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. Palbociclib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but care should be taken. Alfentanil undergoes extensive CYP3A4 metabolism. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of alfentanil. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with alfentanil. Therefore, care should be taken when alfentanil is coadministered with palbociclib. Monitoring for alfentanil toxicity may be required.

Coadministration has not been studied. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Palbociclib is an inhibitor of P-gp in vitro at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered aliskiren due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring of blood pressure may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Palbociclib is unlikely to interfere with this pathway. In healthy volunteers under fed conditions, coadministration of palbociclib and rabeprazole, a proton pump inhibitor, decreased palbociclib AUC by 13%. However, in fasted conditions, coadministration of palbociclib and rabeprazole decreased palbociclib AUC by 62%. After coadministration with famotidine, a H2-receptor antagonist, or antacids under fed conditions, no clinically relevant effect on palbociclib exposure was observed. A similar effect may occur with aluminum hydroxide and the effect of aluminum hydroxide on palbociclib exposure under fed conditions is expected to be minimal. Therefore, coadministration does not need to be avoided when palbociclib is taken with food.

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. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of ambrisentan. Since CYP3A4 is a minor pathway, a clinically relevant effect on ambrisentan exposure is not expected due to CYP3A4 inhibition. However, palbociclib is also an inhibitor of P-gp in vitro at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered ambrisentan due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring of blood pressure may be required.

Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP3A4 and CYP2C8. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of amiodarone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUC_inf by 61%. A similar effect may occur with amiodarone. Coadministration should be approached with caution. Monitor 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 palbociclib may increase due to inhibition of CYP3A4. However, no dose adjustment is necessary for palbociclib. 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. Palbociclib 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 based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Palbociclib is unlikely to interfere with this pathway. In healthy volunteers under fed conditions, coadministration of palbociclib and rabeprazole, a proton pump inhibitor, decreased palbociclib AUC by 13%. However, in fasted conditions coadministration of palbociclib and rabeprazole decreased palbociclib AUC by 62%. After coadministration with famotidine, a H2-receptor antagonist, or antacids under fed conditions, no clinically relevant effect on palbociclib exposure was observed. Therefore, coadministration does not need to be avoided when palbociclib is taken with food.

Coadministration has not been studied but care should be taken. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of aprepitant. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with aprepitant. Therefore, care should be taken when aprepitant is coadministered with palbociclib. Monitoring for aprepitant toxicity may be required. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4. Concentrations of palbociclib may increase during the three days of coadministration. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with aprepitant. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of palbociclib may decrease due to weak induction of CYP3A4. However, a clinically relevant effect on palbociclib exposure is not expected due to CYP3A4 induction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of asenapine. However, since CYP3A4 is a minor pathway, a clinically relevant effect on asenapine exposure is not expected.

Coadministration has not been studied but care should be taken. Bosentan is a substrate of CYP3A4 and CYP2C9. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of bosentan. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with bosentan. Therefore, care should be taken when bosentan is coadministered with palbociclib. Monitoring of blood pressure may be required. Furthermore, bosentan is a weak inducer of CYP3A4 and CYP2C9. Concentrations of palbociclib may decrease due to weak induction of CYP3A4. However, a clinically relevant effect on palbociclib exposure is not expected.

Coadministration has not been studied but care should be taken. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of buprenorphine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with buprenorphine. Therefore, care should be taken when buprenorphine is coadministered with palbociclib. Monitoring for buprenorphine toxicity may be required.

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Palbociclib is a weak inhibitor of CYP3A4 and may increase carbamazepine concentrations. However, since carbamazepine is a strong CYP3A4 inducer itself, no clinically relevant effect on carbamazepine exposure is expected. Carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of palbociclib may decrease due to strong induction of CYP3A4 by carbamazepine. In healthy volunteers, coadministration of palbociclib and rifampicin, a strong CYP3A4 inducer, decreased palbociclib AUC by 85%. A similar effect may occur after coadministration with carbamazepine. Therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2. Palbociclib does not inhibit or induce these CYPs or UGTs.

