Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Apalutamide

Acarbose

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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Potential Interaction

Apalutamide

Acenocoumarol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Apalutamide is a strong inducer of CYP2C19 and a weak inducer of CYP2C9 and may decrease acenocoumarol concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with acenocoumarol. Therefore, coadministration is not recommended. If coadministration is clinically necessary, additional INR monitoring should be conducted. Note: After discontinuation of apalutamide, the effect of the interaction can persist for up to several weeks.

Description:

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Potential Weak Interaction

Apalutamide

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs, major UGT1A6). Apalutamide may be an inducer of UGT and may decrease aspirin exposure. The clinical relevance of UGT induction is unknown. Care should be taken when apalutamide is coadministered with aspirin. Monitoring aspirin efficacy is recommended.

Description:

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Potential Interaction

Apalutamide

Agomelatine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Apalutamide does not inhibit or induce CYP1A2. However, apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP2C19 and may decrease agomelatine concentrations. The clinical relevance of this interaction is unknown as CYP2C9 and CYP2C19 are minor metabolic pathways. Therefore, coadministration should be approached with caution. If coadministration is clinically necessary, monitor agomelatine efficacy. A dose increase of agomelatine may be necessary to achieve comparable efficacy.

Description:

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No Interaction Expected

Apalutamide

Alendronic acid

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Apalutamide

Alfentanil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Alfentanil undergoes extensive CYP3A4 metabolism. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease alfentanil concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with alfentanil. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Alfuzosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Alfuzosin is metabolised by CYP3A. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease alfuzosin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with alfuzosin. Therefore, coadministration should be avoided.

Description:

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Potential Weak Interaction

Apalutamide

Aliskiren

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Aliskiren is also a substrate of P-gp. Apalutamide is a weak inducer of P-gp and may decrease concentrations of aliskiren. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with aliskiren. Care should be taken. Monitoring of aliskiren efficacy is recommended.

Description:

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No Interaction Expected

Apalutamide

Allopurinol

Quality of Evidence: Very Low

Summary:

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. Allopurinol is also an inhibitor of xanthine oxidase. Apalutamide does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Apalutamide

Alosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. In vitro data indicate that alosetron is metabolised by CYPs 2C9, 3A4 and 1A2. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9, and concentrations of alosetron may significantly decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur with alosetron. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Alprazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Alprazolam is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease alprazolam concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with alprazolam. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Aluminium hydroxide

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Apalutamide

Ambrisentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ambrisentan is metabolised by glucuronidation via UGTs 1A3, 1A9 and 2B7 and to a lesser extent by CYP3A4 and CYP2C19. Ambrisentan is also a substrate of P-gp. Apalutamide is a strong inducer of CYP2C19 and CYP3A4, a weak inducer of P-gp, and may be an inducer of UGT. Concentrations of ambrisentan may decrease due to induction of CYP3A4, CYP2C19, UGT and P-gp. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with ambrisentan. Therefore, coadministration is not recommended. If coadministration is clinically necessary, monitoring of ambrisentan efficacy is recommended.

Description:

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No Interaction Expected

Apalutamide

Amikacin

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Weak Interaction

Apalutamide

Amiloride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Apalutamide is an inhibitor of OCT2 in vitro. As the clinical relevance of this interaction is unknown, monitoring for amiloride toxicity may be required.

Description:

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Do Not Coadminister

Apalutamide

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amiodarone is metabolised by CYP3A4 and CYP2C8. Apalutamide is a strong inducer of CYP3A4. Concentrations of amiodarone may decrease significantly due to induction of CYP3A4. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with amiodarone. Apalutamide is also a moderate inhibitor of CYP2C8. Coadministration of pioglitazone (CYP2C8 substrate) with apalutamide decreased pioglitazone AUC by 18%. Therefore, no clinically relevant effect on amiodarone exposure due to CYP2C8 inhibition is expected. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong) and 2B6 (moderate) and P-gp (strong). Concentrations of apalutamide may increase due to CYP3A4 inhibition by desethylamiodarone but a clinically relevant interaction is unlikely. In addition, apalutamide and amiodarone potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG. Due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

Description:

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Potential Weak Interaction

Apalutamide

Amisulpride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amisulpride is weakly metabolised and is primarily eliminated renally (possibly via OCT). Apalutamide is an inhibitor of OCT2 and may increase amisulpride exposure. The clinical relevance of this interaction is unknown. Monitoring for amisulpride toxicity may be required.

Description:

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Do Not Coadminister

Apalutamide

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9. Concentrations of apalutamide may significantly decrease due to induction of CYPs 2C19, 2C9 and 3A4. Coadministration of omeprazole (a sensitive CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. Close monitoring of amitriptyline efficacy is recommended. A dose increase of amitriptyline may be necessary to achieve comparable efficacy. A similar effect may occur with amitriptyline. Furthermore, apalutamide and amitriptyline potentially cause QTc interval prolongation. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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Do Not Coadminister

Apalutamide

Amlodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amlodipine is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease amlodipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with amlodipine. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Amoxicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on amoxicillin exposure is expected.

Description:

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Potential Interaction

Apalutamide

Amphotericin B

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Apalutamide is unlikely to interact with this elimination pathway. However, the European SPC for amphotericin B states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension and so monitoring may be required. In addition, caution should be taken when using amphotericin B with drugs that are known to prolong the QT interval. Apalutamide and amphotericin B potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Ampicillin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with elimination pathway. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours.

Description:

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No Interaction Expected

Apalutamide

Anidulafungin

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Apalutamide

Antacids

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Apalutamide is unlikely to affect the elimination of antacids.

Description:

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Do Not Coadminister

Apalutamide

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Apixaban is a substrate of P-gp and BCRP and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9 and P-gp and may significantly decrease concentrations of apixaban. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with apixaban. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. During treatment, aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of apalutamide. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of apalutamide may decrease due to induction of CYP3A4, but no clinically relevant effect on apalutamide exposure is expected. However, apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may significantly decrease aprepitant concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with aprepitant. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Aripiprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease aripiprazole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with aripiprazole. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of aripiprazole efficacy is recommended. A dose increase of aripiprazole may be necessary to achieve comparable efficacy.

Description:

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Potential Interaction

Apalutamide

Asenapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor) and 2D6 (minor)). Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and decrease asenapine concentrations. Therefore, coadministration should be approached with caution. If coadministration is clinically necessary, monitoring of asenapine efficacy is recommended. A dose increase of asenapine may be necessary to achieve comparable efficacy.

Description:

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Do Not Coadminister

Apalutamide

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease astemizole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with astemizole. In addition, apalutamide and astemizole potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Atenolol

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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Do Not Coadminister

Apalutamide

Atorvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and OATP1B1, and may significantly decrease concentrations of atorvastatin. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Coadministration of rosuvastatin (a BCRP and OATP1B1 substrate) with apalutamide decreased rosuvastatin AUC by 41%. Similar effect may occur with atorvastatin. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Azathioprine

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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Potential Interaction

Apalutamide

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Apalutamide is a weak inducer of P-gp and may decrease azithromycin concentrations. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with azithromycin. Monitoring of azithromycin efficacy is recommended. Azithromycin is also an inhibitor of P-gp. Apalutamide and the active moiety N-desmethyl apalutamide are in vitro substrates for P-gp. However, since apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide. In addition, apalutamide and azithromycin potentially cause QTc interval prolongation. Therefore, coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Beclometasone

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Apalutamide

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Bedaquiline is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease bedaquiline concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with bedaquiline. In addition, apalutamide and bedaquiline potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters, but a clinically significant interaction is unlikely in the range of observed clinical concentrations. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on bendroflumethiazide exposure is expected.

