction is unknown. If coadministration appears necessary, monitoring of blood pressure is recommended. 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. Lapatinib does not interact with this pathway. Lapatinib and indapamide may cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Lapatinib does not inhibit or induce CYP2C9. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring of blood pressure may be required.

Coadministration has been studied and should be avoided. Ketoconazole is a substrate of CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered ketoconazole may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45% increase. A similar effect may occur with ketoconazole. If coadministration is unavoidable, care should be taken when orally administered ketoconazole is coadministered with lapatinib. Monitoring for ketoconazole toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant effect on ketoconazole exposure is not expected. Furthermore, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp, and may increase concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and ketoconazole increased lapatinib exposure by approximately 3.6-fold. Coadministration should be avoided. If coadministration is unavoidable, a dose reduction of 50-65% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for labetalol toxicity may be required.

Coadministration has not been studied. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of lansoprazole may increase. Since CYP3A4 is a minor pathway, no clinically relevant effect due on lansoprazole exposure is expected. However, the solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with lansoprazole. A decrease in exposure may lead to a decrease in lapatinib efficacy. If coadministration is unavoidable, monitor lapatinib efficacy and lapatinib plasma concentrations, if available.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. Since glucuronidation is a minor pathway, a clinically relevant effect due to UGT inhibition is unlikely. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of levonorgestrel may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with levonorgestrel. Care should be taken when orally administered levonorgestrel is coadministered with lapatinib. Monitoring for levonorgestrel toxicity may be required. For administration routes other than oral, no clinically relevant interaction is expected.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. However, the use of levonorgestrel as emergency contraception is a relative contraindication due to the risk of a pregnancy while having a hormone-sensitive tumour. Therefore, the following information is applicable: Coadministration has not been studied. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of levonorgestrel may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with levonorgestrel. Care should be taken when orally administered levonorgestrel is coadministered with lapatinib. Monitoring for levonorgestrel toxicity may be required. Furthermore, lapatinib is in vitro inhibitor of UGT1A1 and UGT2B7 at clinical relevant concentrations. Since glucuronidation is a minor pathway, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring of TSH and T4 may be required.

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor metabolic pathway. Linagliptin is also a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway, no clinically relevant effect due to CYP3A4 inhibition is expected. However, lapatinib is also an inhibitor of P-gp. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with linagliptin. Monitoring of blood glucose levels is recommended and adjust linagliptin dose accordingly. Furthermore, linagliptin is an inhibitor of CYP3A4 and may increase concentrations of lapatinib. The clinical relevance of this interaction is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is renally eliminated unchanged via glomerular filtration. Lapatinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. However, lapatinib and lithium may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Lormetazepam is mainly glucuronidated. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for lormetazepam toxicity may be required.

Coadministration has not been studied. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Lapatinib is an in vitro inhibitor of CYP2C8 at clinically relevant concentrations. Since CYP2C8 is a minor pathway, a clinically relevant effect due to CYP2C8 inhibition is not expected. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered macitentan may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with macitentan. Care should be taken when orally administered macitentan is coadministered with lapatinib. If coadministration with orally administered macitentan appears necessary, monitoring of blood pressure is recommended.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since medroxyprogesterone IM depot injection is not orally administered, no clinically relevant interaction is expected.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Medroxyprogesterone is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of medroxyprogesterone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with medroxyprogesterone. Care should be taken when orally administered medroxyprogesterone is coadministered with lapatinib. Monitoring for medroxyprogesterone toxicity may be required. For administration routes other than oral, no clinically relevant interaction is expected.

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 a substrate of OCT1/2/3, MATE1 and MATE2K. Lapatinib does not interact with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Methadone is demethylated by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered methadone may increase. Care should be taken when orally administered methadone is coadministered with lapatinib and monitoring for methadone toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), no clinically relevant effect on methadone exposure is expected. However, lapatinib and methadone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway, no clinically relevant interaction is expected.

Coadministration has not been studied but should be avoided. Miconazole is extensively metabolised by the liver. Lapatinib is unlikely to interfere with this metabolic pathway. However, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of lapatinib may increase due to inhibition of CYP3A4. In healthy volunteers, coadministration of lapatinib and ketoconazole, a strong CYP3A4 inhibitor, increased lapatinib exposure by approximately 3.6-fold. A similar effect may occur with miconazole. Coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, a dose reduction of 50-66% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Midazolam is metabolised by CYP3A4. Coadministration of lapatinib with orally administered midazolam increased midazolam AUC by 45%. Care should be taken when orally administered midazolam is coadministered with lapatinib. Monitoring for midazolam toxicity is recommended.

