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 by the microbial flora. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and a weak inducer of CYP1A2. Concentrations of acenocoumarol may decrease due to induction of CYP2C9 and CYP2C19. Therefore, coadministration should be avoided. Patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives. Note: After discontinuation of enzalutamide, the effect of the interaction can persist up to several weeks. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs (major UGT1A6)). Enzalutamide does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19, and also a weak inducer of CYP1A2. Since CYP2C9 and CYP2C19 mediated metabolism is only a minor pathway, no clinically significant effect on agomelatine is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Alendronate is not metabolised and 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 and should be avoided. Alfentanil undergoes extensive CYP3A4 metabolism. Enzalutamide is a strong inducer of CYP3A4 and concentrations of alfentanil may significantly decrease. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of alfentanil efficacy is recommended. A dose increase of alfentanil may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Alfuzosin is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease alfuzosin metabolism. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of alfuzosin is recommended. A dose increase of alfuzosin may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Aliskiren is minimally metabolised and is mainly excreted unchanged in the faeces. P-gp is a major determinant of aliskiren bioavailability. Enzalutamide is an inhibitor of P-gp in vitro and may increase aliskiren concentrations. As the clinical relevance of this interaction is unknown, monitoring of aliskiren toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Enzalutamide not interfere with these metabolic pathways. 

Coadministration has not been studied and should be avoided. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and a weak inducer of CYP1A2, Concentrations of alosetron may significantly decrease due to induction of CYP2C9 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C9 should be considered. If coadministration is clinically necessary, monitoring of alosetron efficacy is recommended. A dose increase of alosetron may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Alprazolam is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease alprazolam concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of alprazolam efficacy is recommended. A dose increase of alprazolam may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised by CYPs. Enzalutamide is unlikely to affect aluminium hydroxide elimination and aluminium hydroxide is unlikely to alter enzalutamide absorption.

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. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19, and may decrease concentrations of ambrisentan. However, since CYP3A4 and CYP2C19 metabolism are minor pathways, this is unlikely to be clinically relevant. However, ambrisentan is also a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro and may increase concentrations of ambrisentan. As the clinical relevance of this interaction is unknown, monitoring for ambrisentan toxicity and efficacy may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amikacin is eliminated by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Enzalutamide is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but should be avoided. Amiodarone is metabolised by CYP2C8 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a weak inhibitor of CYP2C8. Concentrations of amiodarone may significantly decrease due to strong induction of CYP3A4 by enzalutamide but concentrations may also increase due to inhibition of CYP2C8. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of amiodarone efficacy is recommended. A dose increase of amiodarone may be necessary to achieve comparable efficacy. In addition, amiodarone is an inhibitor of CYP3A4 and may increase enzalutamide concentrations but a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily renally eliminated (possibly via OCT). Enzalutamide is unlikely to significantly affect amisulpride elimination. 

Coadministration has not been studied and should be avoided. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Enzalutamide is a moderate inducer of CYPs 2D6, 2C19 and 2C9, and a strong inducer of CYP3A4. Concentrations of amitriptyline may significantly decrease due to induction of CYPs 2D6, 2C19, 2C9 and 3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2D6, 2C19, 2C9 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of amitriptyline efficacy is recommended. A dose increase of amitriptyline may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Amlodipine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease amlodipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of amlodipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. It is unknown if enzalutamide interferes with amoxicillin renal elimination, but a clinical relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Enzalutamide does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20-40% of an oral dose may be excreted unchanged in the urine within 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours. Enzalutamide is unlikely to significantly affect ampicillin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperatures. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as antacids are unlikely to alter enzalutamide absorption. Antacids are not metabolised by CYPs and enzalutamide is unlikely to affect antacids elimination.

Coadministration has not been studied and should be avoided. Apixaban is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Enzalutamide is a weak inhibitor of CYP2C8 but no clinically significant effect is expected. However, enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19 and a weak inducer of CYP1A2. Concentrations of apixaban may significantly decrease due to induction of CYPs 3A4, 2C9 and 2C19 by enzalutamide. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of anti-Xa levels is recommended.

Coadministration has not been studied but should be avoided. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Enzalutamide is a strong inducer of CYP3A4, a weak inducer of CYP1A2 and a moderate inducer of CYP2C19. Concentrations of aprepitant may significantly decrease due to induction of CYPs 3A4, 1A2 and 2C19. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of enzalutamide, but this is unlikely to be clinically relevant. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of enzalutamide may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied and should be avoided. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of aripiprazole may significantly decrease due to induction of CYP3A4 and CYP2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of aripiprazole efficacy is recommended. A dose increase of aripiprazole may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (via CYPs 1A2 (major), 3A4 and 2D6 (minor)). Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of asenapine may decrease due to induction of CYP3A4 and CYP2D6. Although these are minor metabolic pathways, the clinical relevance of these interactions is unknown. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of asenapine efficacy is recommended. A dose increase of asenapine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease astemizole concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of astemizole efficacy is recommended. A dose increase of astemizole may be necessary to achieve comparable efficacy. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp in vitro. Concentrations of atorvastatin may significantly decrease due to CYP3A4 induction but concentrations may also increase due to inhibition of P-gp. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered (i.e. pravastatin, rosuvastatin). If coadministration is clinically necessary, close monitoring of atorvastatin efficacy is recommended. A dose increase of atorvastatin may be necessary to achieve comparable efficacy.

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

Coadministration has not been studied. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Enzalutamide is an inhibitor for P-gp in vitro and may increase azithromycin concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Beclometasone is a prodrug which is not metabolised by CYP450, but is hydrolysed via esterase enzymes to the highly active metabolite beclometasone -17-monopropionate. Enzalutamide does not interact with this pathway. 

Coadministration has not been studied and should be avoided. Bedaquiline is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease bedaquiline concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of bedaquiline efficacy is recommended. A dose increase of bedaquiline may be necessary to achieve comparable efficacy.

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 is excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that enzalutamide inhibits these renal transporters but a clinically relevant interaction is unlikely in the range of observed clinical concentrations. In addition, there is no evidence that bendroflumethiazide inhibits or induces CYPs and is therefore unlikely to impact enzalutamide.

Coadministration has not been studied and should be avoided. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6, which may significantly decrease bepridil concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of bepridil efficacy is recommended. A dose increase of bepridil may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Betamethasone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease betamethasone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of betamethasone efficacy is recommended. A dose increase of betamethasone may be necessary to achieve comparable efficacy. Note: A clinically significant interaction is unlikely with the local use of betamethasone.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Half of a bezafibrate dose is eliminated unchanged in the urine. Enzalutamide does not interfere with this elimination 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. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of bisoprolol may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of bisoprolol efficacy is recommended. A dose increase of bisoprolol may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Bosentan is a substrate and inducer of CYP3A4 and CYP2C9. Concentrations of enzalutamide may decrease due to strong induction of CYP3A4 by bosentan. However, enzalutamide is also a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of bosentan may significantly decrease due to induction of CYP3A4 and CYP2C9 by enzalutamide. A decrease in exposure can lead to decreased efficacy. Inducers of CYP3A4 and CYP2C9 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 and CYP2C9 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available. A dose increase of bosentan may also be necessary to achieve comparable efficacy. If coadministration is clinically necessary, close monitoring of both bosentan and enzalutamide concentrations is recommended.

Coadministration has not been studied. Bromazepam undergoes oxidative biotransformation. Interaction studies indicate that CYP3A4 has a minor role in bromazepam metabolism with CYP2D6 and CYP1A2 also potentially having a role. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2D6 and a weak inducer of CYP1A2. Concentrations of bromazepam may decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. The clinical relevance of this interaction is unknown but coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of bromazepam efficacy is recommended. A dose increase of bromazepam may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Budesonide is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease budesonide concentrations. The clinical relevance of this interaction is unknown as budesonide is not used as a systemic drug, but as an inhalation drug. Monitoring may be required. 

Coadministration has not been studied and should be avoided. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Enzalutamide is a strong inducer of CYP3A4 and also induces UGT1A1. Therefore, formation of the active metabolites may increase. The clinical relevance of this interaction is unknown and selection of an alternate concomitant medicinal product, which is not or minimally affected by CYP3A4 inducers should be considered. If coadministration is clinically necessary, monitoring of buprenorphine toxicity is recommended. 

Coadministration has not been studied. Bupropion is primarily metabolised by CYP2B6. Enzalutamide is an inhibitor of CYP2B6 in vitro and may increase bupropion concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied and should be avoided. Buspirone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significant decrease buspirone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of buspirone is recommended. A dose increase of buspirone may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine and sweat. 

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. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Enzalutamide does not 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. Enzalutamide does not interfere with captopril elimination.

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease carbamazepine concentrations. Furthermore, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Carbamazepine may significantly decrease enzalutamide concentrations due to induction of CYP2C8 and CYP3A4. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 or CYP2C8 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Close monitoring for carbamazepine efficacy is recommended and a dose increase of carbamazepine may also be necessary to achieve comparable efficacy. Consider monitoring of both enzalutamide and carbamazepine plasma concentrations, if available.