Description:

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Do Not Coadminister

Apalutamide

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Apalutamide does not affect CYP2D6 at clinically relevant concentrations. However, apalutamide is a strong inducer of CYP3A4 and may significantly decrease bepridil concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with bepridil. In addition, apalutamide and bepridil potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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Do Not Coadminister

Apalutamide

Betamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Betamethasone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease betamethasone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with betamethasone. Therefore, coadministration should be avoided. Note: A clinically significant interaction is unlikely with the local use of betamethasone.

Description:

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No Interaction Expected

Apalutamide

Bezafibrate

Quality of Evidence: Very Low

Summary:

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. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1. Apalutamide does not interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Bisacodyl

Quality of Evidence: Very Low

Summary:

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. Apalutamide may be an inducer of UGT and may decrease exposure to bisacodyl. However, since only a small amount of bisacodyl is glucuronidated, this interaction is unlikely to be clinically relevant.

Description:

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Do Not Coadminister

Apalutamide

Bisoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Apalutamide is a strong inducer of CYP3A4 and may decrease bisoprolol concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with bisoprolol. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Bosentan

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be avoided. Bosentan is a substrate of CYP3A4 and CYP2C9. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur after coadministration of bosentan. Furthermore, bosentan is a weak inducer of CYP3A4 and CYP2C9. Imatinib concentrations, on average, decreased by 33% in the presence of bosentan in a phase III clinical study and a similar effect may be expected with apalutamide. Coadministration should be avoided. If coadministration is clinically necessary, close monitoring of apalutamide efficacy is recommended. Monitoring for apalutamide plasma concentrations should be considered, if available.

Description:

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Potential Weak Interaction

Apalutamide

Bromazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bromazepam undergoes oxidative biotransformation. Interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may also play a role. Apalutamide is a strong inducer of CYP3A4 and may decrease bromazepam concentrations. The clinical relevance of this interaction is unknown as CYP3A4 is a minor pathway. Monitoring of bromazepam efficacy should be considered. A dose increment for bromazepam may be necessary.

Description:

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Do Not Coadminister

Apalutamide

Budesonide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Budesonide is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease budesonide concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with budesonide. Therefore, coadministration should be avoided. Note: A clinically significant interaction is unlikely with the local use of budesonide.

Description:

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Do Not Coadminister

Apalutamide

Buprenorphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and concentrations of buprenorphine may decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with buprenorphine. Therefore, coadministration should be avoided.

Description:

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Potential Weak Interaction

Apalutamide

Bupropion

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Bupropion is primarily metabolised by CYP2B6. Apalutamide is a moderate inducer and inhibitor of CYP2B6 in vitro. As the clinical relevance of this interaction is unknown, care should be taken. Monitoring for bupropion toxicity and efficacy may be required. Furthermore, bupropion is a strong inhibitor of CYP2D6. Apalutamide is not metabolised by CYP2D6.

Description:

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Do Not Coadminister

Apalutamide

Buspirone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Buspirone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease buspirone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with buspirone. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Calcium

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Candesartan

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Capreomycin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Captopril

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not inhibit or induce OAT1.

Description:

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Do Not Coadminister

Apalutamide

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Apalutamide is a strong inducer of CYP3A4 and in vitro a moderate inhibitor of CYP2C8. Concentrations of carbamazepine may decrease significantly due to CYP3A4 induction. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with carbamazepine. Moreover, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6, UGT1A1 and P-gp (moderate). Concentrations of apalutamide may decrease due to strong induction of CYP2C8 and CYP3A4 by carbamazepine. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Therefore, coadministration should be avoided. If coadministration is unavoidable, closely monitor both carbamazepine and apalutamide efficacy. Monitor carbamazepine and apalutamide plasma concentrations, if available.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent CYP2C9 and CYP1A2. Apalutamide is a weak inducer of CYP2C9 and may be an inducer of UGT and may decrease concentrations of carvedilol. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with carvedilol. Monitoring of carvedilol efficacy may be required. Furthermore, carvedilol is an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown. Apalutamide and the active moiety N-desmethyl apalutamide are in vitro substrates for P-gp, but no clinically relevant effect of P-gp inhibition on apalutamide exposure is expected.

Description:

See Summary

No Interaction Expected

Apalutamide

Caspofungin

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Cefalexin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Cefalexin is predominantly renally eliminated unchanged by glomerular filtration and tubular secretion via OAT1 and MATE1. Apalutamide is an inhibitor of OAT1 and MATE1 in vitro. As the clinical relevance of this interaction is unknown, monitoring for cefalexin toxicity may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Cefazolin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on cefazolin exposure is expected.

Description:

See Summary

No Interaction Expected

Apalutamide

Cefixime

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Cefotaxime

Quality of Evidence: Very Low

Summary:

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. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on cefazolin exposure is expected.

Description:

See Summary

No Interaction Expected

Apalutamide

Ceftazidime

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Ceftriaxone

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Celecoxib

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Celecoxib is primarily metabolised by CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease celecoxib concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with celecoxib. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of celecoxib efficacy is recommended. A dose increase of celecoxib may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Cetirizine

Quality of Evidence: Very Low

Summary:

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 is also an inhibitor of OCT2. Apalutamide is not transported by OCT and does not interact with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Chloramphenicol is predominantly glucuronidated. Apalutamide may be an inducer of UGT and may decrease exposure to chloramphenicol. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with chloramphenicol. Monitoring for chloramphenicol efficacy may be required. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYP3A4 (strong), CYP2C19 (strong) and CYP2D6 (weak). Inhibition of CYP3A4 by chloramphenicol may increase apalutamide concentrations. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase was 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations 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.

Description:

See Summary

Do Not Coadminister

Apalutamide

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Chlordiazepoxide is extensively metabolised by CYP3A4 but does not inhibit or induce cytochromes. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease chlordiazepoxide concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with chlordiazepoxide. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Chlorphenamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorphenamine is predominantly metabolised in the liver via CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

See Summary

Potential Interaction

Apalutamide

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Apalutamide does not inhibit or induce CYP2D6 or CYP1A2. However, caution should be taken when using chlorpromazine with drugs that are known to prolong the QT interval. Apalutamide and chlorpromazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Chlortalidone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ciclosporin is a substrate of CYP3A4 and P-gp and also an inhibitor of CYP3A4 and OATP1B1. Inhibition of CYP3A4 by ciclosporin may increase apalutamide concentrations but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease ciclosporin exposure. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with ciclosporin. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Cilazapril

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cimetidine is metabolised by CYP450 enzymes. In vitro data indicate that cimetidine also inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Furthermore, cimetidine is a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Concentrations of apalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, and may decrease concentrations of cimetidine. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with cimetidine. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciprofloxacin is primarily eliminated unchanged by the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on ciprofloxacin exposure is expected. Furthermore, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. Apalutamide is not metabolised by CYP1A2. Therefore, no clinically relevant effect on apalutamide exposure is expected after coadministration with ciprofloxacin. However, apalutamide and ciprofloxacin potentially cause QTc interval prolongation. If co-administration is necessary, close monitoring including ECG assessment is recommended.

