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. Abemaciclib does not interact with this metabolic pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Abemaciclib is unlikely to interfere with this metabolic pathway. No clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of aluminium hydroxide on abemaciclib absorption is expected.

Coadministration has not been studied but care should be taken. 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. Abemaciclib is an inhibitor of P-gp and may increase concentrations of ambrisentan. As the clinical relevance of this interaction is unknown, monitoring for ambrisentan toxicity may be required.

Coadministration has not been studied but care should be taken. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Abemaciclib and its major metabolites are inhibitors of OCT2 and may increase concentrations of amiloride. As the clinical relevance of this interaction is unknown, monitoring for amiloride toxicity may be required.

Coadministration has not been studied but care should be taken. Amiodarone is metabolised by CYP3A4 and CYP2C8. Abemaciclib 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 abemaciclib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for abemaciclib toxicity may be required. No a priori dose adjustment for abemaciclib is necessary. Furthermore, amiodarone may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered. 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 care should be taken. Amisulpride is weakly metabolised and is primarily renally eliminated (possibly via OCT). Abemaciclib does not inhibit OCT1 at clinically relevant concentrations. However, concentrations of amisulpride may increase due to inhibition of OCT2 by abemaciclib or its major metabolites. Coadministration of abemaciclib and metformin (OCT2, MATE2 and MATE2-K substrate) increased metformin AUC by 37%. A similar effect may occur with amisulpride. Therefore, monitoring for amisulpride toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Abemaciclib does not inhibit OAT3 at clinically relevant concentrations. Therefore, no effect on amoxicillin exposure is expected.

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. Abemaciclib 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. Abemaciclib is unlikely to interfere with this metabolic pathway. No clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of antacids on abemaciclib absorption is expected.

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. Abemaciclib does not inhibit or induce CYPs. During treatment, aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of abemaciclib. In simulation studies, it was predicted that moderate CYP3A4 inhibitors (e.g. diltiazem and verapamil) increase the AUC of abemaciclib by 2- to 4-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increase by 1.5- to 2.5-fold. A similar effect may occur with aprepitant. The clinical relevance of this interaction is unknown. No a priori dose decrease is necessary for abemaciclib during the three days of coadministration. Monitor closely for abemaciclib toxicity if coadministered. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of abemaciclib may decrease due to induction of CYP3A4 by aprepitant but this is not considered to be clinically relevant.

Coadministration has not been studied but care should be taken. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Abemaciclib does not inhibit OATP1B1 at clinically relevant concentrations. However, concentrations of atorvastatin may increase due to inhibition of P-gp. As the clinical relevance of this interaction is unknown, monitoring for atorvastatin toxicity may be required.

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

Coadministration has not been studied but care should be taken. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Abemaciclib is an inhibitor of P-gp and may increase concentrations of azithromycin. As the clinical relevance of this interaction is unknown, monitoring for azithromycin toxicity may be required. Azithromycin is also an inhibitor of P-gp but the clinical relevance is unknown. Abemaciclib and its metabolite M2 are substrates of P-gp. The interaction has not been studied but a clinically significant effect on abemaciclib and M2 exposure is not expected. Furthermore, azithromycin may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

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

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

Coadministration has not been studied but should be approached with caution. Bosentan is a substrate of CYP3A4 and CYP2C9. Abemaciclib does not inhibit or induce CYPs. However, bosentan is weak inducer of CYP3A4 and CYP2C9. Abemaciclib concentrations may decrease due to CYP3A4 induction. Imatinib (a CYP3A4 substrate) concentrations, on average decreased by 33% in the presence of bosentan in a phase III clinical study and a similar effect may be expected with abemaciclib. Therefore, coadministration should be approached with caution, since a decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, closely monitor abemaciclib efficacy. Monitor abemaciclib plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Candesartan is mainly eliminated unchanged via urine and bile. Abemaciclib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Abemaciclib does not inhibit OAT1 at clinically relevant concentrations. Therefore, no effect on captopril exposure is expected.