Coadministration has not been studied. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Enzalutamide is a moderate inducer of CYP2D6 and CYP2C9, and a weak inducer of CYP1A2. Concentrations of carvedilol may decrease due to induction of CYP2D6 by enzalutamide. The clinical relevance of this interaction is unknown but coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of carvedilol efficacy is recommended. A dose increase of carvedilol may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Caspofungin undergoes spontaneous chemical degradation and metabolism via a non-CYP mediated pathway. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly renally eliminated unchanged by glomerular filtration and tubular secretion via OAT1 and MATE1. It is unknown if enzalutamide interferes with this elimination pathway, but a clinical relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. It is unknown if enzalutamide interferes with this elimination pathway, but a clinically relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefixime is renally excreted predominantly by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

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. It is unknown if enzalutamide interferes with this elimination pathway, but a clinically relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftazidime is excreted predominantly by renal glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ceftriaxone is eliminated mainly as unchanged drug, approximately 60% of the dose being excreted in the urine predominantly by glomerular filtration and the remainder via the biliary and intestinal tracts. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Celecoxib is primarily metabolised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may significantly decrease celecoxib concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of celecoxib efficacy is recommended. A dose increase of celecoxib may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine inhibits OCT2. Enzalutamide is not transported by OCT and does not interfere with this elimination pathway.

Coadministration has not been studied. Chloramphenicol is predominately glucuronidated. Enzalutamide is unlikely to interact with this pathway. However, in vitro studies have shown that chloramphenicol inhibits CYP3A4 and may increase concentrations of enzalutamide. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. As the net effect is unknown, monitoring of enzalutamide efficacy and toxicity may be required. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction. 

Coadministration has not been studied but should be avoided. Chlordiazepoxide is extensively metabolised by CYP3A4, but does not inhibit or induce cytochromes. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of chlordiazepoxide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, monitoring for efficacy is recommended. A dose increase of chlordiazepoxide may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Chlorphenamine is predominantly metabolised in the liver via CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease chlorphenamine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of chlorphenamine efficacy is recommended. A dose increase of chlorphenamine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of chlorpromazine may decrease due to induction of CYP3A4 and CYP2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of chlorpromazine efficacy is recommended. A dose increase of chlorpromazine may be necessary to achieve comparable efficacy.

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. 

Coadministration has not been studied and should be avoided. Ciclosporin is metabolised mainly by CYP3A4 and is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. However, enzalutamide is a strong inducer of CYP3A4 and may significantly decrease ciclosporin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, the ciclosporin dose should be increased dependent on the indication and protocol involved, and monitoring of ciclosporin plasma concentrations is recommended. Ciclosporin is an inhibitor of CYP3A4 and OATP1B1 and may increase enzalutamide concentrations. However, this is unlikely to be clinically relevant as enzalutamide is strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway. No a priori dosage adjustment is recommended for enzalutamide, but close monitoring for enzalutamide toxicity should be considered. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cilazapril is mainly eliminated unchanged by the kidneys. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine inhibits CYP3A4 and may increase concentrations of enzalutamide, but this is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only party metabolised by CYP3A4.

Coadministration has not been studied. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. Ciprofloxacin is also metabolised and partially cleared through the bile and intestine. It is unknown if enzalutamide interferes with the elimination of ciprofloxacin, but a clinical significant effect is not expected. Ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and strong inhibitor of CYP1A2. Concentrations of enzalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant.

Coadministration has not been studied and should be avoided. Cisapride is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease cisapride concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, monitoring of cisapride efficacy is recommended.

Coadministration has not been studied and should be avoided. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Enzalutamide is a moderate inducer of CYP2D6 and CYP2C19 and a strong inducer of CYP3A4. Concentrations of citalopram may significantly decrease due to induction of CYPs 3A4, 2D6 and 2C19 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2C19, 2D6 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of citalopram efficacy is recommended. A dose increase of citalopram may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Clarithromycin is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease clarithromycin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of clarithromycin efficacy is recommended. A dose increase of clarithromycin may also be necessary to achieve comparable efficacy. Furthermore, clarithromycin may increase enzalutamide concentrations due to inhibition of CYP3A4 and P-gp. However, this is unlikely to be clinically relevant because enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4.  

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolised (likely non-CYP mediated pathway) and excreted in the urine by glomerular filtration. Enzalutamide does not interact with this pathway. 

Coadministration has not been studied. Clemastine is predominantly metabolised in the liver via CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease clemastine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of clemastine efficacy is recommended. A dose increase of clemastine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Clindamycin is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease clindamycin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of clindamycin efficacy is recommended. A dose increase of clindamycin may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely with the topical use of clobetasol.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are also metabolised by CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19 and CYP2D6. Concentrations of clomipramine may significantly decrease due to induction of CYPs 3A4, 2C19 and 2D6 by enzalutamide. However, induction of CYPs 3A4, 1A2 and 2C19 may increase concentrations of the active metabolite, desmethylclomipramine, which may lead to a supratherapeutic effect. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of clomipramine efficacy is recommended. A dose increase of clomipramine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 70% of administered clonidine is excreted in the urine, mainly in the form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 and is unlikely to interact with enzalutamide elimination. In addition, enzalutamide does not interfere with clonidine elimination.

Coadministration has not been studied and should be avoided. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C19 and a weak inducer of CYP1A2. Concentrations of the active metabolites may increase due to induction of CYP3A4 and CYP2C19. Therefore, a supratherapeutic effect may occur. Selection of an alternate concomitant medicinal product, with no or minimal potential to interact with bioactivation of clopidogrel should be considered. Furthermore, clopidogrel is an inhibitor of CYP2C8 and may increase enzalutamide concentrations. Concurrent use of CYP2C8 inhibitors is not recommended. If coadministration is clinically necessary, the product labels for enzalutamide recommend a dose reduction from 160 mg to 80 mg once daily, based on careful monitoring of tolerability. Further dose reductions may be needed if adverse effects occur during therapy. Monitoring of enzalutamide plasma concentrations should be considered, if available.

Coadministration has not been studied and should be avoided. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease clorazepate concentrations. However, concentrations of oxazepam, the active metabolite, may increase due to induction of CYP3A4. The clinical relevance of this interaction is unknown and coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of clorazepate efficacy is recommended. A dose increase of clorazepate may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied but should be avoided. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C19 and CYP2D6, and a weak inducer of CYP1A2. Concentrations of clozapine may significantly decrease due to induction of CYPs 3A4, 2C19 and 2D6. Coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of clozapine efficacy is recommended. A dose increase of clozapine will be necessary to achieve comparable efficacy. 

Coadministration has not been studied but should be avoided. 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). Morphine is also a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro and may increase concentrations of morphine. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Enzalutamide is a potent inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of codeine may decrease due to induction of CYP3A4 which may lead to decreased concentrations of morphine. However, the modest induction of CYP2D6 could increase concentrations of morphine. The net effect of enzalutamide on codeine and morphine exposure is unknown. Therefore, coadministration should be avoided. 

Coadministration has not been studied and should be avoided. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. However, enzalutamide is a strong inducer of CYP3A4 and may significantly decrease colchicine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of colchicine efficacy is recommended. A dose increase of colchicine may be necessary to achieve comparable efficacy.

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

Coadministration has not been studied. Dabigatran is transported via P-gp and is renally excreted. Enzalutamide is an inhibitor for P-gp in vitro and may increase dabigatran concentrations. The clinical relevance of this interaction is unknown. If possible, selection of an alternate concomitant medicinal product, with no or minimal transportation via P-gp should be considered. If coadministration is clinically necessary, close monitoring of dabigatran toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys. Enzalutamide does not interfere with the renal excretion of dalteparin. 

Coadministration has not been studied and should be avoided. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYPs 2C9, 2C19 and 2D6. Concentrations of dapsone may significantly decrease due to induction of CYPs 3A4, 2D6, 2C9 and 2C19. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2D6, 2C9 and 2C19 should be considered. If coadministration is clinically necessary, close monitoring of dapsone efficacy is recommended. A dose increase of dapsone may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Desipramine is metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease concentrations of desipramine. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of desipramine efficacy is recommended. A dose increase of desipramine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concentrations of the active metabolite, etonogestrel may increase due to induction of CYP2C9 and CYP2C19, but then the concentrations of etonogestrel may significantly decrease due to induction of CYP3A4. Therefore, coadministration should be avoided. 

Coadministration has not been studied and should be avoided. Dexamethasone is a weak inducer of CYP3A4 and may decrease enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway. However, dexamethasone is metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is a strong inducer of CYP3A4 and a weak inhibitor of P-gp in vitro. Concentrations of dexamethasone may increase due to inhibition of P-gp, although the clinical relevance of this interaction is unknown. However, dexamethasone concentrations may significantly decrease due to CYP3A4 induction. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of dexamethasone efficacy is recommended. A dose increase of dexamethasone may be necessary to achieve comparable efficacy. 

Coadministration has not been studied and should be avoided. Dextropropoxyphene is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease dextropropoxyphene concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of dextropropoxyphene efficacy is recommended. A dose increase of dextropropoxyphene may be necessary to achieve comparable efficacy.

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). Enzalutamide is an inducer of UGT1A1 in vitro and may decrease diamorphine concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied and should be avoided. Diazepam is metabolised to nordiazepam (via CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of diazepam may decrease due to induction of CYP3A4 and CYP2C19 by enzalutamide. However, concentrations of the active metabolites, temazepam and nordiazepam, may increase due to induction of CYP3A4. The clinical relevance of this interaction is unknown and coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of diazepam efficacy is recommended. A dose increase of diazepam may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may decrease diclofenac concentrations. However, CYP2C9 mediated metabolism is only a minor pathway. As the clinical relevance of this interaction is unknown, close monitoring of diclofenac efficacy is recommended. 