Description:

See Summary

Do Not Coadminister

Apalutamide

Cisapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cisapride is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease cisapride concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with cisapride. Therefore, coadministration should be avoided. Furthermore, coadministration of cisapride with other drugs that prolong the QTc interval, such as apalutamide, should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and may significantly decrease concentrations of citalopram. Coadministration of omeprazole (a sensitive CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with citalopram. Furthermore, apalutamide and citalopram potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clarithromycin is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease clarithromycin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with clarithromycin. Clarithromycin is also an inhibitor of CYP3A4 (strong) and P-gp and may increase concentrations of apalutamide. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change in the AUC of apalutamide and its active metabolites. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase was 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and clarithromycin potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Clavulanic acid

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Clemastine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clemastine is predominantly metabolised in the liver via CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clindamycin is metabolised by CYP3A4. In vitro data suggest that clindamycin is also a CYP3A4 inhibitor, which could increase apalutamide concentrations. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and may significantly decrease clindamycin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with clindamycin. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Clobetasol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Apalutamide

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Clofazimine is largely excreted unchanged in the faeces. Apalutamide does not interact with this elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor and may increase concentrations of apalutamide. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide and clofazimine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Clofibrate

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not inhibit or induce OAT1.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but 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 metabolised by CYP2D6. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and may decrease concentrations of clomipramine. However, induction of CYP3A4 and CYP2C19 will increase concentrations of the active metabolite, desmethylclomipramine, which may outweigh the decrease of clomipramine concentrations. The effect of apalutamide on the sum concentration of clomipramine and desmethylclomipramine is unknown. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 and CYP3A4 should be considered. Close monitoring of clomipramine efficacy and toxicity is recommended. A dose increase or decrease may be necessary to achieve comparable efficacy. Furthermore, apalutamide and clomipramine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Clonidine

Quality of Evidence: Very Low

Summary:

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 also a weak inhibitor of OCT2. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clopidogrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Apalutamide is a strong inducer of CYP3A4 and CYP2C19. Coadministration of midazolam (a CYP3A4 substrate) and apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (a CYP2C19 substrate) and apalutamide decreased omeprazole AUC by 85%. Concentrations of the active metabolite of clopidogrel may significantly increase due to induction of CYP3A4 and CYP2C19 by apalutamide. As a result, a supratherapeutic effect may occur. Coadministration should be avoided. In addition, apalutamide is a moderate inducer and inhibitor of CYP2B6 in vitro. The clinical relevance of this interaction is unknown. Clopidogrel is also an inhibitor of CYP2C8 (strong) and may increase apalutamide concentrations. Coadministration of gemfibrozil, a strong CYP2C8 inhibitor, with a single dose of apalutamide increased apalutamide AUC by 68%. A simulation study predicted gemfibrozil to increase the steady state apalutamide AUC by 44%. However, for the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by 23%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clorazepate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease nordiazepam concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nordiazepam. However, oxazepam concentrations may increase due to induction of CYP3A4. Therefore, the effect of apalutamide on the efficacy of clorazepate is unknown and coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Cloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Apalutamide is an inhibitor of the renal transporters OCT2/ MATE1 and MATE-2K in vitro. As the clinical relevance of this interaction is unknown, monitoring for cloxacillin toxicity may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Clozapine

Quality of Evidence: Very Low

Summary:

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. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may decrease concentrations of clozapine. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with clozapine. Furthermore, apalutamide and clozapine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG. If coadministration is clinically necessary, close monitoring of clozapine efficacy is recommended. A dose increase of clozapine may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Codeine

Quality of Evidence: Very Low

Summary:

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). Apalutamide may be an inducer of UGT and may decrease morphine exposure and increase morphine-6-glucuronide exposure. The clinical relevance of UGT induction is unknown. Additionally, the metabolite morphine is a substrate of P-gp. Apalutamide is a weak inducer of P-gp. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with morphine. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease concentrations of codeine. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with codeine. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Colchicine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease colchicine exposure. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with colchicine. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Cycloserine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Apalutamide

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dabigatran is transported via P-gp and is renally excreted. Apalutamide is a weak inducer of P-gp and may decrease dabigatran concentrations. Coadministration of fexofenadine (a P-gp substrate) and apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with dabigatran. Care should be taken. Monitoring of dabigatran efficacy via ecarine clotting time (ECT) or diluted thrombin time (dTT) is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Dalteparin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation and is via multiple CYP450 enzymes. Apalutamide is a strong inducer of CYP3A4 and CYP2C19, and a weak inducer of CYP2C9, and may decrease dapsone concentrations. However, as multiple CYP enzymes are involved the clinical relevance of this interaction is unknown. Therefore, coadministration should be approached with caution. If coadministration is clinically necessary, close monitoring of dapsone efficacy is recommended. A dose increase of dapsone may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Desipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Desipramine is metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6. However, caution should be taken when using desipramine with drugs that are known to prolong the QT interval. Apalutamide and desipramine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Desogestrel

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP2C19 and CYP3A4. Concentrations of the active metabolite etonogestrel may increase due to induction of CYP2C9 and decrease due to induction of CYP3A4. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with desogestrel. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied and should be avoided. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease apalutamide plasma concentrations. However, the clinical relevance of this interaction is not known. Moreover, the induction of CYP3A4 by dexamethasone has not been established yet. Furthermore, dexamethasone is a substrate of CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease dexamethasone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with dexamethasone. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Dextropropoxyphene is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease dextropropoxyphene concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with alfentanil. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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). Additionally, morphine is a substrate of P-gp. Apalutamide is a weak inducer of P-gp and may be an inducer of UGT. Therefore, apalutamide may decrease exposure to diamorphine and increase exposure to morphine. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with morphine. Care should be taken. Monitoring for morphine efficacy and toxicity is recommended.

Description:

See Summary

Do Not Coadminister

Apalutamide

Diazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may decrease concentrations of diazepam. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with diazepam. However, concentrations of the active metabolites, nordiazepam and temazepam, will increase due to induction of CYP3A4 and CYP2C19. Therefore, the effect of apalutamide on the efficacy of diazepam is unknown and coadministration should be avoided.

Description:

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Potential Interaction

Apalutamide

Diclofenac

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may be an inducer of UGT. Therefore, apalutamide may decrease diclofenac exposure. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with diclofenac. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of diclofenac efficacy is recommended. A dose increase of diclofenac may be necessary to achieve comparable efficacy.

Description:

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Potential Weak Interaction

Apalutamide

Digoxin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Digoxin is eliminated renally via OATP4C1 and P-gp. Apalutamide is a weak inducer of P-gp and may decrease digoxin concentrations. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with digoxin. Care should be taken. Monitoring of digoxin efficacy and, if available, digoxin plasma concentrations is recommended.

Description:

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Potential Weak Interaction

Apalutamide

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Apalutamide is a strong CYP3A4 inducer and may be an inducer of UGT. Since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely. The clinical relevance of UGT induction is unknown. Care should be taken when apalutamide is coadministered with dihydrocodeine. Monitoring of dihydrocodeine efficacy is recommended.

Description:

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Do Not Coadminister

Apalutamide

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Diltiazem is metabolised by CYP3A4 and CYP2D6. Diltiazem is also an inhibitor of CYP3A4 (moderate) and P-gp and may increase apalutamide concentrations. The clinical relevance of P-gp inhibition by diltiazem is unknown. Apalutamide and the active moiety N-desmethyl apalutamide are in vitro substrates for P-gp, but no clinically relevant effect of P-gp inhibition on apalutamide exposure is expected. Furthermore, strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. Therefore, no clinically relevant effect on apalutamide exposure is expected. However, apalutamide is a strong inducer of CYP3A4 and may significantly decrease diltiazem concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with diltiazem. Therefore, coadministration should be avoided.

Description:

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Potential Interaction

Apalutamide

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is also a weak inhibitor of CYP2D6. Apalutamide is a strong inducer of CYP2C19 and a weak inducer of CYP2C9 and may decrease concentrations of diphenhydramine. Although CYP2C9 and CYP2C19 metabolism are not major pathways, they may become clinically relevant due to induction by apalutamide. Furthermore, apalutamide and diphenhydramine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG. If coadministration is clinically necessary, close monitoring of diphenhydramine efficacy is recommended. A dose increase of diphenhydramine may be necessary to achieve comparable efficacy.