Coadministration has not been studied but should be approached with caution. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYP3A4 and CYP2C9. Lapatinib is an in vitro inhibitor of CYP2C8 at clinically relevant concentrations, but the clinical relevance of CYP2C8 inhibition is unknown. Furthermore, lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Montelukast concentrations may increase and caution should be exercised. A dose reduction of montelukast should be considered. Monitor closely for montelukast toxicity.

Coadministration has not been studied. 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. Lapatinib is an in vitro inhibitor of UGT1A1 at clinical relevant concentrations. Since UGT1A1 is a minor pathway, a clinically relevant effect due to UGT1A1 inhibition is not expected. However, lapatinib is also an inhibitor of P-gp. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with morphine. Monitoring for morphine toxicity is recommended.

Coadministration has not been studied but should be avoided. Nefazodone is metabolised mainly by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered nefazodone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with nefazodone. Care should be taken when orally administered nefazodone is coadministered with lapatinib. Monitoring for nefazodone toxicity is recommended. Furthermore, nefazodone is a strong inhibitor of CYP3A4 and may increase concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and ketoconazole, a strong CYP3A4 inhibitor, increased lapatinib exposure by approximately 3.6-fold. A similar effect may occur with nefazodone. Coadministration should be avoided. If coadministration is unavoidable, a dose reduction of 55-60% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since nicardipine is not orally administered, a clinically relevant effect on nicardipine exposure is not expected. However, nicardipine is a weak inhibitor of CYP3A4 and may increase lapatinib concentrations. As the clinical relevance of this interaction is unknown, selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered.

Coadministration has not been studied. Nifedipine is metabolised mainly by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of nifedipine may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with orally administered nifedipine. Care should be taken when orally administered nifedipine is coadministered with lapatinib. Monitoring for nifedipine toxicity is recommended.

Coadministration has not been studied. Nisoldipine is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of nisoldipine may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with orally administered nifedipine. Care should be taken when orally administered nisoldipine is coadministered with lapatinib. Monitoring for nisoldipine toxicity is recommended.

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%). Lapatinib does not interact with this metabolic pathway.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: 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). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since norelgestromin is not orally administered, a clinically relevant interaction is not expected.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for norethisterone toxicity may be required.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib also inhibits CYP2C8 in vitro at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for norgestimate toxicity may be required.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. Since glucuronidation is a minor pathway, a clinically relevant effect due to glucuronidation is unlikely. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of norgestrel may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with levonorgestrel. Care should be taken when orally administered levonorgestrel is coadministered with lapatinib. Monitoring for levonorgestrel toxicity may be required. For administration routes other than oral, no clinically relevant interaction is expected.

Coadministration has not been studied. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway, no clinically relevant effect on omeprazole exposure is expected. Furthermore, omeprazole induces CYP1A2 and inhibits CYP2C19. Since CYP2C19 is a minor pathway in lapatinib metabolism, no clinically significant effect due to CYP2C19 inhibition is expected. However, the solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with omeprazole. A decrease in exposure may lead to a decrease in lapatinib efficacy. If coadministration is unavoidable, monitor lapatinib efficacy and lapatinib plasma concentrations, if available.

Coadministration has not been studied. Oxazepam is mainly glucuronidated. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations, and may increase concentrations of oxazepam. As the clinical relevance of this interaction is unknown, monitoring for oxazepam toxicity may be required.

Coadministration has not been studied but should be approached with caution. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Lapatinib does not interact with this metabolic pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Concentrations of lapatinib may decrease due to CYP3A4 induction. The clinical relevance of this interaction is unknown. No a priori dose adjustment for lapatinib is recommended. Monitor closely for decreased lapatinib efficacy. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Oxprenolol is largely metabolised via glucuronidation. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations, and may increase concentrations of oxprenolol. As the clinical relevance of this interaction is unknown, monitoring of blood pressure may be required.

Coadministration has not been studied. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered oxycodone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with oxycodone. Care should be taken when orally administered oxycodone is coadministered with lapatinib. Monitoring for oxycodone toxicity is recommended. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pamidronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Lapatinib does not interfere with this elimination pathway.