Coadministration has not been studied. Digoxin is renally eliminated via the renal transporters OATP4C1 and P-gp. Enzalutamide is an inhibitor of P-gp in vitro and may increase digoxin concentrations. As the clinical relevance of this interaction is unknown, close monitoring of digoxin is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Enzalutamide is a strong inducer of CYP3A4 and may decrease dihydrocodeine concentrations. Since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely.

Coadministration has not been studied and should be avoided. Diltiazem is metabolised by CYP3A4 and CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of diltiazem may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of diltiazem efficacy is recommended. A dose increase of diltiazem may be necessary to achieve comparable efficacy. Furthermore, diltiazem is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. No a priori dose adjustment is recommended for enzalutamide.

Coadministration has not been studied. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Enzalutamide is a moderate inducer of CYPs 2D6, 2C9 and 2C19 and may decrease diphenhydramine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2D6, 2C9 and 2C19 should be considered. If coadministration is clinically necessary, close monitoring of diphenhydramine efficacy is recommended. A dose increase of diphenhydramine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Enzalutamide is an inducer of UGT1A1 in vitro and may decrease dipyridamole concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease disopyramide concentrations. If coadministration is clinically necessary, monitoring of disopyramide efficacy is recommended. A dose increase of disopyramide may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. However, since CYP3A4 and CYP2D6 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely, but monitoring may be required.

Coadministration has not been studied and should be avoided. Domperidone is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease domperidone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of domperidone efficacy is recommended. A dose increase of domperidone may be necessary to achieve comparable efficacy.

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 disposition of enzalutamide, or to be affected if co-administered with enzalutamide.

Coadministration has not been studied and should be avoided. Doxazosin is metabolised mainly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease doxazosin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of doxazosin efficacy is recommended. A dose increase of doxazosin may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are also metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2C19 and CYP2D6. Concentrations of the active metabolite may increase due to induction of CYP2C19 and a supratherapeutic effect may occur. However, concentrations of doxepin and nordoxepin may decrease due to induction of CYP2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of doxepin efficacy is recommended. A dose increase of doxepin may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40-60% of an administered dose can be accounted for in the urine. Enzalutamide does not interact with this pathway. 

Coadministration has not been studied and should be avoided. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of dronabinol may significantly decrease due to induction of CYP2C9 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C9 should be considered. If coadministration is clinically necessary, monitoring of dronabinol efficacy is recommended. A dose increase of dronabinol may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Drospirenone is metabolised to a minor extent via CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of drospirenone. Therefore, coadministration should be avoided. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since the efficacy of enzalutamide is more likely to be correlated to trough plasma concentrations instead of maximum plasma concentrations, the clinical relevance of delayed absorption is considered to be limited.

Coadministration has not been studied. Duloxetine is metabolised by CYP2D6 and CYP1A2. Enzalutamide is a moderate inducer of CYP2D6 and may decrease duloxetine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of duloxetine efficacy is recommended. A dose increase of duloxetine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Dutasteride is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease dutasteride concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of dutasteride is recommended. A dose increase of dutasteride may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of dydrogesterone. Coadministration should be avoided. 

Coadministration has not been studied. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Enzalutamide is a strong inducer of CYP3A4 and may decrease edoxaban concentrations, but since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely. However, enzalutamide is an inhibitor of P-gp in vitro and may increase edoxaban concentrations. The clinical relevance of this interaction is unknown. If possible, selection of an alternate concomitant medicinal product, with no or minimal transportation via P-gp should be considered. If coadministration is clinically necessary, close monitoring of edoxaban is recommended.

Coadministration has not been studied. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Enzalutamide is an inducer of UGT1A1 in vitro, a weak inducer of CYP1A2 and a weak inhibitor of CYP2C8. Concentrations of eltrombopag may decrease due to induction of UGT1A1 and CYP1A2 but concentrations may also increase due to CYP2C8 inhibition. As the clinical relevance of this interaction is unknown, monitoring may be required.

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). Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enoxaparin does not undergo cytochrome metabolism; it is desulphated and depolymerised in the liver, and then predominantly renally excreted. Enzalutamide does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as eprosartan is largely excreted in bile and urine as unchanged drug. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor role. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied and should be avoided. Erythromycin is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease erythromycin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of erythromycin efficacy is recommended. A dose increase of erythromycin may be necessary to achieve comparable efficacy. In addition, erythromycin is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4.

Coadministration has not been studied and should be avoided. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Enzalutamide is a moderate inducer of CYP2D6 and CYP2C19 and a strong inducer of CYP3A4. Concentrations of escitalopram may significantly decrease due to induction of CYPs 2D6, 2C19 and 3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2C19, 2D6 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of escitalopram efficacy is recommended. A dose increase of escitalopram may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of esomeprazole may significantly decrease due to induction of CYP2C19 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C19 should be considered. If coadministration is clinically necessary, monitoring of esomeprazole efficacy is recommended. A dose increase of esomeprazole may be necessary to achieve comparable efficacy. Note: No clinically significant effect of gastric pH increasing drugs on enzalutamide exposure is expected.

Coadministration has not been studied and should be avoided. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease estazolam concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of estazolam efficacy is recommended. A dose increase of estazolam may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of estradiol. Therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolised by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and urine (50%). Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied and is unlikely due to the differing target populations. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of ethinylestradiol. Therefore, coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethionamide is extensively metabolised in the liver with animal studies suggesting involvement of flavin-containing monooxygenases. Enzalutamide does not interfere with this pathway. 

Coadministration has not been studied and is unlikely due to the differing target populations. Etonogestrel is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of etonogestrel. Therefore, coadministration should be avoided.

Coadministration has not been studied but should be avoided. Everolimus is mainly metabolised via CYP3A4 and is a substrate of P-gp. Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp in vitro. A clinically relevant interaction via P-gp is unlikely but everolimus concentrations may decrease significantly due to CYP3A4 induction. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of efficacy of everolimus is recommended. Monitoring of everolimus plasma concentrations should be considered, if available. A dose increase of everolimus may be necessary to achieve comparable efficacy. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Exenatide is cleared mainly by glomerular filtration. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since the efficacy of enzalutamide is more likely to be correlated to trough plasma concentrations instead of maximum plasma concentrations, the clinical relevance of delayed absorption is considered to be limited.

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. Enzalutamide is an inducer of UGT1A1 in vitro but the in vivo effect has yet to be determined. However, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as famotidine is unlikely to alter enzalutamide absorption. Famotidine is excreted via OAT1/OAT3. Enzalutamide does not interact with this pathway.

Coadministration has not been studied and should be avoided. Felodipine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease felodipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of felodipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. Enzalutamide does not interact with this pathway.

Coadministration is contraindicated. Fentanyl undergoes extensive CYP3A4 metabolism. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease fentanyl concentrations. After coadministration with enzalutamide, fentanyl concentrations were decreased with a median of 0.07 µg/L (range 0.00-0.30). The population median concentration was 1.33 µg/L (range 0.12-10.70). Increasing the dose of fentanyl when coadministered with enzalutamide is unlikely to sufficiently compensate for the loss of exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fexofenadine undergoes negligible metabolism and is mainly eliminated unchanged in the faeces. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Finasteride is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease finasteride concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of finasteride efficacy is recommended. A dose increase of finasteride may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated as unchanged drug. Enzalutamide is a moderate inducer of CYP2D6 and may decrease flecainide concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of flecainide efficacy is recommended. A dose increase of flecainide may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Enzalutamide does not interact with this pathway. However, flucloxacillin was shown to induce CYP3A4 and P-gp, potentially decreasing enzalutamide concentrations. Although CYP3A4 mediated metabolism is only a minor pathway, the clinical relevance of this interaction is unknown and monitoring may be required.

Coadministration has not been studied. Fluconazole is only metabolised to a minor extent. Enzalutamide does not interfere with this metabolic pathway. However, fluconazole is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. Monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil which is further metabolised by dihydropyrimidine dehydrogenase. Enzalutamide does not interfere with this metabolic pathway. 

Coadministration has not been studied. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease fludrocortisone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of fludrocortisone efficacy is recommended. A dose increase of fludrocortisone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of flunitrazepam may significantly decrease due to induction of CYP3A4 and CYP2C19 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of flunitrazepam efficacy is recommended. A dose increase of flunitrazepam may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Fluoxetine is metabolised by CYPs 2D6 and 2C9 and to a lesser extent by CYPs 2C19 and 3A4 to form norfluoxetine. Enzalutamide is a moderate inducer of CYPs 2D6, 2C9 and 2C19 and a strong inducer of CYP3A4. Concentrations of fluoxetine may significantly decrease due to induction of CYPs 2D6, 2C9, 2C19 and 3A4, but concentrations of norfluoxetine may increase. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2C19, 2C9, 2D6 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of fluoxetine efficacy is recommended. A dose increase of fluoxetine may be necessary to achieve comparable efficacy. 