Coadministration has not been studied but is contraindicated. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Abemaciclib does not inhibit or induce CYPs. However, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of abemaciclib may decrease due to induction of CYP3A4. In simulation studies, it was predicted that carbamazepine decreases the AUC of abemaciclib by 80%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 52%. The clinical relevance of this interaction is unknown. Furthermore, coadministration of rifampicin, a potent CYP3A4 inducer, with abemaciclib decreased abemaciclib AUC by 95%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 77%. A similar effect may occur after coadministration with carbamazepine. Therefore, coadministration with carbamazepine is contraindicated.

Coadministration has not been studied but care should be taken. Cefalexin is predominantly renally eliminated unchanged by glomerular filtration and tubular secretion via OAT1 and MATE1. Abemaciclib does not inhibit OAT1 at clinically relevant concentrations but cefalexin concentrations may increase due to inhibition of MATE1 by abemaciclib or its major metabolites. Coadministration of abemaciclib and metformin (OCT2, MATE2 and MATE2-K substrate) increased metformin AUC by 37%. A similar effect may occur with cefalexin. Therefore, monitoring for cefalexin toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolised by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates in the renal elimination of cefotaxime. Abemaciclib does not inhibit OAT3 at clinically relevant concentrations. Therefore, no effect on cefotaxime exposure is expected.

Coadministration has not been studied but care should be taken. Chloramphenicol is predominantly glucuronidated. Abemaciclib does not inhibit or induce UGTs. However, in vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of abemaciclib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for abemaciclib toxicity may be required. No a priori dose adjustment for abemaciclib is necessary. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlordiazepoxide is extensively metabolised by CYP3A4, but does not inhibit or induce cytochromes. Abemaciclib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on chlortalidone exposure is expected.

Coadministration has not been studied but care should be taken. Ciclosporin is a substrate of CYP3A4 and P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of ciclosporin. Furthermore, ciclosporin is an inhibitor of CYP3A4 and OATP1B1. Concentrations of abemaciclib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for ciclosporin and abemaciclib toxicity may be required. No a priori dose adjustment for abemaciclib is necessary.

Coadministration has not been studied but care should be taken. No clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of cimetidine on abemaciclib absorption is expected. Furthermore, cimetidine is metabolised by CYP450 enzymes. Abemaciclib does not inhibit or induce CYPs. Cimetidine may decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine also inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Abemaciclib does not interact with this pathway. However, cimetidine is a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Concentrations of abemaciclib may increase due to inhibition of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring for abemaciclib toxicity may be required. No a priori dose adjustment for abemaciclib is necessary.

Coadministration has not been studied but should be approached with caution. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Abemaciclib does not inhibit OAT3 at clinically relevant concentrations. Therefore, no effect on ciprofloxacin exposure is expected. However, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Concentrations of abemaciclib may increase due to inhibition of CYP3A4. In simulation studies, it was predicted that moderate CYP3A4 inhibitors (e.g. diltiazem and verapamil) increase the AUC of abemaciclib by 2- to 4-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 1.5- to 2.5-fold. A similar effect may occur with ciprofloxacin. No a priori dose decrease is necessary for abemaciclib but closely monitor for abemaciclib toxicity. Monitor abemaciclib concentrations, if available. Furthermore, ciprofloxacin may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

Coadministration has not been studied but should be avoided. Cisapride is metabolised by CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, coadministration with other drugs that prolong the QTc interval should be avoided. No large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place and if coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolised by CYP2D6. Abemaciclib does not inhibit or induce CYPs. However, clomipramine may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

Coadministration has not been studied. 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. The metabolite morphine is also a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of morphine. As the clinical relevance of this interaction is unknown, monitoring for morphine toxicity may be required.

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

Coadministration has not been studied but care should be taken. Dexamethasone is a substrate of CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease abemaciclib plasma concentrations. However, the clinical relevance of this interaction is not known as the induction of CYP3A4 by dexamethasone has not yet been established. Monitoring of abemaciclib efficacy may be required.

