Coadministration has not been studied. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of aliskiren may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood pressure should be considered.

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. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of ambrisentan may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood pressure should be considered.

Coadministration has not been studied but care should be taken. Amiodarone is metabolised by CYP3A4 and CYP2C8. Neratinib does not inhibit or induce CYPs. However, 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 neratinib may decrease due to weak inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity is recommended. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

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

Coadministration has not been studied but should be avoided. Antacids are not metabolised by CYPs. Neratinib is unlikely to interfere with this metabolic pathway. However, the absorption of neratinib decreases when used concomitantly with antacids, leading to decreased neratinib exposure. Therefore, coadministration should be avoided. If coadministration is clinically necessary, neratinib should be administered at least 3 hours after antacids.

Coadministration has not been studied. Apixaban is a substrate of P-gp and BCRP, and is also metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for apixaban toxicity is recommended.

Coadministration has not been studied but should be approached with caution. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Neratinib does not inhibit or induce CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4. Concentrations of neratinib may increase during the three days of coadministration due to CYP3A4 inhibition. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for neratinib toxicity. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of neratinib may decrease due to CYP3A4 induction, but this is unlikely to be of clinical relevance.

Coadministration has not been studied. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Atorvastatin concentrations may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. It should be considered to start with the lowest dose of atorvastatin and titrate up to the desired clinical effect while monitoring for safety.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azathioprine is converted to 6-mercaptopurine which is metabolised analogously to natural purines. Neratinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. A clinically relevant interaction is unlikely.

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

Coadministration has not been studied. Chloramphenicol is predominantly glucuronidated. Neratinib does not inhibit or induce UGTs. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of neratinib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity should be considered. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically relevant interaction.

Coadministration has not been studied but is not recommended. Ciclosporin is a substrate of CYP3A4 and P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of ciclosporin may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for ciclosporin toxicity is recommended. Furthermore, ciclosporin inhibits CYP3A4 and OATP1B1. Concentrations of neratinib may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. Therefore, coadministration is not recommended and 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 neratinib toxicity and a dose reduction of neratinib should be considered. Consider monitoring of neratinib plasma concentrations, if available.

Coadministration has not been studied but should be avoided. Clarithromycin is metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong) and P-gp. Neratinib does not inhibit or induce CYPs. However, concentrations of neratinib may increase due to inhibition of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with clarithromycin. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration has not been studied. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Colchicine concentrations may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for colchicine toxicity is recommended.

Coadministration has not been studied. Dabigatran is transported via P-gp and is renally excreted. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for dabigatran toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys and is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp. However, for administration routes other than oral, no clinically significant interaction is expected as the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied. Dexamethasone is a substrate of CYP3A4. Neratinib does not inhibit or induce CYPs. However, dexamethasone has been described as a weak inducer of CYP3A4 and may decrease neratinib plasma concentrations. The clinical relevance of this interaction is not known as the induction of CYP3A4 by dexamethasone has not yet been established. Monitoring of neratinib efficacy may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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). Neratinib does not inhibit or induce UGTS. Additionally, morphine is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp. However, no clinically significant interaction is expected as the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Digoxin is renally eliminated via OATP4C1 and P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Coadministration of digoxin and neratinib increased digoxin AUC and Cmax by 32% and 54%, respectively. Monitoring for digoxin toxicity should be considered.

Coadministration has not been studied. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for edoxaban toxicity is recommended.

Coadministration has not been studied but is not recommended. Erythromycin is a substrate of CYP3A4 and P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. As the clinical relevance of this interaction is unknown, monitoring for erythromycin toxicity should be considered. Furthermore, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Concentrations of neratinib may increase due to inhibition of CYP3A4. Therefore, coadministration with erythromycin is not recommended and 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 neratinib toxicity. A dose reduction of neratinib should be considered. Consider monitoring of neratinib plasma concentrations, if available.

Coadministration has not been studied. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for everolimus toxicity is recommended. Monitor everolimus plasma concentrations, if available. For administration routes other than oral, no clinically relevant interaction is expected, since the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied but should be avoided. Famotidine is excreted via OAT1/OAT3. Neratinib does not inhibit or induce OATs. However, the solubility of neratinib decreases with increasing pH of the stomach. Coadministration of neratinib and the proton pump inhibitor, lansoprazole, decreased neratinib exposure by ~65%. A similar effect may occur after coadministration with famotidine. Therefore, coadministration should be avoided. If coadministration is clinically necessary, neratinib should be administered at the moment at which acid secretion is less inhibited, just before a new dose of famotidine. Monitor neratinib 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. Neratinib does not inhibit or induce CYPs.