Coadministration has not been studied. Fluphenazine is metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease fluphenazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of fluphenazine efficacy is recommended. A dose increase of fluphenazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. The metabolism of flurazepam is most likely CYP-mediated. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYPs 2C9, 2C19 and 2D6, and a weak inducer of CYP1A2. Concentrations of flurazepam may significantly decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6 by enzalutamide. The clinical relevance of this interaction is unknown but coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19, and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of flurazepam efficacy is recommended. A dose increase of flurazepam may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Fluticasone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease fluticasone concentrations. However, fluticasone is not used as systemic therapy so a clinically relevant interaction is unlikely. 

Coadministration has not been studied and should be avoided. Fluvastatin is mainly metabolised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may significantly decrease fluvastatin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered (i.e. pravastatin, rosuvastatin). If coadministration is clinically necessary, close monitoring of fluvastatin efficacy is recommended. A dose increase of fluvastatin may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Enzalutamide is a moderate inducer of CYP2D6 and may decrease fluvoxamine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of fluvoxamine efficacy is recommended. A dose increase of fluvoxamine may be necessary to achieve comparable efficacy. In addition, fluvoxamine inhibits CYP3A4 and may increase enzalutamide concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism and is predominantly renally excreted. Enzalutamide does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation. Enzalutamide is a moderate inducer of CYPs 2C9, 2C19 and 2D6, and may decrease formoterol concentrations. Since CYP mediated metabolism is one of multiple pathways, a clinically relevant interaction is unlikely. 

Coadministration has not been studied but should be avoided. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Enzalutamide does not interact with this metabolic pathway. However, aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Enzalutamide is a strong inducer of CYP3A4, a weak inducer of CYP1A2 and a moderate inducer of CYP2C19. Concentrations of aprepitant may significantly decrease due to induction of CYPs 3A4, 1A2 and 2C19. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of enzalutamide, but this is unlikely to be clinically relevant. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of enzalutamide may decrease due to weak induction of CYP3A4, but this is not considered to be clinically relevant.

Coadministration has not been studied but should be avoided. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19, and may decrease concentrations of phenytoin. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of phenytoin efficacy is recommended. A dose increase of phenytoin may be necessary to achieve comparable efficacy. Furthermore, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of enzalutamide may decrease due to strong induction of CYP3A4. A decrease in exposure can lead to decreased efficacy. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Monitor closely for both phenytoin and enzalutamide efficacy. Monitor phenytoin and enzalutamide plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also renally eliminated unchanged (via OATs). Enzalutamide does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gabapentin is cleared mainly by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Gemfibrozil is a strong inducer of CYP2C8 and may increase enzalutamide concentrations. In healthy volunteers (n=41), coadministration of gemfibrozil (600 mg twice daily for 21 days) and enzalutamide (160 mg single dose) increased the AUC of enzalutamide by 4.3-fold and increased the AUC of enzalutamide plus active metabolite by 2.2-fold. Concurrent use of CYP2C8 inhibitors is not recommended. If coadministration is clinically necessary, the product labels for enzalutamide recommend a dose reduction from 160 mg to 80 mg once daily, based on careful monitoring of tolerability. Further dose reductions may be needed if adverse effects occur during therapy. Monitoring of enzalutamide plasma concentrations should be considered, if available. In addition, gemfibrozil is metabolised by UGT2B7. Enzalutamide does not inhibit or induce UGT2B7.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gentamicin is eliminated unchanged predominantly via glomerular filtration. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied and is unlikely due to the differing target populations. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concentrations of gestodene may significantly decrease due to induction of CYPs 3A4, 2C9 and 2C19. Therefore, coadministration should be avoided.

Coadministration has not been studied and should be avoided. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of glibenclamide may significantly decrease due to induction of CYP3A4 and CYP2C9. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of glibenclamide may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Gliclazide is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C19. Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and may significantly decrease concentrations of gliclazide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of gliclazide may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Glimepiride is mainly metabolised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may significantly decrease concentrations of glimepiride. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of glimepiride may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Glipizide is mainly metabolised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may significantly decrease concentrations of glipizide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of glipizide may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. Enzalutamide is also a strong inducer of CYP3A4 and may significantly decrease granisetron concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of granisetron efficacy is recommended. A dose increase of granisetron may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Grapefruit juice is known to inhibit CYP3A4 enzymes. Concentrations of enzalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied and should be avoided. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Enzalutamide does not interfere with the elimination of griseofulvin. However, griseofulvin is an inducer of CYP3A4 and may decrease enzalutamide concentrations. A decrease in exposure can lead to decreased efficacy. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available.

Coadministration has not been studied and should be avoided. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4 and 1A9), carbonyl reduction, as well as oxidative metabolism (CYP3A4 and CYP2D6). Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of haloperidol may decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of haloperidol efficacy is recommended. A dose increase of haloperidol may be necessary to achieve comparable efficacy.

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. Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydralazine is metabolised via primary oxidative metabolism and acetylation. Although in vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6, it is not expected to lead to a clinical relevant interaction with enzalutamide. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. Significant interactions are not expected with enzalutamide.

Coadministration has not been studied but should be avoided. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of both hydromorphone and norhydrocodone may increase due to induction of CYP2D6 and CYP3A4, respectively, therefore, a supratherapeutic effect may occur. Coadministration should be avoided and if possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of hydrocodone toxicity is recommended. A dose decrease of hydrocodone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Hydrocortisone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease hydrocortisone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of hydrocortisone efficacy is recommended. A dose increase of hydrocortisone may be necessary to achieve comparable efficacy.

Coadministration has not been studied but a clinically significant interaction is unlikely with the topical use of hydrocortisone. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7. Enzalutamide does not inhibit or induce UGT2B7. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is not a substrate of CYP enzymes or P-gp, therefore enzalutamide is unlikely to interfere with the metabolism of hydroxyurea.

Coadministration has not been studied. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease hydroxyzine concentrations. The clinical relevance of this interaction is unknown and coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of hydroxyzine efficacy is recommended. A dose increase of hydroxyzine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ibandronic acid is not metabolised and 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 and should be avoided. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Enzalutamide is a moderate inducer of CYP2C9 and a weak inhibitor of CYP2C8. Concentrations of ibuprofen may decrease due to moderate induction of CYP2C9 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of ibuprofen efficacy is recommended. A dose increase of ibuprofen may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Iloperidone is metabolised by CYP3A4 and CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of iloperidone may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of iloperidone efficacy is recommended. A dose increase of iloperidone may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipenem and cilastatin are eliminated by glomerular filtration and to a lesser extent by active tubular secretion. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied and should be avoided. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 (minor) to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2C19 and CYP2D6, and a strong inducer of CYP3A4. Concentrations of the active metabolite may increase due to induction of CYP3A4 and CYP2C19. However, concentrations of imipramine and desipramine may decrease due to induction of CYP2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2C19, 2D6 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of imipramine efficacy is recommended. A dose increase of imipramine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Indapamide is extensively metabolised by CYP P450. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYPs 2C9, 2C19 and 2D6. Concentrations of indapamide may significantly decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of indapamide efficacy is recommended. A dose increase of indapamide may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. A small proportion of an inhaled ipratropium dose is systemically absorbed (6.9%). Metabolism is via ester hydrolysis and conjugation. Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied and should be avoided. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Enzalutamide is a moderate inducer of CYP2C9 and may decrease irbesartan concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of irbesartan efficacy is recommended. A dose increase of irbesartan may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Enzalutamide is a strong inducer of CYP3A4 and may decrease isosorbide dinitrate concentrations. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration should be avoided. In healthy volunteers (n=41), coadministration of enzalutamide (160 mg single dose) and itraconazole (200 mg once daily for 21 days) increased enzalutamide AUC by 41% while enzalutamide Cmax was unchanged. Therefore, concentrations of enzalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant. However, itraconazole is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of itraconazole. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring for itraconazole efficacy is recommended. A dose increase of itraconazole may also be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Ivabradine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease ivabradine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of ivabradine efficacy is recommended. A dose increase of ivabradine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Kanamycin is eliminated unchanged predominantly via glomerular filtration. Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied and should be avoided. Ketoconazole is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4, but monitoring may be required. However, ketoconazole is metabolised by CYP3A4 and enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of ketoconazole. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring for ketoconazole efficacy is recommended. A dose increase of ketoconazole may also be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Enzalutamide in an inducer of UGT1A1 in vitro and may decrease concentrations of labetalol. As the clinical relevance of this interaction is unknown, monitoring may be required. 

Coadministration has not been studied and should be avoided. Lacidipine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease lacidipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of lacidipine efficacy is recommended. A dose increase of lacidipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of lactulose to lactic acid occurs via gastro-intestinal microbial flora only. 

Coadministration has not been studied and should be avoided. Lansoprazole is mainly metabolised by CYP2C19 and to lesser extent by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of lansoprazole may significantly decrease due to induction of CYP2C19 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 and CYP3A4 should be considered. If coadministration is clinically necessary, monitoring of lansoprazole efficacy is recommended. A dose increase of lansoprazole may be necessary to achieve comparable efficacy. Note: No clinically significant effect of gastric pH increasing drugs on enzalutamide exposure is expected.

Coadministration has not been studied and should be avoided. Lercanidipine is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease lercanidipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of lercanidipine efficacy is recommended. A dose increase of lercanidipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied. Levomepromazine is metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease levomepromazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of levomepromazine efficacy is recommended. A dose increase of levomepromazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of levonorgestrel. Therefore, coadministration should be avoided.