Coadministration has not been studied. Diamorphine is rapidly metabolised by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of morphine. As the clinical relevance of this interaction is unknown, monitoring for morphine toxicity may be required.

Coadministration has not been studied but should be approached with caution. Diltiazem is metabolised by CYP3A4 and CYP2D6. Abemaciclib does not inhibit or induce CYPs. However, diltiazem is a moderate inhibitor of CYP3A4 and may increase concentrations of abemaciclib. In simulation studies, it was predicted that diltiazem increases the AUC of abemaciclib by 3.95-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 2.41-fold. As the clinical relevance of this interaction is unknown, monitor closely for abemaciclib toxicity. Monitor abemaciclib concentrations, if available. No a priori dose decrease is necessary for abemaciclib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dopamine is metabolised in the liver, kidneys, and plasma by monoamine oxidase (MAO) and catechol-O-methyltransferase to inactive compounds. About 25% of a dose of dopamine is metabolised to norepinephrine within the adrenergic nerve terminals. There is little potential for dopamine to affect the disposition of abemaciclib, or to be affected if co-administered with abemaciclib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is renally eliminated (possibly via OATs). Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on enalapril exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Abemaciclib does not inhibit or induce CYPs. Esomeprazole is also an inhibitor of CYP2C19. Abemaciclib is not metabolised by CYP2C19. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of esomeprazole on abemaciclib absorption is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Abemaciclib does not inhibit OAT1 or OAT3 at clinically relevant concentrations. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of famotidine on abemaciclib absorption is expected.

Coadministration has not been studied but care should be taken. Fexofenadine is a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of fexofenadine. As the clinical relevance of this interaction is unknown, monitoring for fexofenadine toxicity may be required.

Coadministration has not been studied but care should be taken. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Abemaciclib does not inhibit OAT1 at clinically relevant concentrations. Therefore, no effect on flucloxacillin exposure is expected. However, flucloxacillin has been described as a CYP3A4 inducer and may decrease concentrations of abemaciclib. As the mechanism and clinical relevance of this interaction is unknown, monitoring of abemaciclib efficacy may be required.

Coadministration has not been studied but should be approached with caution. Fluconazole is cleared primarily by renal excretion. Abemaciclib is unlikely to interfere with this elimination pathway. However, fluconazole is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of abemaciclib may increase due to inhibition of CYP3A4. In simulation studies, it was predicted that moderate CYP3A4 inhibitors (e.g. diltiazem and verapamil) increase the AUC of abemaciclib by 2- to 4-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 1.5- to 2.5-fold. A similar effect may occur with fluconazole. As the clinical relevance of this interaction is unknown, monitor closely for abemaciclib toxicity. Monitor abemaciclib concentrations, if available. No a priori dose decrease is necessary for abemaciclib. Furthermore, fluconazole may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

Coadministration has not been studied but should be approached with caution. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Abemaciclib does not inhibit or induce CYPs. However, fluvoxamine is an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of abemaciclib may increase due to inhibition of CYP3A4. In simulation studies, it was predicted that moderate CYP3A4 inhibitors (e.g. diltiazem and verapamil) increase abemaciclib AUC by 2- to 4-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 1.5- to 2.5-fold. A similar effect may occur with fluvoxamine. As the clinical relevance of this interaction is unknown, monitor closely for abemaciclib toxicity. Monitor abemaciclib concentrations, if available. No a priori dose decrease is necessary for abemaciclib.

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. Abemaciclib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Abemaciclib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Abemaciclib does not inhibit or induce CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of abemaciclib. In simulation studies, it was predicted that moderate CYP3A4 inhibitors (e.g. diltiazem and verapamil) increase the AUC of abemaciclib by 2- to 4-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 1.5- to 2.5-fold. A similar effect may occur with aprepitant. The clinical relevance of this interaction is unknown. No a priori dose decrease is necessary for abemaciclib during the three days of coadministration. Monitor closely for abemaciclib toxicity if coadministered. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of abemaciclib may decrease due to induction of CYP3A4. This interaction is not considered to be clinically relevant.