Description:

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Potential Weak Interaction

Apalutamide

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Apalutamide may be an inducer of UGT and may decrease exposure to dipyridamole. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with dipyridamole. Monitoring of dipyridamole efficacy is recommended.

Description:

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Potential Interaction

Apalutamide

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease disopyramide concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with disopyramide. If coadministration is clinically necessary, monitoring of disopyramide efficacy is recommended. A dose increase of disopyramide may be necessary to achieve comparable efficacy. In addition, apalutamide and disopyramide potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Potential Interaction

Apalutamide

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. 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%). Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT, and may decrease concentrations of dolasetron. The clinical relevance of UGT induction is unknown. The clinical relevance of CYP3A4 induction is also unknown as CYP3A4 mediated metabolism is only a minor pathway for dolasetron. Furthermore, apalutamide and dolasetron potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG. Monitoring of dolasetron efficacy is also recommended.

Description:

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Do Not Coadminister

Apalutamide

Domperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Domperidone is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease domperidone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with domperidone. Furthermore, apalutamide and domperidone potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Dopamine

Quality of Evidence: Very Low

Summary:

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 apalutamide, or to be affected if coadministered with apalutamide.

Description:

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Do Not Coadminister

Apalutamide

Doxazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Doxazosin is metabolised mainly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease doxazosin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with doxazosin. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Doxepin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but 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 metabolised by CYP2D6. Apalutamide is a strong inducer of CYP2C19 and may significantly decrease doxepin concentrations. However, concentrations of the active metabolite nordoxepin will increase which may outweigh the decrease of doxepin concentrations. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2C19 should be considered. If coadministration is clinically necessary, close monitoring for doxepin toxicity is recommended. A dose increase or decrease of doxepin may be necessary to achieve comparable efficacy.

Description:

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No Interaction Expected

Apalutamide

Doxycycline

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway. Between 40-60% of an administered dose can be accounted for in the urine.

Description:

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Do Not Coadminister

Apalutamide

Dronabinol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Dronabinol is mainly metabolised by CYP2C9 and to a lesser extent by CYP3A4. Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP3A4 and may significantly decrease concentrations of alosetron. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Similar effects may occur with dronabinol. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Drospirenone

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Drospirenone is metabolised to a minor extent via CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease drospirenone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with drospirenone. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Dulaglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases. Apalutamide does not interact with this metabolic pathway. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The clinical relevance of delayed absorption is considered to be limited.

Description:

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No Interaction Expected

Apalutamide

Duloxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Duloxetine is metabolised by CYP2D6 and CYP1A2. Apalutamide does not inhibit or induce these CYPs.

Description:

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Do Not Coadminister

Apalutamide

Dutasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Dutasteride is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease dutasteride concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with dutasteride. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Dydrogesterone

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Apalutamide is a strong inducer of CYP3A4 and may significantly decrease dydrogesterone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with dydrogesterone. Therefore, coadministration should be avoided.

Description:

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Potential Weak Interaction

Apalutamide

Edoxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp, and may decrease edoxaban exposure. The clinical relevance of this interaction is unknown, since CYP3A4 is only a minor metabolic pathway. 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, monitoring of anti-Xa activity is recommended.

Description:

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Potential Weak Interaction

Apalutamide

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Apalutamide is a moderate inhibitor of CYP2C8 in vitro and may be an inducer of UGT. Coadministration of pioglitazone (CYP2C8 substrate) with apalutamide decreased pioglitazone AUC by 18%. Therefore, no clinically relevant effect on eltrombopag exposure due to CYP2C8 inhibition is expected. However, as the clinical relevance of UGT induction by apalutamide is unknown, care should be taken. Monitoring of eltrombopag efficacy is recommended.

Description:

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No Interaction Expected

Apalutamide

Enalapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is eliminated renally (possibly via OATs). Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on enalapril exposure is expected.

Description:

See Summary

No Interaction Expected

Apalutamide

Enoxaparin

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Apalutamide

Eprosartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eprosartan is largely excreted in bile and urine as unchanged drug. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Ertapenem

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this elimination pathway.

Description:

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Do Not Coadminister

Apalutamide

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Erythromycin is a substrate of CYP3A4 and P-gp. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp and may increase concentrations of apalutamide. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. In addition, apalutamide is completely absorbed after oral administration, P-gp does not limit the absorption of apalutamide. No clinically relevant effect on apalutamide exposure is expected after coadministration with erythromycin. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease concentrations of erythromycin. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with erythromycin. Furthermore, apalutamide and erythromycin potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and may decrease escitalopram concentrations. Coadministration of omeprazole (a sensitive CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with escitalopram. Furthermore, apalutamide and escitalopram potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG. 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, close monitoring of escitalopram efficacy is recommended. A dose increase may be necessary to achieve comparable efficacy.

Description:

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Do Not Coadminister

Apalutamide

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Esomeprazole is also an inhibitor of CYP2C19. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may significantly decrease esomeprazole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with esomeprazole. Therefore, coadministration should be avoided. Note: No clinically significant effect of gastric pH increasing drugs on apalutamide exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Estazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Estazolam is metabolised to its major metabolite 4-hydroxyestazolam via CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease estazolam concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with estazolam. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Estradiol

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT, and concentrations of estradiol may decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with estradiol. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Ethambutol

Quality of Evidence: Very Low

Summary:

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%). Apalutamide is unlikely to interact with this metabolic or elimination pathway.

Description:

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Do Not Coadminister

Apalutamide

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Apalutamide is a strong inducer of CYP3A4, a weak inducer of CYP2C9 and may be an inducer of UGT, and concentrations of ethinylestradiol may significantly decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ethinylestradiol. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Ethionamide

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Apalutamide

Etonogestrel

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Etonogestrel is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease etonogestrel concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with etonogestrel. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease everolimus exposure. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with everolimus. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Exenatide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Exenatide is cleared mainly by glomerular filtration. Apalutamide is unlikely to interact with this elimination pathway. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. The clinical relevance of delayed absorption is considered to be limited.

Description:

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Potential Weak Interaction

Apalutamide

Ezetimibe

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Apalutamide may be an inducer of UGT and may decrease exposure to ezetimibe. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with ezetimibe. Monitoring of ezetimibe efficacy is recommended.

Description:

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No Interaction Expected

Apalutamide

Famotidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on famotidine exposure is expected.

Description:

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Do Not Coadminister

Apalutamide

Felodipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Felodipine is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease felodipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with felodipine. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Fenofibrate

Quality of Evidence: Very Low

Summary:

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. In vitro data suggest that fenofibric acid inhibits OAT3. Apalutamide does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Apalutamide

Fentanyl

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fentanyl undergoes extensive CYP3A4 metabolism. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease fentanyl concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with fentanyl. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Fexofenadine

Quality of Evidence: Low

Summary:

Coadministration has been studied and care should be taken. Fexofenadine is a substrate of P-gp. Apalutamide is a weak inducer of P-gp. In prostate cancer patients (n=23), coadministration of fexofenadine (30 mg single dose, day 1 and 43) with apalutamide (240 mg once daily, day 15 to 42) decreased fexofenadine AUC by 30%. Care should be taken. Monitoring of fexofenadine efficacy is recommended.