Coadministration has not been studied but should be approached with caution. Chloramphenicol is predominantly glucuronidated. Palbociclib does not inhibit or induce UGTs. However, in vitro studies have shown that chloramphenicol may inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of palbociclib may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown and coadministration should be approached with caution. Monitoring for palbociclib toxicity is recommended. Monitoring of palbociclib concentrations should be considered, if available. 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 based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine is metabolised by CYP450 enzymes. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of cimetidine. The clinical relevance of this interaction is unknown. Furthermore, cimetidine is a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Concentrations of palbociclib may increase due to CYP3A4 inhibition. However, no dose adjustment is necessary for palbociclib. Cimetidine may also decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Palbociclib is not a substrate of OAT1 or OCT2. In healthy volunteers under fed conditions, coadministration of palbociclib and rabeprazole, a proton pump inhibitor, decreased palbociclib AUC by 13%. In fasted conditions, coadministration of palbociclib and rabeprazole decreased palbociclib AUC by 62%. After coadministration with famotidine, a H2-receptor antagonist, or antacids under fed conditions, no clinically relevant effect on palbociclib exposure was observed. A similar effect may occur with cimetidine and the effect of cimetidine on palbociclib exposure under fed conditions is expected to be minimal. Therefore, coadministration does not need to be avoided when palbociclib is taken with food.

Coadministration has not been studied. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Palbociclib does not interact with this pathway. However, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of palbociclib may increase due to moderate inhibition of CYP3A4. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with ciprofloxacin. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. Consider monitoring palbociclib plasma concentrations, if available.

Coadministration has not been studied but should be approached with caution. Clofazimine is largely excreted unchanged in the faeces. Palbociclib does not interact with this elimination pathway. Furthermore, in vitro data suggest that clofazimine is a CYP3A4 inhibitor and may increase concentrations of palbociclib. The clinical relevance of this interaction is unknown and coadministration should be approached with caution. Monitoring for palbociclib toxicity is recommended. Monitoring of palbociclib concentrations should be considered, if available.

Coadministration has not been studied but care should be taken. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolised by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of codeine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with codeine. Therefore, care should be taken when codeine is coadministered with palbociclib. Monitoring for codeine and morphine toxicity may be required. Additionally, the metabolite morphine is a substrate of P-gp. Palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Since the systemic exposure of palbociclib is too low to inhibit systemic P-gp, a clinically relevant effect on morphine exposure is not expected.

Coadministration has not been studied. Dabigatran is transported via P-gp and is renally excreted. Palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered dabigatran due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring for dabigatran toxicity, ecarine clotting time or diluted thrombin time may be required, if available.

Coadministration has not been studied but care should be taken. Dexamethasone is a substrate of CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of dexamethasone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with dexamethasone. Care should be taken if coadministered. Monitoring for dexamethasone toxicity may be required. Furthermore, dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease palbociclib plasma concentrations. However, the clinical relevance of this interaction is unknown as the induction of CYP3A4 by dexamethasone has not yet been established. Therefore, a clinically relevant effect on palbociclib exposure is not expected.

Coadministration has not been studied but care should be taken. Diltiazem is metabolised by CYP3A4 and CYP2D6. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of diltiazem. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with diltiazem. Therefore, care should be taken when diltiazem is coadministered with palbociclib. Monitoring of blood pressure may be required. Furthermore, diltiazem is a moderate inhibitor of CYP3A4. In a PBPK model, coadministration of palbociclib and diltiazem increased palbociclib exposure by approximately 40%. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. Consider monitoring palbociclib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of disopyramide. However, since CYP3A4 is a minor pathway, a clinically relevant effect on disopyramide exposure is not expected.

Coadministration has not been studied but care should be taken. Domperidone is mainly metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of domperidone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with domperidone. Therefore, care should be taken when domperidone is coadministered with palbociclib. Monitoring for domperidone toxicity may be required.