Coadministration has not been studied but is contraindicated. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Abemaciclib does not interact with this metabolic pathway. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Abemaciclib does not inhibit or induce CYPs. However, phenytoin is a strong inducer of CYP3A4, UGT and P-gp. Concentrations of abemaciclib may decrease due to induction of CYP3A4 and P-gp. Coadministration of rifampicin, a potent CYP3A4 inducer, with abemaciclib decreased abemaciclib AUC by 95%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 77%. A similar effect may occur after coadministration with fosphenytoin. Therefore, coadministration with fosphenytoin is contraindicated.

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). Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on furosemide exposure is expected. In vitro data indicate that furosemide is also an inhibitor of the renal transporters OAT1/OAT3. Abemaciclib is not transported by these OATs.

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. Abemaciclib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised but is cleared by the kidneys via OAT1. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant drug concentrations. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on hydrochlorothiazide exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ibandronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Indapamide is extensively metabolised by CYP450s. Abemaciclib does not inhibit or induce CYPs. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. No effect on indapamide exposure is expected. However, indapamide may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

Coadministration has been studied but is contraindicated. Ketoconazole is a substrate of CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp, and may increase concentrations of abemaciclib. In simulation studies, it was predicted that ketoconazole increases the AUC of abemaciclib by 16-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 6.9-fold. Therefore, coadministration is contraindicated. Furthermore, ketoconazole may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Abemaciclib does not inhibit or induce CYPs. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of lansoprazole on abemaciclib absorption is expected.

Coadministration has not been studied but care should be taken. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Abemaciclib and its major metabolites are inhibitors of OCT2 and may increase concentrations of levofloxacin. Coadministration of abemaciclib and metformin (OCT2, MATE2 and MATE2-K substrate) increased metformin AUC by 37%. A similar effect may occur with levofloxacin. Monitoring for levofloxacin toxicity may be required. Furthermore, levofloxacin may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. ECG monitoring should be considered.

Coadministration is contraindicated if abemaciclib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Abemaciclib does not inhibit or induce CYPs or UGTs.

Coadministration is contraindicated if abemaciclib 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. Abemaciclib does not inhibit or induce CYPs or UGTs.

Loperamide is mainly metabolised by CYP3A4 and CYP2C8, and is also a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of loperamide. In healthy volunteers, coadministration of loperamide and a supratherapeutic dose of abemaciclib resulted in an increased AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) by 12%. Coadministration of loperamide with a supratherapeutic dose of abemaciclib increased loperamide AUC by 9%. These AUC increases are not clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Megestrol acetate is mainly eliminated in the urine. Abemaciclib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of OAT3>OAT1. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on meropenem exposure is expected.

Coadministration has not been studied but should be approached with caution. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Abemaciclib does not interact with this metabolic pathway. However, metamizole is an inducer of CYP3A4 and may decrease abemaciclib concentrations. The clinical relevance of this interaction is unknown. Therefore, coadministration should be approached with caution, since a decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, closely monitor abemaciclib efficacy. Monitor abemaciclib plasma concentrations, if available.

Metformin is mainly eliminated unchanged in the urine and is a substrate of OCTs 1, 2, 3, MATE1 and MATE2K. Coadministration of abemaciclib and metformin increased metformin AUC by 37%. Therefore, monitoring of blood glucose levels and metformin toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on metolazone exposure is expected.