Description:

See Summary

Do Not Coadminister

Apalutamide

Finasteride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Finasteride is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease finasteride concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with finasteride. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Fish oils

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Apalutamide

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. Apalutamide does not affect CYP2D6 at clinically relevant concentrations. Therefore, no effect on flecainide exposure is expected. However, apalutamide and flecainide potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Flucloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Apalutamide does not inhibit or induce OAT1. Flucloxacillin has been described as a CYP3A4 inducer, potentially decreasing apalutamide concentrations. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. However, no clinically relevant effect on apalutamide exposure is expected after coadministration with flucloxacillin.

Description:

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Potential Interaction

Apalutamide

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fluconazole is cleared primarily by renal excretion. Apalutamide is unlikely to interact with this elimination pathway. Fluconazole is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of apalutamide may increase due to CYP3A4 inhibition. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, caution should be taken when using fluconazole with drugs that are known to prolong the QT interval. Apalutamide and fluconazole potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Flucytosine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase (DPD) to an inactive metabolite. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Fludrocortisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease fludrocortisone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with fludrocortisone. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Flunitrazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may decrease concentrations of flunitrazepam, Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with flunitrazepam. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Fluoxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fluoxetine is mainly metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form the active metabolite norfluoxetine. Fluoxetine is also a strong inhibitor of CYP2D6 and CYP2C19. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9. Concentrations of fluoxetine may significantly decrease due to induction of CYPs 2C9, 2C19 and 3A4. However, concentrations of norfluoxetine may increase but the effect on the sum exposure is unknown. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring for fluoxetine toxicity is recommended. A dose increase or decrease may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Fluphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fluphenazine is metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6. However, caution should be taken when using fluphenazine with drugs that are known to prolong the QT interval. Apalutamide and fluphenazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Flurazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. The metabolism of flurazepam is most likely CYP-mediated. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9 and may decrease concentrations of flurazepam. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Fluticasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease fluticasone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with fluticasone. However, fluticasone is not used as systemic therapy, so a clinically relevant interaction is unlikely with the topical use of fluticasone.

Description:

See Summary

Potential Interaction

Apalutamide

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Fluvastatin also potentially inhibits CYP2C9, but the clinical relevance of CYP2C9 inhibition is unknown. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may significantly decrease fluvastatin concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Similar effects may occur after coadministration with fluvastatin. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of fluvastatin efficacy is recommended. A dose increase of fluvastatin may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Fluvoxamine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Apalutamide does not affect CYP2D6 and CYP1A2 at clinically relevant concentrations. No effect on fluvoxamine exposure is expected. However, fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). CYP3A4 inhibition by fluvoxamine may increase apalutamide exposure, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. Therefore, no clinically relevant effect on apalutamide exposure is expected after coadministration with fluvoxamine.

Description:

See Summary

No Interaction Expected

Apalutamide

Fondaparinux

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Formoterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation. As multiple CYP450 and UGT enzymes catalyse the transformation the potential for a pharmacokinetic interaction is low. Apalutamide is a strong inducer of CYP2C19, a weak inducer of CYP2C9 and may be an inducer of UGT and formoterol exposure may decrease. However, the systemic exposure of formoterol is low, and a clinically relevant interaction is unlikely.

Description:

See Summary

Do Not Coadminister

Apalutamide

Fosaprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. During treatment, aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of apalutamide. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of apalutamide may decrease due to induction of CYP3A4, but no clinically relevant effect on apalutamide exposure is expected. However, apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may significantly decrease aprepitant concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with aprepitant. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Fosphenytoin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is a weak inducer of CYP2C9 and strong inducer of CYP2C19 and may significantly decrease concentrations of phenytoin. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with phenytoin. Moreover, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of apalutamide may decrease due to CYP3A4 induction. A decrease in exposure can lead to decreased efficacy. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically necessary, closely monitor both phenytoin and apalutamide efficacy. Monitor phenytoin and apalutamide plasma concentrations, if available.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Furosemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. In vitro data indicate that furosemide is also an inhibitor of OAT1/OAT3. Apalutamide is an inhibitor of OAT3 in vitro, but no clinically significant effect on furosemide exposure is expected. However, apalutamide may also be an inducer of UGT and may decrease exposure to fosinopril. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with furosemide. Monitoring of furosemide efficacy is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Gabapentin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Apalutamide

Gemfibrozil

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and care should be taken. Gemfibrozil is metabolised by UGT2B7. Apalutamide may be an inducer of UGT and may decrease gemfibrozil exposure. The clinical relevance of this interaction is unknown. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9, but in vivo data showed no clinically relevant effect on CYP2C9. Moreover, gemfibrozil is an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. Concentrations of apalutamide may increase due to inhibition of CYP2C8 by gemfibrozil. In healthy male patients (n=15), coadministration of gemfibrozil (600 mg twice daily, day 1 to 32) with apalutamide (240 mg single dose, day 4) increased apalutamide AUC by 68%. A simulation study predicted gemfibrozil to increase apalutamide steady-state AUC by 44%. However, for the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by only 23%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations and gemfibrozil efficacy may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Gentamicin

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Gestodene

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, and may significantly decrease concentrations of gestodene. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ethinylestradiol. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Glibenclamide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may significantly decrease concentrations of glibenclamide. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with glibenclamide. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Gliclazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Gliclazide is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C19. Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP2C19 and may significantly decrease concentrations of glibenclamide. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. Coadministration of omeprazole (a sensitive CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with glibenclamide. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Glimepiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Glimepiride is mainly metabolised by CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease glimepiride concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur with glimepiride. Therefore, coadministration is not recommended. 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.

Description:

See Summary

Potential Interaction

Apalutamide

Glipizide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Glipizide is mainly metabolised by CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease glipizide concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur with glipizide. Therefore, coadministration is not recommended. 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.

Description:

See Summary

Do Not Coadminister

Apalutamide

Granisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease concentrations of granisetron. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide resulted in a decreased AUC by 30%. A similar effect may occur with granisetron. Furthemore, apalutamide and granisetron potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Grapefruit juice is known to inhibit CYP3A4 enzymes and may increase apalutamide concentrations. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase was 28%. The clinical relevance of this interaction is unknown. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Apalutamide

Griseofulvin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. However, griseofulvin is an inducer of liver enzymes, such as CYP3A4, and may decrease apalutamide concentrations. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Therefore, coadministration should be approached with caution. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 should be considered. If coadministration is unavoidable, closely monitor apalutamide efficacy and apalutamide plasma concentrations, if available. Dose increments of apalutamide should be considered.

Description:

See Summary

Do Not Coadminister

Apalutamide

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and may decrease concentrations of haloperidol. The clinical relevance of UGT induction is unknown. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with haloperidol. Furthermore, apalutamide and haloperidol potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG. If coadministration is clinically necessary, close monitoring of haloperidol efficacy is recommended. A dose increase of haloperidol may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Heparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro, coadministration with a modified heparin was synergistic and showed increased heparin efficacy. Heparin is thought to be eliminated via the reticuloendothelial system. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Hydralazine

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Concentrations of apalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. Therefore, no clinically relevant effect on apalutamide exposure is expected after coadministration with hydralazine.

Description:

See Summary

No Interaction Expected

Apalutamide

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

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. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant drug concentrations. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Apalutamide does not inhibit or induce OAT1.

Description:

See Summary

Do Not Coadminister

Apalutamide

Hydrocodone

Quality of Evidence: Very Low

Summary:

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. Apalutamide is a strong inducer of CYP3A4 and may decrease concentrations of hydrocodone and increase concentrations of norhydrocodone. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with hydrocodone. However, the net effect on the sum exposure of hydrocodone and its metabolites is unknown. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP3A4 should be considered.