Coadministration has not been studied. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of pantoprazole may increase. Since CYP3A4 is a minor pathway, no clinically relevant effect on pantoprazole exposure is expected. However, the solubility of lapatinib is pH-dependent. Pre-treatment with a proton pump inhibitor (esomeprazole) decreased lapatinib exposure by an average of 26%. A similar effect may occur with pantoprazole. A decrease in exposure may lead to a decrease in lapatinib efficacy. If coadministration is unavoidable, monitor lapatinib efficacy and lapatinib plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, 2B15), sulfation and to a lesser extent by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Lapatinib is an in vitro inhibitor of UGT1A1 at clinically relevant concentrations. In vitro data showed an IC50 for glucuronidation of paracetamol of >100 µM, while lapatinib Cmax reaches concentrations up to 4.2 µM. Therefore, UGT1A1 inhibition is unlikely to lead to a clinically relevant effect on paracetamol exposure. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered paracetamol may increase, but since paracetamol already has high bioavailability a clinically relevant effect on paracetamol exposure is not expected. However, animal studies have shown that paracetamol does have an effect on lapatinib exposure. The clinical relevance of this interaction is unknown. Coadministration should be approached with caution. Monitor for lapatinib toxicity and plasma concentrations, if available.

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. Lapatinib does not inhibit or induce CYP2D6.

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. Lapatinib does not interfere with this metabolic pathway.

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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway in pethidine metabolism, a clinically relevant interaction is unlikely.

Coadministration has not been studied but should be avoided. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Lapatinib does not inhibit or induce CYPs 2C19, 2C9 or 2E1. However, phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Concentrations of lapatinib may decrease due to CYP3A4 induction. In healthy volunteers, coadministration of lapatinib and carbamazepine, a strong CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with phenobarbital. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If patients must be co-treated with phenobarbital, pharmacokinetic studies suggest titrating the dose of lapatinib up by a factor of 3-4 based on tolerability. If phenobarbital is discontinued the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered phenprocoumon may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with phenprocoumon. Care should be taken when orally administered phenprocoumon is coadministered with lapatinib. Monitoring for phenprocoumon toxicity and INR/PT is recommended.

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Lapatinib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of lapatinib may decrease due to CYP3A4 and P-gp induction. In healthy volunteers, coadministration of lapatinib and carbamazepine, a strong CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with phenytoin. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If patients must be co-treated with phenytoin, pharmacokinetic studies suggest titrating the dose of lapatinib up by a factor of 3-4 based on tolerability. If phenytoin is discontinued the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

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. Lapatinib does not inhibit or induce CYP4F2.

Coadministration has not been studied but care should be taken. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Pitavastatin is also a substrate of OATP1B1. Lapatinib inhibits CYP2C8 and OATP1B1 in vitro at clinically relevant concentrations and may increase concentrations of pitavastatin. A clinically relevant effect due to CYP2C8 inhibtion is unlikely. However, the clinical relevance of OATP1B1 inhibition is unknown. Monitoring for pitavastatin toxicity may be required.

Coadministration has not been studied but should be avoided. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Lapatinib is an inhibitor of P-gp and an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with posaconazole. If coadministration is unavoidable, caution should be exercised and a dose reduction of posaconazole should be considered. Monitor for posaconazole toxicity. Furthermore, posaconazole is a strong inhibitor of CYP3A4 and may increase lapatinib concentrations. In healthy volunteers, coadministration of lapatinib and ketoconazole, a strong CYP3A4 inhibitor, increased lapatinib exposure by approximately 3.6-fold. A similar effect may occur with posaconazole. Coadministration should be avoided. If coadministration is unavoidable, a dose reduction of 50-65% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. 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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered prasugrel may increase and thus concentrations of the active metabolite may decrease. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with prasugrel. Care should be taken when orally administered prasugrel is coadministered with lapatinib. Monitoring for prasugrel toxicity and efficacy is recommended. A thrombocyte aggregation function test is also recommended.

Coadministration has not been studied but care should be taken. Pravastatin is minimally metabolised (via CYP3A4) and is a substrate of OATP1B1. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an in vitro inhibitor of OATP1B1. Concentrations of pravastatin may increase. A clinically relevant effect due to CYP3A4 inhibition is unlikely. However, the clinical relevance of OATP1B1 inhibition is unknown. Monitoring for pravastatin toxicity may be required.