Coadministration is contraindicated if enzalutamide 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 and is unlikely due to the differing target populations. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Enzalutamide is an inducer of CYP3A4 (strong) and UGT1A1 (in vitro), and may significantly decrease concentrations of levonorgestrel. Coadministration should be avoided.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolised by deiodination (by enzymes of deiodinase family) and glucuronidation. Enzalutamide does not interact with these metabolic pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP1A2. However, since CYP3A4 mediated metabolism is a minor pathway and CYP1A2 is only weakly induced, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp in vitro. Linagliptin concentrations may decrease due to induction of CYP3A4 but concentrations may also increase due to inhibition of P-gp. The clinical relevance of these interactions is unknown. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and P-gp should be considered. If coadministration is clinically necessary, close monitoring of linagliptin efficacy is recommended and a dose increase of linagliptin may be necessary to achieve comparable efficacy. In addition, linagliptin is an inhibitor of CYP3A4 and may increase concentrations of enzalutamide. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linezolid undergoes non-CYP mediated metabolism. Enzalutamide is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Liraglutide is degraded by endogenous endopeptidases. Enzalutamide does not interact with this pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lithium is mainly eliminated unchanged in the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In patients receiving enzalutamide, the use of live vaccines for immunisation is not contraindicated. 

Coadministration has not been studied and should be avoided. Loperamide is mainly metabolised by CYP3A4 and CYP2C8. Enzalutamide is a weak inhibitor of CYP2C8 in vitro and may increase concentrations of loperamide, but this is unlikely to be clinically relevant. However, enzalutamide is a strong inducer of CYP3A4 and may significantly decrease loperamide concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, monitoring of loperamide efficacy is recommended. A dose increase of loperamide may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of loratadine may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of loratadine efficacy is recommended. A dose increase of loratadine may be necessary to achieve comparable efficacy. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lorazepam is eliminated by non-CYP mediated pathways and no effect on plasma concentrations is expected when coadministered with enzalutamide. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated. Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied and should be avoided. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Enzalutamide is a moderate inducer of CYP2C9 and may decrease losartan concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of losartan efficacy is recommended. A dose increase of losartan may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Lovastatin is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease lovastatin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered (i.e. pravastatin, rosuvastatin). If coadministration is clinically necessary, close monitoring of lovastatin efficacy is recommended. A dose increase of lovastatin may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Enzalutamide is a weak inhibitor of CYP2C8 in vitro and may increase concentrations of macitentan, but this is unlikely to be clinically relevant. However, enzalutamide is also a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concentrations of macitentan may significantly decrease due to induction of CYPs 3A4, 2C9 and 2C19 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9 and 2C19 should be considered. If coadministration is clinically necessary, close monitoring of macitentan efficacy is recommended. A dose increase of macitentan may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Magnesium is eliminated in the kidney, mainly by glomerular filtration. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied. Maprotiline is mainly metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease maprotiline concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of maprotiline efficacy is recommended. A dose increase of maprotiline may be necessary to achieve comparable efficacy.

Coadministration has not been studied and is unlikely due to the differing target populations. Medroxyprogesterone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of medroxyprogesterone. Therefore, coadministration should be avoided.

Coadministration has not been studied and is unlikely due to the differing target populations. Medroxyprogesterone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of medroxyprogesterone. Therefore, coadministration should be avoided.

Coadministration has not been studied and should be avoided. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Enzalutamide is a moderate inducer of CYP2C9 and may decrease mefenamic acid concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of mefenamic acid efficacy is recommended. A dose increase of mefenamic acid may be necessary to achieve comparable efficacy.

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. 

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 the renal transporters OAT3>OAT1. It is unknown if enzalutamide interferes with meropenem elimination, but a clinically relevant interaction is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mesalazine is metabolised to N-acetyl-mesalazine by N-acetyltransferase. Enzalutamide does not interfere with this pathway. 

Coadministration has not been studied. Metamizole is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease metamizole concentrations. Furthermore, metamizole is a weak inducer of CYP3A4 and may decrease enzalutamide concentrations. A decrease in enzalutamide exposure can lead to decreased efficacy. Selection of an alternate concomitant medication with no or minimal enzyme or transporter induction potential is recommended. As the clinical relevance of this interaction is unknown, close monitoring and dose adjustment may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine (via OCT2). Enzalutamide does not interact with this pathway.

Coadministration has not been studied and should be avoided. Methadone is demethylated by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease methadone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of methadone efficacy is recommended. A dose increase of methadone may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methyldopa is excreted in the urine largely by glomerular filtration, primarily unchanged and as the mono-O-sulfate conjugate. It is unlikely to affect the disposition of enzalutamide, or to be altered by coadministration with enzalutamide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolised by CYP450s to a clinically relevant extent and does not inhibit or induce CYP450s. 

Coadministration has not been studied and should be avoided. Methylprednisolone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease methylprednisolone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of methylprednisolone efficacy is recommended. A dose increase of methylprednisolone may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Metoclopramide is partially metabolised by the CYP450 system (mainly CYP2D6). Enzalutamide is a moderate inducer of CYP2D6 and may decrease metoclopramide concentrations. However, since CYP2D6 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely, but monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as metolazone is largely excreted unchanged in the urine. 

Coadministration has not been studied. Metoprolol is mainly metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease metoprolol concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of metoprolol efficacy is recommended. A dose increase of metoprolol may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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). As CYP3A4 mediated metabolism is a minor pathway for enzalutamide, this interaction is unlikely to be clinically relevant. 

Coadministration has not been studied. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Enzalutamide is a weak inducer of CYP1A2 but this is unlikely to be clinically relevant. However, enzalutamide is also a moderate inducer of CYP2D6 and may decrease mexiletine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of mexiletine efficacy is recommended. A dose increase of mexiletine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Mianserin is metabolised by CYP2D6, CYP1A2, and to a lesser extent by CYP3A4. Enzalutamide is a weak inhibitor of CYP1A2, a moderate inducer of CYP2D6 and a strong inducer of CYP3A4. Concentrations of mianserin may decrease due to induction of CYP2D6 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of mianserin efficacy is recommended. A dose increase of mianserin may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Miconazole is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. Miconazole is metabolised via O-dealkylation and oxidative N-dealkylation, potentially CYP-mediated. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYPs 2C9, 2C19 and 2D6, and weak inducer of CYP1A2. Concentrations of miconazole may decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6. As the clinical relevance of these interactions is unknown, monitoring may be required. 

Midazolam is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease midazolam concentrations. In healthy volunteers (n=14), coadministration of enzalutamide (160 mg once daily for 84 days) and midazolam (single dose of 2 mg) decreased midazolam AUC and Cmax by 86% and 77%, respectively. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered such as temazepam, flurazepam or oxazepam, as these benzodiazepines are directly glucuronidated and therefore, a clinically relevant interaction is unlikely. If coadministration is clinically necessary, close monitoring of midazolam efficacy is recommended. A dose increase of midazolam may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Midazolam is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease midazolam concentrations. In healthy volunteers (n=14), coadministration of enzalutamide (160 mg once daily for 84 days) and oral midazolam (single dose of 2 mg) decreased midazolam AUC and Cmax by 86% and 77%, respectively. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered such as temazepam, flurazepam or oxazepam, as these benzodiazepines are directly glucuronidated and therefore, a clinically relevant interaction is unlikely. If coadministration is clinically necessary, close monitoring of midazolam efficacy is recommended. A dose increase of midazolam may be necessary to achieve comparable efficacy. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). Enzalutamide is unlikely to interfere with these pathways.

Coadministration has not been studied and should be avoided. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and mainly through CYP3A4 to N-desmethylmirtazapine. Enzalutamide is a moderate inducer of CYP2D6 and a strong inducer of CYP3A4. Concentrations of mirtazapine may significantly decrease due to induction of CYP2D6 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of mirtazapine efficacy is recommended. A dose increase of mirtazapine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but a clinically significant interaction is unlikely with the topical use of mometasone.

Coadministration has not been studied. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Enzalutamide is a weak inhibitor of CYP2C8 and may increase concentrations of montelukast, but this is unlikely to be clinically relevant. However, enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of montelukast may decrease due to induction of CYP3A4 and CYP2C9 by enzalutamide. CYP3A4 and CYP2C9 mediated metabolism is only a minor pathway. As the clinical relevance of this interaction is unknown, monitoring may be required. Furthermore, montelukast is an inhibitor of CYP2C8 in vitro and may increase enzalutamide concentrations. As the clinical relevance of this interaction is unknown, monitoring of enzalutamide plasma concentrations may be required.

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). Enzalutamide is an inducer of UGT1A1 in vitro and may decrease morphine concentrations. As the clinical relevance of this interaction is unknown, monitoring of morphine efficacy may be required.

Coadministration has not been studied. Moxifloxacin is predominantly glucuronidated by UGT1A1. Enzalutamide is an inducer of UGT1A1 in vitro and may decrease moxifloxacin concentrations. As the clinical relevance of this interaction is unknown, monitoring of moxifloxacin efficacy may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Enzalutamide does not inhibit or induce UGT1A9 or UGT2B7. In addition, inhibition of OAT1/OAT3 renal transporters by mycophenolic acid (active metabolite) is unlikely to interfere with enzalutamide elimination. 