Description:

See Summary

Do Not Coadminister

Apalutamide

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Hydrocortisone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease hydrocortisone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with hydrocortisone. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Hydrocortisone (topical)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Apalutamide

Hydromorphone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7. Apalutamide may be an inducer of UGT and may decrease hydromorphone concentrations. The clinical relevance of UGT induction is unknown. Care should be taken when apalutamide is coadministered with hydromorphone. Monitoring of hydromorphone efficacy is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys. Hydroxyurea is not a substrate of CYP enzymes or P-gp. Apalutamide is unlikely to interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease hydroxyzine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with hydroxyzine. Furthermore, apalutamide and hydroxyzine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Ibandronic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Apalutamide

Ibuprofen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Apalutamide is a weak inducer of CYP2C9 (in vivo), a moderate inhibitor of CYP2C8 (in vitro) and may be an inducer of UGT. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with ibuprofen. Therefore, coadministration is not recommended. If coadministration is unavoidable, close monitoring of ibuprofen efficacy is recommended. A dose increase of ibuprofen may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Iloperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Iloperidone is metabolised by CYP3A4 and CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease iloperidone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with iloperidone. Furthermore, apalutamide and iloperidone potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Imipenem/Cilastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and may decrease impramine concentrations. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with imipramine. Concentrations of the active metabolite desipramine may increase which may outweigh the decrease of imipramine concentrations. Furthermore, apalutamide and imipramine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Indapamide is extensively metabolised by CYP450s. Furthermore, OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Apalutamide is an inhibitor of OAT3 in vitro, but no clinically significant effect on indapamide exposure is expected. However, apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, and may decrease concentrations of indapamide. Apalutamide and indapamide may also potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Insulin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Interferon alpha

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Ipratropium bromide

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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Potential Interaction

Apalutamide

Irbesartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based should be approached with caution. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Apalutamide is a weak inducer of CYP2C9 and may be an inducer of UGT and may decrease concentrations of irbesartan. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with irbesartan. The clinical relevance of UGT induction is unknown. Therefore, coadministration is not recommended. If coadministration is clinically necessary, a dose increase of irbesartan may be necessary to achieve comparable efficacy.

Description:

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No Interaction Expected

Apalutamide

Iron supplements

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Apalutamide

Isoniazid

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

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Potential Interaction

Apalutamide

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Apalutamide is a strong inducer of CYP3A4 and may decrease isosorbide dinitrate concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with isosorbide dinitrate. The clinical relevance of this interaction is unknown. Therefore, coadministration should be approached with caution.

Description:

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Do Not Coadminister

Apalutamide

Itraconazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be avoided. Itraconazole is primarily metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Apalutamide is a strong inducer of CYP3A4 and may decrease itraconazole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with itraconazole. Therefore, coadministration should be avoided. Apalutamide concentrations may also increase due to inhibition of CYP3A4 by itraconazole. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. In healthy males (n=15), coadministration of itraconazole (200 mg daily, day 1 to 32) and apalutamide (240 mg single dose, day 4) caused no changes in the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and itraconazole potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Do Not Coadminister

Apalutamide

Ivabradine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ivabradine is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease ivabradine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ivabradine. Furthermore, apalutamide and ivabradine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Kanamycin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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Do Not Coadminister

Apalutamide

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied and should be avoided. Ketoconazole is a substrate of CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease ketoconazole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ketoconazole. Therefore, coadministration should be avoided. In addition, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of apalutamide may increase due to CYP3A4 inhibition. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and ketoconazole potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Potential Weak Interaction

Apalutamide

Labetalol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Apalutamide may be an inducer of UGT and may decrease exposure to labetalol. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with labetalol. Monitoring of labetalol efficacy may be required.

Description:

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Do Not Coadminister

Apalutamide

Lacidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Lacidipine is metabolised by CYP3A4. Lacidipine is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease lacidipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with lacidipine. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Lactulose

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Apalutamide

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may significantly decrease lansoprazole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. Similar effects may occur with lansoprazole. Therefore, coadministration should be avoided. Note: No clinically significant effect of gastric pH increasing drugs on apalutamide exposure is expected.

Description:

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Do Not Coadminister

Apalutamide

Lercanidipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Lercanidipine is mainly metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease lercanidipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with lercanidipine. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Levocetirizine

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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Potential Interaction

Apalutamide

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Apalutamide is an inhibitor of OCT2 in vitro and may increase levofloxacin exposure. As the clinical relevance of this interaction is unknown, monitoring for levofloxacin toxicity may be required. Furthermore, apalutamide and levofloxacin potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Potential Interaction

Apalutamide

Levomepromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Levomepromazine is metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6. However, caution should be taken when using levomepromazine with drugs that are known to prolong the QT interval. Apalutamide and levomepromazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Do Not Coadminister

Apalutamide

Levonorgestrel

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and may significantly decrease concentrations of levonorgestrel. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with levonorgestrel. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and may significantly decrease concentrations of levonorgestrel. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with levonorgestrel. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Levothyroxine

Quality of Evidence: Very Low

Summary:

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. Apalutamide may be an inducer of UGT. The clinical relevance of this interaction is unknown. However, no clinically relevant effect on levothyroxine exposure is expected.

Description:

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Potential Weak Interaction

Apalutamide

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Apalutamide is a strong inducer of CYP3A4 but does not affect CYP1A2. Due to induction, CYP3A4 may become a more prominent metabolic pathway at steady state. The clinical relevance of this interaction is unknown. Care should be taken. Monitoring of lidocaine efficacy may be required.

Description:

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Potential Interaction

Apalutamide

Linagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor metabolic pathway. Linagliptin is also a substrate of P-gp and a weak inhibitor of CYP3A4. Concentrations of apalutamide may increase due to CYP3A4 inhibition, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease concentrations of linagliptin. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with linagliptin. Since CYP3A4 is a minor pathway in linagliptin metabolism, the clinical relevance of this interaction is unknown. Coadministration is not recommended. If coadministration is clinically necessary, close monitoring of blood glucose levels is recommended. A dose increase of linagliptin may be necessary to achieve comparable efficacy.

Description:

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No Interaction Expected

Apalutamide

Linezolid

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Apalutamide

Liraglutide

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Apalutamide

Lisinopril

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Apalutamide

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Lithium is mainly eliminated unchanged through the kidneys. Apalutamide is unlikely to interact with this elimination pathway. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. However, caution should be taken when using lithium with drugs that are known to prolong the QT interval. Apalutamide and lithium potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Live vaccines

Quality of Evidence: Very Low

Summary:

Coadministration of live vaccines (such as BCG vaccine; measles, mumps, and rubella vaccines; varicella vaccines; typhoid vaccines; rotavirus vaccines; yellow fever vaccines; oral polio vaccine) has not been studied. In patients, who are receiving cytotoxics or other immunosuppressant drugs, use of live vaccines for immunisation is contraindicated. In patients receiving apalutamide, the use of live vaccines for immunisation is not contraindicated.

Description:

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Do Not Coadminister

Apalutamide

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Loperamide is mainly metabolised by CYP3A4 and CYP2C8 and is a substrate of P-gp. Apalutamide is a moderate inhibitor of CYP2C8 in vitro. Coadministration of pioglitazone (CYP2C8 substrate) with apalutamide decreased pioglitazone AUC by 18%. No clinically relevant effect due to CYP2C8 inhibition is expected on loperamide exposure. However, apalutamide is also a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease concentrations of loperamide. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with loperamide. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Loratadine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease loratadine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with loratadine. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Lorazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lorazepam undergoes non-CYP-mediated elimination. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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Potential Weak Interaction

Apalutamide

Lormetazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Lormetazepam is mainly glucuronidated. Apalutamide may be an inducer of UGT and may decrease concentrations of lormetazepam. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with lormetazepam. Monitoring of lormetazepam efficacy may be required.