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). Lapatinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Lapatinib does not inhibit or induce CYP2D6 or CYP2C19. However, lapatinib and prochlorperazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. 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). Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring of blood pressure may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prucalopride is minimally metabolised and mainly renally eliminated, partly by active secretion by renal transporters. No clinically relevant interactions were observed when prucalopride was coadministered with inhibitors of renal P-gp, OAT and OCT transporters.

Coadministration has not been studied but is not recommended. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of orally administered quinidine may increase due to inhibition of CYP3A4 and P-gp. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with quinidine. Monitoring for quinidine toxicity is recommended. Furthermore, quinidine is also an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Concentrations of lapatinib may increase due to inhibition of CYP3A4. The clinical relevance of this interaction is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. Lapatinib and quinidine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of OATP1B1. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Furthermore, lapatinib is an in vitro inhibitor of CYP2C8 and OATP1B1 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring of blood glucose levels is recommended and adjust repaglinide dose accordingly.

Coadministration has not been studied but should be avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered rifabutin may increase. Since rifabutin is a strong CYP3A4 inducer itself, a clinically relevant effect on rifabutin exposure is not expected. However, rifabutin is a strong CYP3A4 and P-gp inducer, and may decrease concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and carbamazepine, a strong CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with rifabutin. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If lapatinib must be concomitantly used with a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated up by a factor of 3-4, based on tolerability. If rifabutin is discontinued, the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied but should be avoided. Rifampicin is metabolised via deacetylation. Lapatinib does not interact with this metabolic pathway. However, rifampicin is a strong CYP3A4 and P-gp inducer and may decrease concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and carbamazepine, a strong CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with rifampicin. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If lapatinib must be concomitantly used with a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated up by a factor of 3-4, based on tolerability. If rifampicin is discontinued, the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied but should be avoided. Rifapentine is metabolised via deacetylation. Lapatinib does not interact with this metabolic pathway. However, rifapentine is a strong CYP3A4, CYP2C8 and P-gp inducer, and may decrease concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and carbamazepine, a strong CYP3A4 inducer, decreased systemic exposure of lapatinib by approximately 72%. A similar effect may occur after coadministration with rifapentine. Coadministration should be avoided. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If lapatinib must be concomitantly used with a strong CYP3A4 inducer, based on pharmacokinetic studies, the dose of lapatinib should be titrated up by a factor of 3-4, based on tolerability. If rifapentine is discontinued, the lapatinib dose should be reduced to the indicated dose. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine (by P-gp and BCRP). Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of rivaroxaban may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with rivaroxaban. Furthermore, coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with rivaroxaban. Caution should be exercised and a dose reduction of rivaroxaban should be considered. Monitoring for rivaroxaban toxicity and anti-Xa activity, if available, is recommended.

Coadministration has not been studied. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of saxagliptin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with saxagliptin. Monitoring of blood glucose levels is recommended and adjust saxagliptin dose accordingly.

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4 and the metabolite is a substrate of OATP1B1. Simvastatin is also a substrate of BCRP. Lapatinib is an in vitro inhibitor of BCRP and OATP1B1 at clinically relevant concentrations. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an in vitro inhibtior of OATP1B1. Concentrations of simvastatin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with simvastatin. If coadministration is unavoidable, monitor for simvastatin toxicity.

Coadministration has not been studied. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents a minor elimination pathway. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of sitagliptin may increase. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with sitagliptin. Monitoring of blood glucose levels is recommended and adjust sitagliptin dose accordingly.

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. Lapatinib does not interfere with this metabolic pathway.

Coadministration has not been studied but should be avoided. St John’s Wort is an inducer of CYP3A4 and P-gp, and may cause significant and unpredictable decreases in the plasma concentrations of lapatinib.

Coadministration has not been studied but should be avoided. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered telithromycin may increase. Care should be taken when orally administered telithromycin is coadministered with lapatinib. Monitoring for telithromycin toxicity is recommended. Furthermore, telithromycin is a strong inhibitor of CYP3A4 and may increase concentrations of lapatinib. In healthy volunteers, coadministration of lapatinib and ketoconazole, a strong CYP3A4 inhibitor, increased lapatinib exposure by approximately 3.6-fold. A similar effect may occur with telithromycin. Coadministration should be avoided. If coadministration is unavoidable, a dose reduction of 50-66% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Temazepam is mainly glucuronidated. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for temazepam toxicity may be required.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Testosterone is metabolised by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered testosterone may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with testosterone. Care should be taken when orally administered testosterone is coadministered with lapatinib. Monitoring for testosterone toxicity is recommended. For administration routes other than oral, no clinically relevant interaction is expected.