Coadministration has not been studied but care should be taken. Doxazosin is metabolised mainly by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of doxazosin. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with doxazosin. Therefore, care should be taken when doxazosin is coadministered with palbociclib. Monitoring of blood pressure may be required.

Coadministration has not been studied but care should be taken. Erythromycin is a substrate of CYP3A4 and P-gp. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of erythromycin. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with erythromycin. Palbociclib is also an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered erythromycin due to intestinal P-gp inhibition cannot be excluded. Care should be taken when erythromycin is coadministered with palbociclib. Monitoring for erythromycin toxicity may be required. For administration routes other than oral, a clinically relevant interaction is not expected due to P-gp inhibition, since the systemic exposure of palbociclib is too low to inhibit P-gp. Furthermore, erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp. Concentrations of palbociclib may increase due to moderate inhibition of CYP3A4. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with erythromycin. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. Consider monitoring palbociclib plasma concentrations, if available.

Coadministration has not been studied but care should be taken. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of estazolam. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with estazolam. Therefore, care should be taken when estazolam is coadministered with palbociclib. Monitoring for estazolam toxicity may be required.

Coadministration is contraindicated if palbociclib 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 care should be taken. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of estradiol. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with estradiol. Therefore, care should be taken when estradiol is coadministered with palbociclib. Monitoring for estradiol toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3, and to a lesser extent by UGTs 2B15 and 2B7. Palbociclib does not inhibit or induce UGTs.

Coadministration has not been studied but care should be taken. Felodipine is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of felodipine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with felodipine. Therefore, care should be taken when felodipine is coadministered with palbociclib. Monitoring of blood pressure may be required.

Coadministration has not been studied but care should be taken. Fentanyl undergoes extensive CYP3A4 metabolism. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of fentanyl. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with fentanyl. Therefore, care should be taken when fentanyl is coadministered with palbociclib. Monitoring for fentanyl toxicity may be required.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Palbociclib is unlikely to interfere with this elimination pathway. Furthermore, flucloxacillin has been described as a CYP3A4 inducer and may decrease concentrations of palbociclib. As the mechanism and clinical relevance of this interaction is unknown, monitoring of palbociclib efficacy may be required. Monitoring of palbociclib concentrations should be considered, if available.

Coadministration has not been studied. Fluconazole is cleared primarily by renal excretion. Palbociclib is unlikely to interfere with this elimination pathway. However, fluconazole is an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of palbociclib may increase due to moderate inhibition of CYP3A4. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with fluconazole. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. Consider monitoring palbociclib plasma concentrations, if available.

Coadministration has not been studied but care should be taken. The metabolism of flurazepam is most likely CYP-mediated. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of flurazepam. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with flurazepam. Therefore, care should be taken when flurazepam is coadministered with palbociclib. Monitoring for flurazepam toxicity may be required.

Coadministration has not been studied but care should be taken. Fluticasone is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of fluticasone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with fluticasone. Therefore, care should be taken if coadministered. Monitoring for fluticasone toxicity may be required. Note: A clinically significant interaction is unlikely with the topical use of fluticasone.

Coadministration has not been studied. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Palbociclib does not inhibit or induce CYP2D6 or CYP1A2. However, fluvoxamine is an inhibitor of CYPs 1A2 (strong), 2C19 (moderate-strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of palbociclib may increase due to moderate inhibition of CYP3A4. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with fluvoxamine. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. Consider monitoring palbociclib 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. Palbociclib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but care should be taken. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Palbociclib does not interact with this pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of aprepitant. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with aprepitant. Care should be taken when aprepitant is coadministered with palbociclib. Monitoring for aprepitant toxicity may be required. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4. Therefore, concentrations of palbociclib may increase during the three days of coadministration. In a PBPK model, coadministration of palbociclib and diltiazem, a moderate CYP3A4 inhibitor, increased palbociclib exposure by approximately 40%. A similar effect may occur after coadministration with aprepitant. As the clinical relevance of this interaction is unknown, monitoring for palbociclib toxicity should be considered. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of palbociclib may decrease due to weak induction of CYP3A4. However, a clinically relevant effect on palbociclib exposure is not expected.