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. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nandrolone is metabolised in the liver by alpha-reductase. Enzalutamide does not interact with this pathway.

Coadministration has not been studied. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Enzalutamide is a moderate inducer of CYP2C9 and a weak inducer of CYP1A2, which may decrease concentrations of naproxen. The clinical relevance of this interaction is unknown. Although naproxen has a wide therapeutic index, close monitoring of naproxen efficacy is recommended.

Coadministration has not been studied and should be avoided. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Enzalutamide is a moderate inducer of CYP2C9 and a strong inducer of CYP3A4. Concentrations of nateglinide may significantly decrease due to induction of CYP2C9 and CYP3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of nateglinide may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Nebivolol metabolism involves CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease nebivolol concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of nebivolol efficacy is recommended. A dose increase of nebivolol may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Nefazodone is an inhibitor of CYP3A4 and may increase concentrations of enzalutamide, but this is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. However, nefazodone is metabolised mainly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease nefazodone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of mirtazapine efficacy is recommended. A dose increase of nefazodone may be necessary to achieve comparable efficacy. 

Coadministration has not been studied and should be avoided. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Enzalutamide is a weak inhibitor of CYP2C8, a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of nicardipine may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of nicardipine may be necessary to achieve comparable efficacy. Furthermore, nicardipine inhibits CYP3A4 and could potentially increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only party metabolised by CYP3A4. No a priori dose adjustment is recommended for enzalutamide. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicotinamide is converted to N-methylnicotinamide by nicotinamide methyltransferase which in turn is metabolised by xanthine oxidase and aldehyde oxidase. Enzalutamide does not interact with this metabolic pathway. In addition, nicotinic acid and its metabolites do not inhibit CYP-mediated reactions in vitro and therefore are unlikely to impact enzalutamide exposure.

Coadministration has not been studied and should be avoided. Nifedipine is metabolised mainly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease nifedipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of nifedipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Nimesulide is extensively metabolised in the liver following multiple pathways including CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may decrease nimesulide concentrations. However, CYP2C9 mediated metabolism is only a minor pathway. As the clinical relevance of this interaction is unknown, monitoring of nimesulide efficacy is recommended.

Coadministration has not been studied and should be avoided. Nisoldipine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease nisoldipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of nisoldipine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Nitrendipine is extensively metabolised mainly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease nitrendipine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood pressure is recommended. A dose increase of nitrendipine may be necessary to achieve comparable efficacy.

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%). Enzalutamide does not interact with this metabolic or elimination pathway. 

Coadministration has not been studied and is unlikely due to the differing target populations. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of norelgestromin. Therefore, coadministration should be avoided.

Coadministration has not been studied and is unlikely due to the differing target populations. Based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Enzalutamide does not interact with these metabolic pathways.

Coadministration has not been studied and is unlikely due to the differing target populations. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concentrations of norgestimate may significantly decrease due to induction of CYPs 3A4, 2C9 and 2C19 by enzalutamide. Therefore, coadministration should be avoided.

Coadministration has not been studied and is unlikely due to the differing target populations. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of levonorgestrel. Therefore, coadministration should be avoided.

Coadministration has not been studied. Nortriptyline is metabolised predominantly by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease nortriptyline concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of nortriptyline efficacy is recommended. A dose increase of nortriptyline may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Systemic absorption of nystatin from oral or topical dosage forms is not significant, therefore no drug interactions are expected. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Enzalutamide is unlikely to interfere with this pathway. 

Coadministration has not been studied. Olanzapine is metabolised mainly by CYP1A2 and CYP2D6, but also by glucuronidation (UGT1A4). Enzalutamide is a moderate inhibitor of CYP2D6 and a weak inhibitor of CYP1A2. Concentrations of olanzapine may decrease due to induction of CYP2D6. If coadministration is clinically necessary, close monitoring of olanzapine efficacy is recommended. A dose increase of olanzapine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olmesartan medoxomil is de-esterified to the active metabolite olmesartan which is eliminated in the faeces and urine. 

Coadministration should be avoided. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of omeprazole may significantly decrease due to induction of CYP3A4 and CYP2C19 by enzalutamide. In healthy volunteers (n=14), coadministration of omeprazole (single dose of 20 mg) and enzalutamide (160 mg once daily for 84 days) decreased omeprazole AUC and Cmax by 70% and 62%, respectively. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C19 should be considered. If coadministration is clinically necessary, monitoring of omeprazole efficacy is recommended. A dose increase of omeprazole may be necessary to achieve comparable efficacy. Note: No clinically significant effect of gastric pH increasing drugs on enzalutamide exposure is expected.

Coadministration has not been studied and should be avoided. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. Enzalutamide is also a strong inducer of CYP3A4, a moderate inducer of CYP2D6 and a weak inducer of CYP1A2. Concentrations of ondansetron may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of ondansetron efficacy is recommended. A dose increase of ondansetron may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied and should be avoided. Oxcarbazepine is mainly metabolised via glucuronidation. Enzalutamide is unlikely to interfere with this metabolic pathway. However, oxcarbazepine is a strong inducer of CYP3A4 and may decrease enzalutamide concentrations. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolised via glucuronidation. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied but should be avoided. Oxycodone is metabolised principally to noroxycodone via CYP3A4 and oxymorphone via CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of oxycodone may significantly decrease due to induction of CYP3A4 and CYP2D6 and concentrations of noroxycodone and oxymorphone may significantly increase due to induction of CYP3A4 and CYP2D6. Oxymorphone is 14 times more potent than oxycodone. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of oxycodone toxicity is recommended. A dose decrease of oxycodone may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Paliperidone is primarily renally eliminated (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Enzalutamide is strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of paliperidone may decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Although these are only minor metabolic pathways, the clinical relevance of these interactions is unknown. Coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of paliperidone efficacy is recommended. A dose increase of paliperidone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Palonosetron is metabolised mainly by CYP2D6 and to a lesser extent by CYP3A4 and CYP1A2. Palonosetron is also a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. Enzalutamide is also a strong inducer of CYP3A4, a moderate inducer of CYP2D6 and a weak inducer of CYP1A2. Concentrations of palonosetron may decrease due to induction of CYP3A4 and CYP2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of palonosetron efficacy is recommended when enzalutamide is coadministered. A dose increase of palonosetron may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as pamidronic acid is not metabolised and is cleared as unchanged drug via urine.

Coadministration has not been studied and should be avoided. Pantoprazole is mainly metabolised by CYP2C19 and to lesser extent by CYPs 3A4, 2D6 and 2C9. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYPs 2C9, 2C19 and 2D6. Concentrations of pantoprazole may significantly decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, monitoring of pantoprazole efficacy is recommended. A dose increase of pantoprazole may be necessary to achieve comparable efficacy. Note: No clinically significant effect of gastric pH increasing drugs on enzalutamide exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1 and 2B15), sulfation, and to a lesser extent by oxidation (via CYPs 2E1, (major), 1A2, 3A4 and 2D6). Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2D6 and induces UGT1A1 in vitro, potentially decreasing paracetamol concentrations. The risk for liver injury after paracetamol administration is suspected to be higher in patients concomitantly treated with enzyme inducers. As the clinical relevance of this interaction is unknown, monitoring may be required.

Coadministration has not been studied and should be avoided. Paroxetine is mainly metabolised by CYP2D6 and CYP3A4. Enzalutamide is a moderate inducer of CYP2D6 and a strong inducer of CYP3A4. Concentrations of paroxetine may significantly decrease due to induction of CYP2D6 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of paroxetine efficacy is recommended. A dose increase of paroxetine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

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). It is unknown if enzalutamide interferes with penicillin elimination, but a clinically relevant interaction is not expected.

Coadministration has not been studied and should be avoided. Perazine is demethylated via CYP3A4 and CYP2C9, and to a lesser extent by CYP2D6 and CYP2C19, with oxidation via FMO3. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYPs 2C9, 2C19 and 2D6. Concentrations of perazine may significantly decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of perazine metabolism is recommended. A dose increase of perazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease periciazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring for efficacy of periciazine is recommended when enzalutamide is coadministered. A dose increase of periciazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Perindopril is hydrolysed to the active metabolite perindoprilat probably via CYP3A4 and is metabolised to other inactive metabolites. Elimination occurs predominantly via the urine. Enzalutamide is a strong inducer of CYP3A4 and may increase the concentration of the active metabolite, perindoprilat. Therefore, a supratherapeutic effect may occur. The clinical relevance of this interaction is unknown but selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, monitoring of perindopril efficacy and toxicity is recommended.

Coadministration has not been studied. Perphenazine is metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease perphenazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of perphenazine efficacy is recommended. A dose increase of perphenazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a weak inhibitor of CYP2B6. Concentrations of pethidine may decrease due to induction of CYP3A4 but concentrations may increase due to inhibition of CYP2B6. As the clinical relevance of this interaction is unknown, monitoring of pethidine efficacy is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenelzine is primarily metabolised by oxidation via monoamine oxidase and to a lesser extent by acetylation. Enzalutamide does not interact with these metabolic pathways.