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor 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 lapatinib.

Coadministration has not been studied. Ticagrelor is a substrate of CYP3A4 and P-gp. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Lapatinib is also an inhibitor of P-gp. Concentrations of ticagrelor may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased ticagrelor AUC by 45%. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. Similar effects may occur with ticagrelor. Care should be taken when orally administered ticagrelor is coadministered with lapatinib. Monitoring for ticagrelor toxicity is recommended. A thrombocyte aggregation function test is also recommended. Furthermore, ticagrelor is a weak inhibitor of CYP3A4 and may increase concentrations of lapatinib. The clinical relevance of this interaction is unknown. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered.

Coadministration has not been studied. Tropisetron is metabolised mainly by CYP2D6 and is a substrate of P-gp. Lapatinib is an inhibitor of P-gp and may increase concentrations of tropisetron. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with tropisetron. Monitoring for toxicity is recommended. Furthermore, lapatinib and tropisetron may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration is contraindicated if lapatinib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of ulipristal may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with ulipristal. Care should be taken when orally administered ulipristal is coadministered with lapatinib. Monitoring for ulipristal toxicity may be required.

Coadministration has not been studied. Valproic acid is primarily metabolised by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolised by CYP2C9 and CYP2C19. Lapatinib is an in vitro inhibitor of UGT1A1 and UGT2B17 at clinically relevant concentrations. As the clinical relevance of this interaction is unknown, monitoring for valproic toxicity may be required. Valproic acid is also an inhibitor of CYP2C9. Lapatinib is not metabolised by CYP2C9.

Coadministration has not been studied but should be approached with caution. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Lapatinib inhibits CYP2C8 in vitro at clinically relevant concentrations, but the clinical relevance of CYP2C8 inhibition is unknown. Lapatinib is also a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of verapamil may increase due to CYP3A4 and CYP2C8 inhibition. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45%. A similar effect may occur with verapamil. Monitoring of blood pressure is recommended. Furthermore, verapamil is a moderate inhibitor of CYP3A4 and may increase lapatinib concentrations. Coadministration of lapatinib with verapamil should be approached with caution. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 should be considered. If coadministration is unavoidable, monitor closely for lapatinib toxicity. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. Vildagliptin is inactivated via non-CYP mediated hydrolysis. Vildagliptin is also a substrate of P-gp. Lapatinib is an inhibitor of P-gp and may increase concentrations of vildagliptin. Coadministration of lapatinib and digoxin, a P-gp substrate, increased digoxin AUC by 80%. A similar effect may occur after coadministration with vildagliptin. Monitoring of blood glucose levels is recommended and adjust vildagliptin dose accordingly.

Coadministration has not been studied but should be avoided. Voriconazole is metabolised by CYP2C19 (major) and to a lesser extent by CYP3A4 and CYP2C9. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Since CYP3A4 is a minor pathway, no clinically relevant effect on voriconazole exposure is expected. Furthermore, voriconazole is a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Concentrations of lapatinib may increase due inhibition of CYP3A4. In healthy volunteers, coadministration of lapatinib and ketoconazole, a strong CYP3A4 inhibitor, increased lapatinib exposure by approximately 3.6-fold. A similar effect may occur with voriconazole. Coadministration should be avoided. If coadministration is unavoidable, a dose reduction of 50-65% for lapatinib is recommended, based on pharmacokinetic studies. Monitor closely for lapatinib toxicity, including ECG. Monitor lapatinib plasma concentrations, if available.

Coadministration has not been studied. 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. Lapatinib is a weak inhibitor of intestinal CYP3A4 but is not an inhibitor of hepatic CYP3A4. Concentrations of orally administered warfarin may increase. Coadministration of lapatinib with orally administered midazolam, a CYP3A4 substrate, increased midazolam AUC by 45% increase. A similar effect may occur with warfarin. Care should be taken when orally administered warfarin is coadministered with lapatinib. Monitoring for warfarin toxicity and INR/PT is recommended when coadministered with lapatinib.