Coadministration has not been studied but should be approached with caution. Miconazole is extensively metabolised by the liver. Abemaciclib is unlikely to interfere with this unspecified pathway. However, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of abemaciclib may increase due to inhibition of CYP3A4. Coadministration of clarithromycin, a strong CYP3A4 inhibitor, with abemaciclib increased abemaciclib AUC by 3.4-fold and increased the AUC of abemaciclib with its three active metabolites by 2.2-fold. A similar effect may occur after coadministration with miconazole. 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 dose of abemaciclib to 100mg twice daily when initially treated with 200 or 150 mg twice daily, or to 50 mg twice daily if the dose of abemaciclib is already reduced due to toxicity. Monitor closely for abemaciclib toxicity. Monitor abemaciclib plasma concentrations, if available. If a patient discontinues the use of miconazole, increase the abemaciclib dose after 65-110 hours to the dose used before starting miconazole. Note: After dermal application miconazole is only minimally absorbed. Therefore, no clinically 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. Abemaciclib is an inhibitor of P-gp and may increase concentrations of morphine. As the clinical relevance of this interaction is unknown, monitoring for morphine toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. Abemaciclib does not inhibit or induce UGTs. Furthermore, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval. However, no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. Therefore, ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nadroparin is renally excreted by a nonsaturable mechanism. Abemaciclib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Nefazodone is metabolised mainly by CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, nefazodone is a strong inhibitor of CYP3A4 and may increase concentrations of abemaciclib. Coadministration of clarithromycin, a strong CYP3A4 inhibitor, with abemaciclib increased abemaciclib AUC by 3.4-fold and increased the AUC of abemaciclib with its three active metabolites by 2.2-fold. A similar effect may occur after coadministration with nefazodone. 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 dose of abemaciclib to 100mg twice daily when initially treated with 200 or 150 mg twice daily, or to 50 mg twice daily if the dose of abemaciclib is already reduced due to toxicity. Monitor closely for abemaciclib toxicity. Monitor abemaciclib plasma concentrations, if available. If a patient discontinues the use of nefazodone, increase the abemaciclib dose after 12-20 hours to the dose used before starting nefazodone.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation, and partly eliminated in the urine as unchanged drug (30-40%). Abemaciclib is unlikely to interfere with this metabolic pathway.

Coadministration is contraindicated if abemaciclib is used for treatment of hormone-sensitive cancer. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Abemaciclib does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied but care should be taken. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Abemaciclib does not inhibit OCT1, OAT1 and OAT3 at clinically relevant concentrations. However, ofloxacin concentrations may increase due to inhibition of OCT2 by abemaciclib and its major metabolites. As the clinical relevance of this interaction is unknown, monitoring for ofloxacin toxicity may be required. Furthermore, ofloxacin may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Abemaciclib does not inhibit or induce CYPs. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Abemaciclib is not metabolised by CYP1A2 or CYP2C19. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of omeprazole on abemaciclib absorption is expected.

Coadministration has not been studied but should be approached with caution. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Abemaciclib does not interact with this metabolic pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Concentrations of abemaciclib may decrease due to induction of CYP3A4. The clinical relevance of this interaction is unknown. Coadministration should be approached with caution, since a decrease in exposure can lead to decreased efficacy. If coadministration is unavoidable, closely monitor abemaciclib efficacy. Monitor abemaciclib plasma concentrations, if available.

Coadministration has not been studied but care should be taken. Paliperidone is primarily renally eliminated (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Abemaciclib does not inhibit OCT1 at clinically relevant concentrations. However, abemaciclib and its major metabolites inhibit OCT2 and may increase paliperidone concentrations. Coadministration of abemaciclib and metformin (OCT2, MATE2 and MATE2-K substrate) increased metformin AUC by 37%. A similar effect may occur with paliperidone. Therefore, monitoring for paliperidone toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Abemaciclib does not inhibit or induce CYPs. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of pantoprazole on abemaciclib absorption is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15), sulfation, and to a lesser extent by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Abemaciclib does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on the exposure of penicillins is expected.

Coadministration has not been studied but is contraindicated. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major) and to a lesser extent by CYP2E1. Abemaciclib does not inhibit or induce CYPs. However, phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Concentrations of abemaciclib may decrease due to induction of CYP3A4. Coadministration of rifampicin, a potent CYP3A4 inducer, with abemaciclib decreased abemaciclib AUC by 95%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 77%. A similar effect may occur after coadministration with phenobarbital. Therefore, coadministration with phenobarbital is contraindicated.