Coadministration has not been studied and should be avoided. Phenobarbital is partially metabolised in the liver by CYP2C19. Enzalutamide is a moderate inducer of CYP2C19 and may decrease phenobarbital concentrations. A dose increase of phenobarbital may be necessary to achieve comparable efficacy. Furthermore, phenobarbital is a strong inducer of CYP3A4 and may decrease enzalutamide concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 and CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Consider monitoring of both phenobarbital and enzalutamide plasma concentrations, if available. 

Coadministration has not been studied but should be avoided. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of phenprocoumon may significantly decrease due to induction of CYP3A4 and CYP2C9. Therefore, coadministration should be avoided. Patients who require anticoagulation should receive low-molecular-weight or standard heparin, instead of coumarin derivatives. 

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Enzalutamide is a moderate inducer of CYP2C9 and CYP2C19, and may decrease concentrations of phenytoin. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of phenytoin efficacy is recommended. A dose increase of phenytoin may be necessary to achieve comparable efficacy. Furthermore, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of enzalutamide may decrease due to strong induction of CYP3A4. A decrease in exposure can lead to decreased efficacy. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Monitor closely for both phenytoin and enzalutamide efficacy. Monitor phenytoin and enzalutamide plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. An in vitro study found that the only CYP450 enzyme involved in phytomenadione metabolism was CYP4F2. Enzalutamide does not inhibit or induce CYP4F2. 

Coadministration has not been studied and should be avoided. Pimozide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of pimozide may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of pimozide efficacy is recommended. A dose increase of pimozide may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Enzalutamide is a moderate inducer of CYP2D6 and may decrease pindolol concentrations. The clinical relevance of this interaction is unknown but coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of pindolol efficacy is recommended. A dose increase of pindolol may be necessary to achieve comparable efficacy.

Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of pioglitazone may decrease due to induction of CYP3A4 and CYP2C9. In healthy volunteers (n=14), coadministration of enzalutamide (160 mg once daily for 84 days) and pioglitazone (single dose of 30 mg) increased pioglitazone AUC by 20% but decreased pioglitazone Cmax by 18%. Therefore, the potential for a clinically relevant interaction between enzalutamide and pioglitazone is unlikely. However, if coadministration is clinically necessary, monitoring of blood glucose levels may be required. 

Coadministration has not been studied. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease pipotiazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of pipotiazine efficacy is recommended. A dose increase of pipotiazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Piroxicam is primarily metabolised by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9 and may significantly decrease piroxicam concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of piroxicam efficacy is recommended. A dose increase of piroxicam may be necessary to achieve comparable efficacy.

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. Enzalutamide is a moderate inducer of CYP2C9 and may decrease pitavastatin concentrations, but since CYP2C9 is only a minor pathway, a clinically relevant interaction is unlikely.

Coadministration has not been studied. Posaconazole undergoes glucuronidation with only a small portion of CYP-mediated metabolism. Enzalutamide is unlikely to interfere with these metabolic pathways. However, posaconazole is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. This is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4, but monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Potassium is renally eliminated.

Coadministration has not been studied and should be avoided. 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. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2C9 and CYP2C19, and an inhibitor of CYP2B6 in vitro. Concentrations of the active metabolite may increase due to induction of CYPs 3A4, 2C9 and 2C19 by enzalutamide. Therefore, a supratherapeutic effect may occur. Selection of an alternate concomitant medicinal product, with no or minimal potential to interact with bioactivation of prasugrel should be considered. Close monitoring of prasugrel is recommended. 

Coadministration has not been studied. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Enzalutamide is a potential inducer of OATP1B1, but the clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prazosin is extensively metabolised, primarily by demethylation and conjugation. Enzalutamide does not interact with these metabolic pathways.

Coadministration has not been studied and should be avoided. Prednisolone undergoes hepatic metabolism via CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease prednisolone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of prednisolone efficacy is recommended. A dose increase of prednisolone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease the concentrations of the active metabolite, prednisolone. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring for efficacy of prednisolone is recommended. A dose increase of prednisolone may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pregabalin is cleared mainly by glomerular filtration. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied and should be avoided. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Enzalutamide is a moderate inducer of CYP2D6 and CYP2C19 and may decrease prochlorperazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of prochlorperazine efficacy is recommended. A dose increase of prochlorperazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Promethazine is metabolised by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease promethazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of promethazine efficacy is recommended. A dose increase of promethazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYP2D6 and a weak inducer of CYP1A2. Concentrations of propafenone may decrease due to induction of CYP2D6 and CYP3A4 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of propafenone efficacy is recommended. A dose increase of propafenone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Propranolol is metabolised by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Enzalutamide is a moderate inducer of CYP2C19 and CYP2D6 and may significantly decrease propranolol concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of propranolol efficacy is recommended. A dose increase of propranolol may be necessary to achieve comparable efficacy.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolised by xanthine oxidase. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied and should be avoided. Quetiapine is primarily metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease quetiapine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of quetiapine efficacy is recommended. A dose increase of quetiapine may be necessary to achieve comparable efficacy.

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. Enzalutamide does not interact with this renal transporter. 

Coadministration has not been studied and should be avoided. Quinidine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease quinidine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of quinidine efficacy is recommended. A dose increase of quinidine may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Rabeprazole is mainly metabolised via non-enzymatic reduction and to lesser extent by CYP2C19 and CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C19. Concentrations of rabeprazole may decrease due to induction of CYP2C19 and CYP3A4 by enzalutamide. Therefore, coadministration is not recommended. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2C19 should be considered. If coadministration is clinically necessary, monitoring of pantoprazole efficacy is recommended. A dose increase of rabeprazole may be necessary to achieve comparable efficacy. Note: No clinically significant effect of gastric pH increasing drugs on enzalutamide exposure is expected.

Coadministration has not been studied. Ramipril is hydrolysed to the active metabolite ramiprilat probably via CYP3A4, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Enzalutamide is a strong inducer of CYP3A4 and may increase the concentrations of the active metabolite, ramiprilat. Therefore, a supratherapeutic effect may occur. The clinical relevance of this interaction is unknown but selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, monitoring of ramipril efficacy and toxicity is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is unlikely to alter enzalutamide absorption. Ranitidine is excreted via OAT1/OAT3. Enzalutamide does not interact with this pathway.

Coadministration has not been studied but should be avoided. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Enzalutamide is an inducer of CYP3A4 (strong) and CYP2D6 (moderate) and may significantly decrease ranolazine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of ranolazine efficacy is recommended. A dose increase of ranolazine may be necessary to achieve comparable efficacy. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of enzalutamide may increase due to CYP3A4 inhibition. However, this is unlikely to be clinical significant as enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway.

Coadministration has not been studied. Reboxetine is a weak inhibitor of CYP3A4 in vitro, potentially increasing enzalutamide concentrations, but in vivo data showed no inhibitory effect on CYP3A4. A clinically relevant interaction would be unlikely as enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor metabolic pathway. However, reboxetine is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease reboxetine concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of reboxetine efficacy is recommended. A dose increase of reboxetine may be necessary to achieve comparable efficacy. 

Coadministration has not been studied and should be avoided. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is also a substrate of the hepatic transporter OATP1B1. Enzalutamide is a strong inducer of CYP3A4 and may decrease repaglinide concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of repaglinide may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver but retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Enzalutamide does not interact with these metabolic pathways. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied and should be avoided. Significant decreases in enzalutamide plasma concentrations may occur due to induction of CYP3A4 and CYP2C8 by rifabutin. A decrease in enzalutamide exposure can lead to decreased efficacy. Inducers of CYP3A4 and CYP2C8 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 and CYP2C8 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP2C8 and CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available. In addition, rifabutin is metabolised by CYP3A and via deacetylation. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of rifabutin. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of rifabutin efficacy is recommended. A dose increase of rifabutin may be necessary to achieve comparable efficacy.

Coadministration should be avoided. Rifampicin is metabolised via deacetylation. Abiraterone does not interfere with this metabolic pathway. However, significant decreases in enzalutamide plasma concentrations may occur due to induction of CYP3A4 and CYP2C8 by rifampicin. In healthy volunteers, coadministration of rifampicin (600 mg once daily) with enzalutamide decreased enzalutamide AUC by 37%. Cmax was unaffected. Decreased enzalutamide exposure can lead to decreased efficacy. Inducers of CYP3A4 and CYP2C8 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 and CYP2C8 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP2C8 and CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available. 

Coadministration has not been studied and should be avoided. Rifapentine is metabolised via deacetylation. Abiraterone does not interfere with this metabolic pathway. However, significant decreases in enzalutamide plasma concentrations may occur due to induction of CYP3A4 and CYP2C8 by rifapentine. A decrease in enzalutamide exposure can lead to decreased efficacy. Inducers of CYP3A4 and CYP2C8 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 and CYP2C8 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP2C8 and CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifaximin is mainly excreted in the faeces, almost entirely as unchanged drug. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied and should be avoided. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Risperidone is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. However, enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6, which may decrease risperidone concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of risperidone efficacy is recommended. A dose increase of risperidone may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine (by P-gp and BCRP). Enzalutamide is a strong inducer of CYP3A4 and an inhibitor of P-gp in vitro. Concentrations of rivaroxaban may decrease due to strong induction of CYP3A4 but concentrations may also increase due to P-gp inhibition. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of anti-Xa levels is recommended.