Coadministration has not been studied. Fexofenadine is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of fexofenadine may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary for fexofenadine. Monitoring for fexofenadine toxicity should be considered.

Coadministration has not been studied but is not recommended. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Neratinib does not inhibit or induce CYPs. However, fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of neratinib may increase due to inhibition of CYP3A4. Therefore, coadministration with fluvoxamine is not recommended and 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 neratinib toxicity and a dose reduction of neratinib should be considered. Consider monitoring of neratinib plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Neratinib does not interact with this pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Neratinib does not inhibit or induce CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4. Concentrations of neratinib may increase during the three days of coadministration due to CYP3A4 inhibition. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for neratinib toxicity. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of neratinib may decrease due to CYP3A4 induction, but this is unlikely to be of clinical relevance.

Coadministration has not been studied but is contraindicated. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Neratinib does not interact with this pathway. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Neratinib does not inhibit or induce CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of neratinib may decrease due to induction of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inducer, rifampicin, decreased neratinib AUC by 87%. A similar effect may occur after coadministration with fosphenytoin. Therefore, coadministration is contraindicated. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 is recommended. Increasing the dose of neratinib when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure.

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). Neratinib does not inhibit or induce UGTs or OATs. In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3. Neratinib is not a substrate of OATs.

Coadministration has not been studied. Granisetron is metabolised by CYP3A4. Granisetron is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of granisetron may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for granisetron toxicity should be considered. For administration routes other than oral, no clinically relevant interaction is expected, since the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied but should be avoided. Grapefruit juice is a known inhibitor of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with grapefruit juice.

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. Neratinib does not interact with this metabolic pathway.

Coadministration has not been studied but should be avoided. Itraconazole is primarily metabolised by CYP3A4. Neratinib does not inhibit or induce CYPs. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Concentrations of neratinib may increase due to inhibition of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with itraconazole. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration should be avoided. Ketoconazole is a substrate of CYP3A4. Neratinib does not inhibit or induce CYPs. However, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Coadministration with ketoconazole substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration should be avoided. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Neratinib does not inhibit or induce CYPs. However, the solubility of neratinib decreases with increasing pH of the stomach. Coadministration of neratinib and lansoprazole decreased neratinib exposure by ~65%. Therefore, coadministration should be avoided. If coadministration is clinically necessary, neratinib should be administered at the moment at which acid secretion is less inhibited, just before a new dose of lansoprazole. Monitor neratinib plasma concentrations, if available.

Coadministration is contraindicated if neratinib 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 but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Neratinib does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. As the clinical relevance of this interaction is unknown, monitoring of blood glucose concentrations should be considered. Furthermore, linagliptin is a weak inhibitor of CYP3A4 and may increase concentrations of neratinib. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity is recommended.

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. Neratinib does not interact with this elimination pathway.

Coadministration has not been studied. Loperamide is mainly metabolised by CYP3A4 and CYP2C8. Loperamide is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of loperamide may increase due to P-gp inhibition. As the clinical relevance of this interaction is unlikely, monitoring for loperamide toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolised by the CYP450 system (mainly CYP2D6). Neratinib does not inhibit or induce CYPs.

Coadministration has not been studied but should be avoided. Miconazole is extensively metabolised by the liver. Neratinib is unlikely to interfere with this unspecified pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of neratinib may increase due to inhibition of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with miconazole. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available. Note: after dermal application miconazole is only minimally absorbed. No clinical relevant interaction is expected.

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. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Monitoring for morphine toxicity should be considered.