Coadministration is contraindicated if palbociclib 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 care should be taken. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of gestodene. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with gestodene. Therefore, care should be taken when gestodene is coadministered with palbociclib. Monitoring for gestodene toxicity may be required.

Coadministration has not been studied but care should be taken. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of glibenclamide. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with glibenclamide. Therefore, care should be taken when glibenclamide is coadministered with palbociclib. Monitoring of blood glucose concentrations may be required.

Coadministration has not been studied but should be approached with caution. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4 and 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of haloperidol. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with haloperidol. Therefore, coadministration should be approached with caution. Monitor for haloperidol toxicity.

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. Palbociclib does not interact with this metabolic pathway.

Coadministration has not been studied but care should be taken. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of hydrocodone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with hydrocodone. Therefore, care should be taken when hydrocodone is coadministered with palbociclib. Monitoring for hydrocodone toxicity may be required.

Coadministration has not been studied but should be approached with caution. Iloperidone is metabolised by CYP3A4 and CYP2D6. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of iloperidone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with iloperidone. Therefore, coadministration should be approached with caution. Monitor for iloperidone toxicity.

Coadministration has not been studied but care should be taken. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Concentrations of imipramine may increase due to weak CYP3A4 inhibition. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with imipramine. Therefore, care should be taken when imipramine is coadministered with palbociclib. Monitoring for imipramine toxicity may be required.

Coadministration has not been studied. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Palbociclib is a weak inhibitor of CYP3A4 and may increase isosorbide dinitrate concentrations and thus decrease concentrations of nitric oxide. As the clinical relevance of this interaction is unknown, monitoring for isosorbide dinitrate toxicity and nitric oxide efficacy may be required.

Coadministration should be approached with caution. Itraconazole is primarily metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase itraconazole concentrations. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with itraconazole. Coadminstration should be approached with caution. Monitor for itraconazole toxicity. Monitor itraconazole plasma concentrations, if available. Furthermore, itraconazole is an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. In healthy volunteers, coadministration of palbociclib and itraconazole increased palbociclib AUC by 87%. Therefore, coadministration should be approached with caution. Selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable reduce the palbociclib dose by 40%. Close monitoring for palbociclib toxicity is recommended. Monitor palbociclib plasma concentrations, if available. If a patient discontinues itraconazole, increase the palbociclib dose after 110-190 hours to the dose that was used before starting itraconazole.

Coadministration has not been studied but care should be taken. Ivabradine is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of ivabradine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with ivabradine. Therefore, care should be taken if coadministered. Monitoring for ivabradine toxicity may be required.

Coadministration has not been studied but should be approached with caution. Ketoconazole is a substrate of CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of ketoconazole. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with ketoconazole. Coadministration should be approached with caution. Monitor for ketoconazole toxicity and, if available, ketoconazole plasma concentrations. Ketoconazole is also an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of palbociclib may increase due to strong inhibition of CYP3A4. In healthy volunteers, coadministration of palbociclib and itraconazole, a strong CYP3A4 inhibitor, increased palbociclib AUC by 87%. A similar effect may occur with ketoconazole. Therefore, coadministration should be approached with caution. Selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable reduce the palbociclib dose by 40%. Close monitoring for palbociclib toxicity is recommended. Monitor palbociclib plasma concentrations, if available. If a patient discontinues ketoconazole, increase the palbociclib dose after 24-40 hours to the dose that was used before starting ketoconazole.

Coadministration is contraindicated if palbociclib 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 care should be taken. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of levonorgestrel. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with levonorgestrel. Therefore, care should be taken when levonorgestrel is coadministered with palbociclib. Monitoring for levonorgestrel toxicity may be required.