Coadministration has not been studied. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Enzalutamide is a moderate inducer of CYP2C9. Concentrations of rosiglitazone may decrease due to induction of CYP2C9 and CYP3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 and should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of rosiglitazone may be necessary to achieve comparable efficacy. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1/B3. Enzalutamide does not interact with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salbutamol is metabolised to the inactive salbutamol-4’-O-sulphate. Enzalutamide does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may decrease salmeterol concentrations. Salmeterol acts locally in the lungs and so a clinically relevant interaction is unlikely.

Coadministration has not been studied and should be avoided. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is a strong inducer of CYP3A4 and is an inhibitor of P-gp in vitro. Concentrations of saxagliptin may increase due to inhibition of P-gp but the clinical relevance of this interaction is unknown. However, concentrations of saxagliptin may significantly decrease due to induction of CYP3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of saxagliptin may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Based on the metabolism/elimination and toxicity profiles of both drugs, there is little potential for an interaction. Senna glycosides are hydrolysed by colonic bacteria in the intestinal tract and the active anthraquinones liberated into the colon. Excretion occurs in the urine and faeces and also in other secretions. No clinically significant drug interactions are known. 

Coadministration has not been studied and should be avoided. Sertindole is metabolised by CYP2D6 and CYP3A4. Enzalutamide is strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of sertindole may significantly decrease due to induction of CYP2D6 and CYP3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of sertindole efficacy is recommended. A dose increase of sertindole may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Enzalutamide is a strong inducer of CYP3A4, a moderate inducer of CYPs 2C9, 2C19 and 2D6, and an inhibitor of CYP2B6 in vitro. Concentrations of sertraline may significantly decrease due to induction of CYPs 3A4, 2C9, 2C19 and 2D6, but concentrations may also increase due to inhibition of CYP2B6. The clinical relevance of these interactions is unknown and coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19, 2D6 and 2B6 should be considered. If coadministration is clinically necessary, close monitoring of sertraline efficacy is recommended. A dose increase of sertraline may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9. Concentrations of sildenafil may significantly decrease due to induction of CYP3A4 and CYP2C9 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 or CYP2C9 should be considered. If coadministration is clinically necessary, close monitoring of sildenafil efficacy is recommended. A dose increase of sildenafil may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Simvastatin is metabolised by CYP3A4 and the metabolite is a substrate of OATP1B1. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease simvastatin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered (i.e. pravastatin, rosuvastatin). If coadministration is clinically necessary, close monitoring of simvastatin metabolism is recommended. A dose increase of simvastatin may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. However, enzalutamide is a strong inducer of CYP3A4 and may significantly decrease sirolimus concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, the sirolimus dose should be increased dependent on the indication and protocol involved, sirolimus plasma concentrations should also be monitored. No a priori dosage adjustment is recommended for enzalutamide and close monitoring of toxicity should be considered.

Coadministration has not been studied. Sitagliptin is primarily eliminated in the urine as unchanged drug (via active secretion by OAT3, OATP4C1, and P-gp) with metabolism by CYP3A4 representing a minor elimination pathway. Enzalutamide is a strong inducer of CYP3A4 and may decrease sitagliptin concentrations. Since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely but monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase. There is little potential for sodium nitroprusside to affect the disposition of enzalutamide, or to be affected if coadministered with enzalutamide. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sotalol is excreted unchanged via renal elimination. Enzalutamide does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spectinomycin is predominantly eliminated unchanged in the kidneys via glomerular filtration. Enzalutamide does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spironolactone is partly metabolised by the flavin containing monooxygenases. Enzalutamide does not interfere this metabolic pathway. 

Coadministration has not been studied and should be avoided. Stanozolol undergoes hepatic metabolism. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYPs 2C9, 2C19 and 2D6. Stanozolol concentrations may significantly decrease due to the induction of CYPs 3A4, 2C9, 2C19 and 2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9, 2C19 and 2D6 should be considered. If coadministration is clinically necessary, close monitoring of stanozolol efficacy is recommended. A dose increase of stanozolol may be necessary to achieve comparable efficacy.

Coadministration has not been studied should be avoided. St John’s wort may cause significant and unpredictable decreases in the plasma concentrations of enzalutamide due to induction of CYP3A4 and P-gp. A decrease in exposure can lead to decreased efficacy. Inducers of CYP3A4 should be avoided, or selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is clinically necessary, the US product label for enzalutamide recommends a dose increase from 160 mg to 240 mg once daily, based on careful monitoring of tolerability (Note: The EU product label states that no dose adjustment is necessary when enzalutamide is coadministered with CYP3A4 inducers). Consider monitoring of enzalutamide plasma concentrations, if available.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Streptokinase is unlikely to affect the disposition of enzalutamide, or to be affected if coadministered with enzalutamide.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Streptomycin is eliminated by glomerular filtration. Enzalutamide not interfere with this elimination pathway.

Coadministration has not been studied. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Enzalutamide is a moderate inducer of CYP2C9 and may decrease sulfadiazine concentrations. Close monitoring of sulfadiazine efficacy is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Tacrolimus is metabolised mainly by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease tacrolimus concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, the tacrolimus dose should be increased dependent on the indication and protocol involved, and monitoring of tacrolimus plasma concentrations is recommended. Tacrolimus is an inhibitor of CYP3A4 and OATP1B1 and may increase concentrations of enzalutamide. However, this is unlikely to be clinically relevant as enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway. No a priori dosage adjustment is recommended for enzalutamide but close monitoring of toxicity should be considered.

Coadministration has not been studied and should be avoided. Tadalafil is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease tadalafil concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of tadalafil efficacy is recommended. A dose increase of tadalafil may be necessary to achieve comparable efficacy.

Coadministration has not been studied and should be avoided. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of tamsulosin may significantly decrease due to induction of CYP3A4 and CYP2D6 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring for efficacy of tamsulosin is recommended. A dose increase of tamsulosin may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is excreted as unchanged drug (approximately 80%) and inactive metabolite (approximately 20%) in the urine. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied and should be avoided. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease telithromycin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of telithromycin efficacy is recommended. A dose increase of telithromycin may be necessary to achieve comparable efficacy. In addition, telithromycin is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. However, this is unlikely to be clinically significant as enzalutamide is a strong inducer of CYP3A4 and is only partly metabolised by CYP3A4. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telmisartan is mainly glucuronidated by UGT1A3. Enzalutamide does not inhibit or induce UGT1A3.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated. Enzalutamide does not interact with this metabolic pathway. 

Coadministration has not been studied and should be avoided. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYPs 2C8 and 2C19. Enzalutamide is a strong inducer of CYP3A4 and a moderate inducer of CYP2C9 and CYP2C19. Concentrations of terbinafine may significantly decrease due to induction of CYPs 3A4, 2C9 and 2C19 by enzalutamide. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 3A4, 2C9 and 2C19 should be considered. If coadministration is clinically necessary, close monitoring of terbinafine efficacy is recommended. A dose increase of terbinafine may be necessary to achieve comparable efficacy. 

Coadministration has not been studied and is contraindicated. Testosterone is metabolised by CYP3A4. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease testosterone concentrations. Testosterone supplementation is contraindicated in patients with prostate cancer.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tetracycline is eliminated unchanged primarily by glomerular filtration. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Theophylline is mainly metabolised by CYP1A2. Enzalutamide is a weak inducer of CYP1A2 and may decrease theophylline concentrations. However, no clinically significant effect on theophylline is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 

Coadministration has not been studied and should be avoided. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Enzalutamide is strong inducer of CYP3A4 and a moderate inducer of CYP2D6. Concentrations of thioridazine may decrease due to induction of CYP2D6 and CYP3A4. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 and CYP2D6 should be considered. If coadministration is clinically necessary, close monitoring of thioridazine efficacy is recommended. A dose increase of thioridazine may be necessary to achieve comparable efficacy.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as tiapride is excreted largely unchanged in urine. Enzalutamide does not interfere with this elimination pathway.

Coadministration has not been studied and should be avoided. Ticagrelor is metabolised by CYP3A4 and is a substrate of P-gp. Enzalutamide is an inhibitor of P-gp in vitro but the clinical relevance of this interaction is unknown. Enzalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of ticagrelor. Therefore, coadministration should be avoided. Selection of an alternate concomitant medicinal product, with no or minimal potential to interact with CYP3A4 should be considered. If coadministration is clinically necessary, close monitoring of ticagrelor efficacy is recommended. A dose increase of ticagrelor may be necessary to achieve comparable efficacy. In addition, ticagrelor is an inhibitor of CYP3A4 and may increase enzalutamide concentrations. However, since enzalutamide is a strong inducer of CYP3A4 and CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Timolol is predominantly metabolised in the liver by CYP2D6. Enzalutamide is a moderate inducer of CYP2D6 and may decrease timolol concentrations. However, the systemic absorption of timolol after ocular administration is low. Therefore, a clinically relevant interaction via CYP2D6 is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tinzaparin is renally excreted as unchanged or almost unchanged drug. Enzalutamide does not interact with this elimination pathway.

Coadministration has not been studied and should be avoided. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C8 and CYP2C19. Enzalutamide is a weak inhibitor of CYP2C8 and may increase concentrations of tolbutamide, but this is unlikely to be clinically relevant. However, enzalutamide is a moderate inducer of CYP2C9 and CYP2C19 and may significantly decrease tolbutamide concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C9 and CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of tolbutamide may be necessary to achieve comparable efficacy.