Coadministration has not been studied but is contraindicated. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Abemaciclib does not inhibit or induce CYPs. However, phenytoin is a strong inducer of CYP3A4, UGT and P-gp. Concentrations of abemaciclib may decrease due to induction of CYP3A4 and P-gp. Coadministration of rifampicin, a potent CYP3A4 inducer, with abemaciclib decreased abemaciclib AUC by 95%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 77%. A similar effect may occur after coadministration with phenytoin. Therefore, coadministration with phenytoin is contraindicated.

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Abemaciclib does not inhibit or induce CYPs. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval. No large QTc prolonging effect has been observed for abemaciclib and the net effect on QT prolongation has not been reported. Therefore, it is unknown whether there is a warning in place and if coadministration is contraindicated.

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. Abemaciclib does not inhibit OATP1B1 at clinically relevant concentrations. Therefore, no effect on pitavastatin exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Abemaciclib does not inhibit OATP1B1 at clinically relevant concentrations. Therefore, no effect on pravastatin exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quinapril is de-esterified to the active metabolite quinaprilat which is eliminated primarily by renal excretion via OAT3. Abemaciclib does not inhibit OAT3 at clinically relevant concentrations. Therefore, no effect on quinapril exposure is expected.

Coadministration has not been studied but care should be taken. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of quinidine. Monitoring for quinidine toxicity may be required. Furthermore, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Concentrations of abemaciclib may increase due to inhibition of CYP3A4 and P-gp. The clinical relevance of this interaction is unknown. Monitoring for abemaciclib toxicity may be necessary. No a priori dose adjustment for abemaciclib is necessary. Quinidine may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Abemaciclib does not inhibit or induce CYPs. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. Therefore, no effect of rabeprazole on abemaciclib absorption is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Abemaciclib does not inhibit OAT1 or OAT3 at clinically relevant concentrations. Furthermore, no clinically relevant effect of gastric acid reducing agents on the absorption of abemaciclib is expected since the drug remains completely soluble in aqueous environments at pH 6.8. No effect on abemaciclib absorption is expected.

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. Abemaciclib is an inhibitor of P-gp and may increase concentrations of ranolazine. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of abemaciclib may increase due to inhibition of CYP3A4 and P-gp. As the clinical relevance of this interaction is unknown, monitoring for ranolazine and abemaciclib toxicity may be required. No a priori dose adjustment for abemaciclib is necessary. Ranolazine may cause QTc interval prolongation but no large QTc prolonging effect has been observed for abemaciclib. The net effect on QT prolongation has not been reported and it is unknown whether there is a warning in place. ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of OATP1B1. Abemaciclib does not inhibit or induce CYPs and does not inhibit OATP1B1 at clinically relevant concentrations. Therefore, no effect on repaglinide exposure is expected.

Coadministration has not been studied but care should be taken. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Abemaciclib does not inhibit OATP1B1 at clinically relevant concentrations. However, concentrations of rosuvastatin may increase due to inhibition of BCRP. As the clinical relevance of this interaction is unknown, 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. Abemaciclib is an inhibitor of P-gp and may increase concentrations of saxagliptin. As the clinical relevance of this interaction is unknown, monitoring of blood glucose levels and saxagliptin toxicity may be required.

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval. No large QTc prolonging effect has been observed for abemaciclib and the net effect on QT prolongation has not been reported. Therefore, it is unknown whether there is a warning in place and if coadministration is contraindicated.

Coadministration has not been studied but care should be taken. Simvastatin is metabolised by CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, simvastatin is a substrate of BCRP and the active metabolite is a substrate of OATP1B1. Abemaciclib does not inhibit OATP1B1 at clinically relevant concentrations. However, concentrations of simvastatin may increase due to inhibition of BCRP. As the clinical relevance of this interaction is unknown, monitoring for simvastatin toxicity may be required.