Coadministration is contraindicated if palbociclib 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 care should be taken. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of levonorgestrel. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with levonorgestrel. Care should be taken when levonorgestrel is coadministered with palbociclib.

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor metabolic pathway. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of linagliptin. Since CYP3A4 is a minor pathway, a clinically relevant effect on linagliptin exposure due to CYP3A4 induction is not expected. However, linagliptin is also a substrate of P-gp. Palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered linagliptin due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring of blood glucose concentrations may be required. Furthermore, linagliptin is a weak inhibitor of CYP3A4 and may increase concentrations of palbociclib. No dose adjustment is necessary for palbociclib.

Coadministration has not been studied but care should be taken. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of loratadine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with loratadine. Therefore, care should be taken when loratadine is coadministered with palbociclib. Monitoring for loratadine toxicity may be required.

Coadministration has not been studied but care should be taken. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of macitentan. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with macitentan. Therefore, care should be taken if coadministered. Monitoring of blood pressure 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). Palbociclib does not inhibit or induce CYP2D6.

Coadministration has not been studied. Metronidazole is eliminated via glomerular filtration. Palbociclib is unlikely to interfere with this elimination pathway. Furthermore, elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with palbociclib cannot be excluded. Monitoring for palbociclib toxicity may be required. Monitoring of palbociclib plasma concentrations may also be required, if available.

Coadministration has not been studied but should be approached with caution. Miconazole is extensively metabolised by the liver. Palbociclib is unlikely to interfere with this unspecified metabolic pathway. However, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of palbociclib may increase due to strong inhibition of CYP3A4. In healthy volunteers, coadministration of palbociclib and itraconazole, a strong CYP3A4 inhibitor, increased palbociclib AUC by 87%. A similar effect may occur with miconazole. Therefore, coadministration should be approached with caution. Selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable reduce the palbociclib dose by 40%. Close monitoring for palbociclib toxicity is recommended. Monitor palbociclib plasma concentrations, if available. If a patient discontinues miconazole, increase the palbociclib dose after 65-110 hours to the dose that was used before starting miconazole. Note: after dermal application miconazole is only minimally absorbed and no clinical relevant interaction is expected.

Midazolam is metabolised by CYP3A4. Palbociclib is weak inhibitor of CYP3A4 and may increase concentrations of midazolam. In healthy volunteers, coadministration of palbociclib and midazolam under fasted conditions increased midazolam AUCinf by 61%. Therefore, care should be taken when midazolam is coadministered with palbociclib. Monitoring for midazolam toxicity may be required.

Coadministration has not been studied but care should be taken. Midazolam is metabolised by CYP3A4. Palbociclib is weak inhibitor of CYP3A4 and may increase concentrations of midazolam. In healthy volunteers, coadministration of palbociclib and oral midazolam under fasted conditions increased midazolam AUCinf by 61%. Therefore, care should be taken when midazolam is coadministered with palbociclib. Monitoring for midazolam toxicity may be required.

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Palbociclib does not inhibit or induce UGTs. Morphine is also a substrate of P-gp. Palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered morphine due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring for morphine toxicity may be required. However, for administration routes other than oral (e.g. i.v. drugs), no clinically relevant interaction is expected since the systemic exposure of palbociclib is too low to inhibit P-gp.

Coadministration has not been studied but care should be taken. Nifedipine is metabolised mainly by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of nifedipine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with nifedipine. Therefore, care should be taken when nifedipine is coadministered with palbociclib. Monitoring of blood pressure may be required.

Coadministration has not been studied but care should be taken. Nisoldipine is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of nisoldipine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with nisoldipine. Therefore, care should be taken when nisoldipine is coadministered with palbociclib. Monitoring of blood pressure may be required.

Coadministration has not been studied but care should be taken. Nitrendipine is extensively metabolised mainly by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of nitrendipine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with nitrendipine. Therefore, care should be taken when nitrendipine is coadministered with palbociclib. Monitoring of blood pressure may be required.