Coadministration has not been studied but should be avoided. Nefazodone is metabolised mainly by CYP3A4. Neratinib does not inhibit or induce CYPs. However, nefazodone is a strong inhibitor of CYP3A4 and may increase concentrations of neratinib. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with nefazodone. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration has not been studied. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of ondansetron may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for ondansetron toxicity should be considered. No a priori dose adjustment is necessary for ondansetron. For administration routes other than oral, no clinically relevant interaction is expected, since the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of palonosetron may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for palonosetron toxicity should be considered. No a priori dose adjustment is necessary for palonosetron. For administration routes other than oral, no clinically relevant interaction is expected, since the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied but should be avoided. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of posaconazole may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary for posaconazole. However, monitoring for posaconazole toxicity is recommended. Monitor posaconazole plasma concentrations, if available. Furthermore, posaconazole is a strong inhibitor of CYP3A4 and may increase neratinib concentrations. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with posaconazole. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised (via CYP3A4) and is a substrate of OATP1B1. Neratinib does not inhibit or induce CYPs or OATP1B1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolised by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Neratinib does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied. Prucalopride is minimally metabolised and mainly renally eliminated, partly by active secretion by renal transporters. Prucalopride is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. As the clinical relevance of this interaction is unknown, monitoring for prucalopride toxicity should be considered.

Coadministration has not been studied. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for quinidine toxicity is recommended. For administration routes other than oral, no clinically significant interaction is expected as the systemic exposure of neratinib is too low to inhibit systemic P-gp. Furthermore, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Concentrations of neratinib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity is recommended.

Coadministration has not been studied. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of ranolazine may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood pressure should be considered. Ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of neratinib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity is recommended.

Coadministration has not been studied but is contraindicated. Rifabutin is metabolised by CYP3A and via deacetylation. Neratinib does not interact with this metabolic pathway. However, rifabutin is a strong CYP3A4 and P-gp inducer. Concentrations of neratinib may decrease due to induction of CYP3A4. Coadministration of neratinib and the strong CYP3A4 inducer, rifampicin, decreased neratinib AUC by 87%. A similar effect may occur after coadministration with rifabutin. Therefore, coadministration is contraindicated. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 is recommended. Increasing the dose of neratinib when co-administering with strong or moderate CYP3A inducers is unlikely to sufficiently compensate for the loss of exposure.

Coadministration has not been studied but should be approached with caution. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Risperidone is also a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of risperidone may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. However, monitoring for risperidone toxicity is recommended. For administration routes other than oral, no clinically relevant interaction is expected, since the systemic exposure of neratinib is too low to inhibit systemic P-gp.

Coadministration has not been studied. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is also a substrate of P-gp and BCRP. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for rivaroxaban toxicity is recommended.

Coadministration has not been studied. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of saxagliptin may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood glucose concentrations should be considered.

Coadministration has not been studied. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Sirolimus concentrations may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary. Monitoring for sirolimus toxicity is recommended.

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 metabolic pathway. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of sitagliptin may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood glucose concentrations should be considered.

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. Neratinib does not inhibit or induce CYPs. However, telithromycin is a strong inhibitor of CYP3A4 and may increase concentrations of neratinib. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2-fold and 4.8-fold, respectively. A similar effect may occur after coadministration with telithromycin. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration has not been studied. Ticagrelor is a substrate of CYP3A4 and P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. It is unknown if P-gp inhibition will lead to a clinically relevant effect on ticagrelor exposure. No a priori dose adjustment is necessary. Monitoring for ticagrelor toxicity is recommended. Ticagrelor is also a weak inhibitor of CYP3A4 and may increase concentrations of neratinib. As the clinical relevance of this interaction is unknown, monitoring for neratinib toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP-enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Neratinib does not inhibit or induce CYPs and is unlikely to interfere with the elimination of trimethoprim. Furthermore, trimethoprim is a weak CYP2C8 inhibitor and in vitro data suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is metabolised via and is a weak inhibitor of CYP2C9. Neratinib does not interact with these pathways.

Coadministration has not been studied. Tropisetron is metabolised mainly by CYP2D6 and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect P-gp present in the gut. Concentrations of tropisetron may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for tropisetron toxicity should be considered. No a priori dose adjustment is necessary for tropisetron.

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

Coadministration has not been studied. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Neratinib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Concentrations of vildagliptin may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring of blood glucose concentrations should be considered.

Coadministration has not been studied but should be avoided. Voriconazole is metabolised by CYP2C19 (major) and to a lesser extent by CYP3A4 and CYP2C9. Neratinib does not inhibit or induce CYPs. However, voriconazole is a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Concentrations of neratinib may increase due to CYP3A4 inhibition. Coadministration of neratinib and the strong CYP3A4 inhibitor, ketoconazole, substantially increased neratinib Cmax and AUC by 3.2- and 4.8-fold, respectively. A similar effect may occur after coadministration with voriconazole. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable, monitor closely for neratinib toxicity. Monitor neratinib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. Neratinib does not inhibit or induce CYPs.