Coadministration has not been studied but care should be taken. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1 and P-gp) and metabolism by CYP3A4 represents a minor metabolic pathway. Abemaciclib does not inhibit or induce CYPs and does not inhibit OAT3 at clinically relevant concentrations. However, concentrations of sitagliptin may increase due to inhibition of P-gp. As the clinical relevance of this interaction is unknown, monitoring of blood glucose levels and sitagliptin toxicity may be required.

Coadministration has not been studied but is contraindicated. St John’s Wort is a P-gp and CYP3A4 inducer and may decrease concentrations of abemaciclib. Coadministration of rifampicin with abemaciclib decreased abemaciclib AUC by 95%. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) decreased by 77%. A similar effect may occur after coadministration with St John’s Wort. Therefore, coadministration with St John’s Wort is contraindicated.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tacrolimus is metabolised mainly by CYP3A4. Abemaciclib does not inhibit or induce CYPs. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Therefore, no clinically relevant effect on abemaciclib exposure is expected. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

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. Abemaciclib does not inhibit or induce CYPs. Telithromycin is an inhibitor of P-gp and CYP3A4 (strong). The clinical relevance of P-gp inhibition is unknown. Abemaciclib and its metabolite M2 are substrates of P-gp but the interaction has not been studied. No clinically significant effect on abemaciclib and M2 exposure is expected due to P-gp inhibition. However, coadministration of clarithromycin, a strong CYP3A4 inhibitor, with abemaciclib increased abemaciclib AUC by 3.4-fold and increased the AUC of abemaciclib with its three active metabolites by 2.2-fold. A similar effect may occur after coadministration 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 dose of abemaciclib to 100mg twice daily when initially treated with 200 or 150 mg twice daily, or to 50 mg twice daily if the dose of abemaciclib is already reduced due to toxicity. Monitor closely for abemaciclib toxicity. Monitor abemaciclib plasma concentrations, if available. If a patient discontinues the use of telithromycin, increase the abemaciclib dose after 30-50 hours to the dose used before starting telithromycin.

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Abemaciclib does not inhibit or induce CYPs. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval. No large QTc prolonging effect has been observed for abemaciclib and the net effect on QT prolongation has not been reported. Therefore, it is unknown whether there is a warning in place and if coadministration is contraindicated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Torasemide is metabolised mainly by CYP2C9. Abemaciclib does not inhibit or induce CYPs. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on torasemide exposure is expected.

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). Trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is metabolised via and is a weak inhibitor of CYP2C9. Abemaciclib is unlikely to interfere with these pathways.

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. Abemaciclib does not inhibit or induce CYPs or UGTs. Valproic acid is also an inhibitor of CYP2C9. Abemaciclib is not metabolised by CYP2C9.

Coadministration has not been studied but should be approached with caution. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Abemaciclib does not inhibit or induce CYPs. However, verapamil is a moderate inhibitor of CYP3A4 and may increase concentrations of abemaciclib. In simulation studies, it was predicted that verapamil increases the AUC of abemaciclib by 2.28-fold. The AUC of the sum of abemaciclib and its active metabolites (M2, M18 and M20) increased by 1.63-fold. As the clinical relevance of this interaction is unknown, monitor closely for abemaciclib toxicity. Monitor abemaciclib concentrations, if available. No a priori dose decrease is necessary for abemaciclib.

Coadministration has not been studied but care should be taken. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Abemaciclib is an inhibitor of P-gp and may increase concentrations of vildagliptin. As the clinical relevance of this interaction is unknown, monitoring of blood glucose levels and for vildagliptin toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Abemaciclib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Abemaciclib does not inhibit OAT1 and OAT3 at clinically relevant concentrations. Therefore, no effect on xipamide exposure is expected.

Coadministration has not been studied but is contraindicated. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Abemaciclib does not inhibit or induce CYPs. However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval. No large QTc prolonging effect has been observed for abemaciclib and the net effect on QT prolongation has not been reported. Therefore, it is unknown whether there is a warning in place and if coadministration is contraindicated.

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