Coadministration has not been studied but care should be taken. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of oxycodone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with oxycodone. Therefore, care should be taken when oxycodone is coadministered with palbociclib. Monitoring for oxycodone toxicity may be required.

Coadministration has not been studied but should be approached with caution. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of phenprocoumon. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with phenprocoumon. Therefore, caution should be taken when phenprocoumon is coadministered with palbociclib. Monitor INR/PT, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Pitavastatin is also a substrate of OATP1B1. Palbociclib does not inhibit or induce CYP2C9, CYP2C8, OATP1B1 or UGTs.

Coadministration has not been studied but care should be taken. 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. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of prasugrel and thus decrease concentrations of the active metabolite. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with prasugrel. Therefore, care should be taken when prasugrel is coadministered with palbociclib. Monitoring for prasugrel toxicity may be required. Thrombocyte aggregation tests may also be required.

Coadministration has not been studied but care should be taken. Quetiapine is primarily metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of quetiapine. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with quetiapine. Therefore, care should be taken when quetiapine is coadministered with palbociclib. Monitoring for quetiapine toxicity may be required.

Coadministration has not been studied but care should be taken. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of OATP1B1. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of repaglinide. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with repaglinide. Therefore, care should be taken when repaglinide is coadministered with palbociclib. Monitoring of blood glucose concentrations may be required.

Coadministration has not been studied but care should be taken. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of risperidone. However, since CYP3A4 is a minor pathway, a clinically relevant effect on risperidone exposure is not expected. Furthermore, risperidone is a substrate of P-gp. Palbociclib is an inhibitor of P-gp in vitro at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered risperidone due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring for risperidone toxicity may be required.

Coadministration has not been studied but care should be taken. 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. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of rivaroxaban. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with rivaroxaban. Furthermore, palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. A further increased exposure of orally administered rivaroxaban due to intestinal P-gp inhibition cannot be excluded. Therefore, care should be taken when rivaroxaban is coadministered with palbociclib. Monitoring for rivaroxaban toxicity and anti-Xa activity may be required, if available.

Coadministration has not been studied. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Palbociclib is an inhibitor of BCRP in vitro at concentrations that are likely to only affect the BCRP present in the gut. Increased exposure of orally administered rosuvastatin due to intestinal BCRP inhibition cannot be excluded. Therefore, monitoring for rosuvastatin toxicity may be required.

Coadministration has not been studied but care should be taken. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of saxagliptin. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with saxagliptin. Furthermore, palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered saxagliptin due to intestinal P-gp inhibition cannot be excluded. Therefore, care should be taken. Monitoring of blood glucose concentrations may be required.

Coadministration has not been studied but care should be taken. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of sildenafil. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with sildenafil. Therefore, care should be taken if coadministered. Monitoring of blood pressure may be required.

Coadministration has not been studied but should be approached with caution. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of sirolimus. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with sirolimus. Furthermore, palbociclib is an inhibitor of P-gp in vitro at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered sirolimus due to intestinal P-gp inhibition cannot be excluded. For administration routes other than oral (e.g. i.v. drugs), a clinically relevant interaction due to P-gp inhibition is not expected, since the systemic exposure of palbociclib is too low to inhibit P-gp. Coadministration should be approached with caution. Monitor for sirolimus toxicity. Monitor sirolimus plasma concentrations, if available. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

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. Palbociclib is a weak inhibitor of CYP3A4 but as CYP3A4 is a minor pathway, a clinically relevant effect on sitagliptin exposure is not expected. However, palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered sitagliptin due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring of blood glucose concentrations may be required.

Coadministration has not been studied but should be avoided. St John’s Wort is a P-gp and CYP3A4 inducer. Concentrations of palbociclib may decrease due to strong induction of CYP3A4. In healthy volunteers, coadministration of palbociclib and rifampicin, a strong CYP3A4 inducer, decreased palbociclib AUC by 85%. A similar effect may occur after coadministration with St John’s Wort. Therefore, coadministration should be avoided.

Coadministration has not been studied but care should be taken. Tadalafil is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of tadalafil. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with tadalafil. Therefore, care should be taken if coadministered. Monitoring of blood pressure may be required.

Coadministration has not been studied but should be approached with caution. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of telithromycin. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with telithromycin. Therefore, care should be taken when telithromycin is coadministered with palbociclib. Monitoring for telithromycin toxicity may be required. Furthermore, telithromycin is a strong inhibitor of CYP3A4 and may increase concentrations of palbociclib. In healthy volunteers, coadministration of palbociclib and itraconazole, a strong CYP3A4 inhibitor, increased palbociclib AUC by 87%. A similar effect may occur with telithromycin. Coadministration should be approached with caution. Selection of an alternate concomitant medication with no or minimal potential to inhibit CYP3A4 is recommended. If coadministration is unavoidable reduce the palbociclib dose by 40%. Close monitoring for palbociclib toxicity is recommended. Monitor palbociclib plasma concentrations, if available. If a patient discontinues telithromycin, increase the palbociclib dose after 30-50 hours to the dose that was used before starting telithromycin.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of terbinafine. However, since CYP3A4 mediated metabolism is only one of the multiple pathways, a clinically relevant interaction is unlikely. Furthermore, terbinafine is a moderate-strong inhibitor of CYP2D6. Palbociclib is not metabolised by CYP2D6.

Coadministration is contraindicated if palbociclib 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 care should be taken. Testosterone is metabolised by CYP3A4. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of testosterone. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with testosterone. Therefore, care should be taken if coadministered. Monitoring for testosterone toxicity may be required.

Coadministration has not been studied but care should be taken. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of tramadol. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with tramadol. Therefore, care should be taken when tramadol is coadministered with palbociclib. Monitoring for tramadol toxicity may be required.

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. Palbociclib is unlikely to interfere with this elimination pathway. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP-enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of trimethoprim. However, since this metabolic pathway has not yet been established and CYP mediated metabolism is only a minor pathway, a clinically relevant interaction is not expected. Furthermore, trimethoprim is also a weak CYP2C8 inhibitor with in vitro data suggesting it is an inhibitor of OCT2 and MATE1. Palbociclib does not interact with this pathway. Sulfamethoxazole is metabolised via and is a weak inhibitor of CYP2C9. Palbociclib is not metabolised by and does not inhibit or induce CYP2C9.

Coadministration has not been studied. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of verapamil. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with verapamil. Therefore, care should be taken when verapamil is coadministered with palbociclib. Monitoring of blood pressure may be required. Furthermore, verapamil is a moderate inhibitor of CYP3A4 and may increase concentrations of palbociclib. In a PBPK simulation, coadministration of verapamil and palbociclib resulted in an increased palbociclib AUC by approximately 40%. The clinical relevance of this interaction is unknown. In a single case report, coadministration of verapamil and palbociclib resulted in serious adverse events. Febrile neutropenia, grade 3 stomatitis with lip swelling, periorbital edema, and transaminitis were hypothesised from elevated levels of palbociclib secondary to verapamil’s inhibition of CYP3A4. Monitoring for palbociclib toxicity may be required.

Coadministration has not been studied. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Palbociclib is an in vitro inhibitor of P-gp at concentrations that are likely to only affect the P-gp present in the gut. Increased exposure of orally administered vildagliptin due to intestinal P-gp inhibition cannot be excluded. Therefore, monitoring of blood glucose concentrations may be required.

Coadministration has not been studied but should be approached with caution. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Palbociclib is a weak inhibitor of CYP3A4 and may increase concentrations of R-warfarin. In healthy volunteers, coadministration of palbociclib and midazolam, a CYP3A4 substrate, under fasted conditions increased midazolam AUCinf by 61%. A similar effect may occur with R-warfarin. Therefore, coadministration should be approached with caution. Monitor INR/PT, if available.