Description:

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Potential Interaction

Apalutamide

Losartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Apalutamide is a weak inducer of CYP2C9 and may decrease losartan concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with losartan resulting in increased concentrations of the active metabolite. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring for losartan toxicity is recommended. A dose decrease of losartan may be necessary to achieve comparable efficacy.

Description:

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Do Not Coadminister

Apalutamide

Lovastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Lovastatin is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease lovastatin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with lovastatin. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Macitentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with macitentan. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Magnesium

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Maprotiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Maprotiline is mainly metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

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Do Not Coadminister

Apalutamide

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Medroxyprogesterone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease medroxyprogesterone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with medroxyprogesterone. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Medroxyprogesterone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease medroxyprogesterone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with medroxyprogesterone. Therefore, coadministration should be avoided.

Description:

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Potential Interaction

Apalutamide

Mefenamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Apalutamide is a weak inducer of CYP2C9 and may be an inducer of UGT. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with mefenamic acid. Therefore, coadministration is not recommended. If coadministration is unavoidable, close monitoring of mefenamic acid efficacy is recommended. A dose increase of mefenamic acid may be necessary to achieve comparable efficacy.

Description:

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No Interaction Expected

Apalutamide

Megestrol acetate

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Meropenem

Quality of Evidence: Very Low

Summary:

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. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on meropenem exposure is expected.

Description:

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No Interaction Expected

Apalutamide

Mesalazine

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Apalutamide

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Apalutamide is unlikely to interact with this pathway. Metamizole is a weak inducer of CYP3A4 and may decrease concentrations of apalutamide. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. However, no clinically relevant effect on apalutamide exposure is expected after coadministration with metamizole.

Description:

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Potential Weak Interaction

Apalutamide

Metformin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1, OCT2, OCT3, MATE1 and MATE2K. Apalutamide is an inhibitor of the renal transporters OCT2, MATE1 and MATE-2K in vitro. As the clinical relevance of this interaction is unknown, monitoring of blood glucose levels may be required.

Description:

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Do Not Coadminister

Apalutamide

Methadone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Methadone is demethylated by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease methadone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with methadone. Furthermore, apalutamide and methadone potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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No Interaction Expected

Apalutamide

Methyldopa

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methyldopa is excreted in urine largely by glomerular filtration, primarily unchanged and as the mono-O-sulfate conjugate. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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No Interaction Expected

Apalutamide

Methylphenidate

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Apalutamide

Methylprednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Methylprednisolone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease methylprednisolone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with methylprednisolone. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Apalutamide

Metoclopramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolised by the CYP450 system (mainly CYP2D6). Apalutamide does not inhibit or induce CYP2C6.

Description:

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No Interaction Expected

Apalutamide

Metolazone

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Apalutamide

Metoprolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoprolol is mainly metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

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No Interaction Expected

Apalutamide

Metronidazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Metronidazole is eliminated via glomerular filtration. Apalutamide is unlikely to interact with this elimination pathway. 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). Therefore, no clinically relevant effect on apalutamide exposure is expected.

Description:

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No Interaction Expected

Apalutamide

Mexiletine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mexiletine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Apalutamide does not affect CYP2D6 and CYP1A2 at clinically relevant concentrations. Therefore, no effect on mexiletine exposure is expected.

Description:

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Potential Interaction

Apalutamide

Mianserin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Mianserin is metabolised by CYP2D6 and CYP1A2, and to a lesser extent by CYP3A4. Apalutamide does not affect CYP2D6 and CYP1A2 at clinically relevant concentrations. However, apalutamide is a strong inducer of CYP3A4 and may decrease concentrations of mianserin. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of mianserin efficacy is recommended. A dose increase of mianserin may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Miconazole is extensively metabolised by the liver. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, and may decrease concentrations of miconazole. In addition, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of apalutamide may increase due to CYP3A4 inhibition. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and miconazole potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG. Note: after dermal application miconazole is only minimally absorbed. Therefore, no clinically relevant interaction is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Midazolam (oral)

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be avoided. Midazolam is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4. In prostate cancer patients (n=23), coadministration of apalutamide (240 mg daily, day 15 to 42) with midazolam (2 mg single oral dose, day 1 and 43) decreased midazolam AUC by 92%. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Midazolam (parenteral)

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be avoided. Midazolam is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4. Coadministration of oral midazolam with apalutamide decreased midazolam AUC by 92%. A similar effect is expected with parenteral midazolam. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Milnacipran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Milnacipran is mainly eliminated unchanged (50%), and as glucuronides (30%) and oxidative metabolites (20%). Apalutamide may be an inducer of UGT and may decrease concentrations of milnacipran. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with milnacipran. Monitoring of milnacipran efficacy is recommended.

Description:

See Summary

Do Not Coadminister

Apalutamide

Mirtazapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease mirtazapine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with mirtazapine. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of mirtazapine efficacy is recommended. A dose increase of mirtazapine may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Mometasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mometasone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 by no clinically relevant interactions are expected as mometasone is used topically.

Description:

See Summary

Potential Interaction

Apalutamide

Montelukast

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may decrease montelukast concentrations. The clinical relevance of this interaction is unknown as CYP3A4 and CYP2C9 are not major pathways. Therefore, caution should be taken if coadministered. If coadministration is clinically necessary, close monitoring of montelukast efficacy is recommended. A dose increase of montelukast may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Morphine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Additionally, morphine is a substrate of P-gp. Apalutamide is a weak inducer of P-gp and may be an inducer of UGT. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with morphine. Care should be taken. Monitoring of morphine efficacy is recommended.

Description:

See Summary

Potential Interaction

Apalutamide

Moxifloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Moxifloxacin is predominantly glucuronidated by UGT1A1. Apalutamide may be an inducer of UGT and may decrease moxifloxacin concentrations. The clinical relevance of this interaction is unknown. Monitoring of moxifloxacin efficacy is recommended. Furthermore, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as apalutamide. If coadministration is unavoidable, use with extreme caution.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3. Apalutamide is an inhibitor of OAT3 in vitro, but no clinically significant effect on mycophenolate exposure due to OAT3 inhibition is expected. However, apalutamide may be an inducer of UGT and may decrease exposure to mycophenolate. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with mycophenolate. Monitoring of mycophenolate plasma concentrations and efficacy is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Nadroparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Nandrolone

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Naproxen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Apalutamide is a weak inducer of CYP2C9 and may be an inducer of UGT. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with naproxen. Although naproxen has a wide therapeutic index, close monitoring of naproxen efficacy is recommended. A dose increase of naproxen may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nateglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP3A4 and may significantly decrease concentrations of nateglinide. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nateglinide. Therefore, coadministration should be avoided. If coadministration is clinically necessary, monitoring of blood glucose levels is recommended. A dose increase of nateglinide may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Nebivolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nebivolol metabolism involves CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nefazodone is metabolised mainly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease nefazodone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nefazodone. Therefore, coadministration should be avoided. In addition, nefazodone is a strong inhibitor of CYP3A4 and may increase apalutamide concentrations. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change in the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with ketoconazole, a strong CYP3A4 inhibitor, would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nicardipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Nicardipine is also a weak inhibitor of CYP3A4 and may increase apalutamide concentrations. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and a moderate inhibitor of CYP2C8 in vitro and may decrease concentrations of nicardipine. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nicardipine. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Nicotinamide (Niacinamide)

Quality of Evidence: Very Low

Summary:

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.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nifedipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nifedipine is metabolised mainly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease nifedipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nifedipine. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Nimesulide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nimesulide is extensively metabolised in the liver following multiple pathways including CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease nimesulide concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with nimesulide. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of nimesulide efficacy is recommended. A dose increase of nimesulide may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nisoldipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nisoldipine is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease nisoldipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nisoldipine. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Nitrendipine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nitrendipine is extensively metabolised mainly by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease nitrendipine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with nitrendipine. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Apalutamide may be an inducer of UGT and may decrease exposure to nitrofurantoin. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with nitrofurantoin. Monitoring of nitrofurantoin efficacy may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Norelgestromin

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Apalutamide is a strong inducer of CYP3A4 and may significantly decrease norelgestromin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with norelgestromin. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but care should be taken. Norethindrone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Apalutamide may be an inducer of UGT and may decrease exposure to norethisterone. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with norethisterone. Monitoring of norethisterone efficacy may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Norgestimate

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Do Not Coadminister

Apalutamide

Norgestrel

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT, and concentrations of levonorgestrel may significantly decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with levonorgestrel. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Nortriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Nortriptyline is metabolised mainly by CYP2D6. Apalutamide does not inhibit or induce CYP2D6. However, caution should be taken when using nortriptyline with drugs that are known to prolong the QT interval. Apalutamide and nortriptyline potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Nystatin

Quality of Evidence: Very Low

Summary:

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.

Description:

See Summary

Potential Interaction

Apalutamide

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Apalutamide is an inhibitor of the renal transporters OCT2/ MATE1 and MATE-2K in vitro. As the clinical relevance of this interaction is unknown, monitoring for ofloxacin toxicity may be required. However, caution should be taken when using levofloxacin with drugs that are known to prolong the QT interval. Apalutamide and ofloxacin potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Olanzapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Olanzapine is metabolised mainly by CYP1A2 (major pathway in CYP-mediated metabolism) and CYP2D6, but also by glucuronidation (UGT1A4). Apalutamide may be an inducer of UGT and may decrease exposure to olanzapine. The clinical relevance of UGT induction is unknown. Care should be taken when apalutamide is coadministered with olanzapine. Monitoring for olanzapine efficacy may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Olmesartan

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this metabolic or elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Omeprazole

Quality of Evidence: Low

Summary:

Coadministration has been studied and should be avoided. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and will significantly decrease concentrations of omeprazole. In prostate cancer patients (n=23), coadministration of apalutamide (240 mg daily, day 15 to 42) and omeprazole (40 mg single dose, day 1 and 43) decreased omeprazole AUC by 85%. Therefore, coadministration should be avoided. Note: No clinically significant effect of gastric pH increasing drugs on apalutamide exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Ondansetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ondansetron is a substrate of P-gp and is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease ondansetron concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with ondansetron. Furthermore, apalutamide and ondansetron potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Oxazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxazepam is mainly glucuronidated. Apalutamide may be an inducer of UGT and may decrease exposure to oxazepam. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with oxazepam. Monitoring of oxazepam efficacy may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cytosolic enzymes. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Concentrations of apalutamide may decrease due to CYP3A4 induction by oxcarbazepine and MHD. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. Therefore, no clinically relevant effect on apalutamide exposure is expected after coadministration with oxcarbazepine.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Oxprenolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Oxprenolol is largely metabolised via glucuronidation. Apalutamide may be an inducer of UGT and may decrease oxprenolol concentrations. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with oxprenolol. Monitoring of oxprenolol efficacy may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Oxycodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Apalutamide is a strong inducer of CYP3A4. Concentrations of oxycodone may significantly decrease due to induction of CYP3A4 and concentrations of noroxycodone may significantly increase. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with oxycodone. Therefore, coadministration should be avoided

Description:

See Summary

Potential Weak Interaction

Apalutamide

Paliperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Apalutamide is an inhibitor of OCT2 in vitro and may increase paliperidone exposure. In addition, apalutamide is a strong inducer of CYP3A4 and may decrease paliperidone concentrations. The clinical relevance of this interaction is unknown, since CYP3A4 is only a minor pathway. Therefore, monitoring for paliperidone efficacy and toxicity may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Palonosetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Palonosetron is a substrate of P-gp and is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease palonosetron concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with palonosetron. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Pamidronic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9, and may significantly decrease concentrations of pantoprazole. Coadministration of omeprazole (a CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with pantoprazole. Therefore, coadministration should be avoided. Note: No clinically significant effect of gastric pH increasing drugs on apalutamide exposure is expected.

Description:

See Summary

No Interaction Expected

Apalutamide

Para-aminosalicylic acid

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this metabolic or elimination pathway.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Paracetamol (Acetaminophen)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15), sulfation, and to a lesser extent by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Apalutamide may be an inducer of UGT and may decrease exposure to paracetamol. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with paracetamol. Monitoring of paracetamol efficacy may be required. Furthermore, apalutamide is a strong inducer of CYP3A4. Since CYP3A4 mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely.

Description:

See Summary

No Interaction Expected

Apalutamide

Paroxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paroxetine is mainly metabolised by CYP2D6. Moreover, paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Penicillins

Quality of Evidence: Very Low

Summary:

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). Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on penicillin exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Perazine is mainly metabolised by CYPs 1A2, 3A4 and 2C19, and to a lesser extent by CYPs 2C9, 2D6 and 2E1, with oxidation via FMO3. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and a weak inducer of CYP2C9 and may decrease concentrations of perazine. Coadministration of midazolam (a CYP3A4 substrate) and apalutamide decreased midazolam AUC by 92%. Coadministration of omeprazole (CYP2C19 substrate) and apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with perazine. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of perazine efficacy is recommended. A dose increase of perazine may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Periciazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of periciazine has not been well characterized but is likely to involve CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

See Summary

No Interaction Expected

Apalutamide

Perindopril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perindopril is hydrolysed to the active metabolite perindoprilat and is metabolised to other inactive metabolites. Elimination occurs predominantly via the urine. Apalutamide is unlikely to interact with this metabolic or elimination pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Perphenazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Perphenazine is metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6 at clinically relevant concentrations. However, caution should be taken when using perphenazine with drugs that are known to prolong the QT interval. Apalutamide and perphenazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. In vitro, apalutamide is a both a moderate inhibitor and inducer of CYP2B6. However, the clinical relevance of this interaction is unknown. Furthermore, apalutamide is a strong inducer of CYP3A4 and may decrease concentrations of pethidine. The net effect on pethidine is unknown. Care should be taken. No a priori dose adjustment for pethidine is necessary. Monitoring for pethidine toxicity and efficacy is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Phenelzine

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major pathway) and to a lesser extent by CYP2E1. Apalutamide is a strong inducer of CYP2C19 and a weak inducer of CYP2C9. Concentrations of phenobarbital may decrease significantly due to induction of CYP2C19 and CYP2C9 by apalutamide. Coadministration of omeprazole (a CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with phenobarbital. Moreover, phenobarbital is a strong inducer of CYP3A4, CYP2C9, CYP2C8 and UGTs. Concentrations of apalutamide may decrease due to induction of CYP3A4 and CYP2C8. A decrease in exposure can lead to decreased efficacy. The clinical relevance of this interaction is unknown. Coadministration should be avoided. 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, closely monitor both phenobarbital and apalutamide efficacy. Monitor phenobarbital and apalutamide plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Apalutamide

Phenprocoumon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Phenprocoumon is mainly metabolised by CYP2C9 and CYP3A4. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may significantly decrease phenprocoumon concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with phenprocoumon. Therefore, coadministration should be avoided. Note: After discontinuation of apalutamide, the effect of the interaction can persist for up to several weeks.

Description:

See Summary

Do Not Coadminister

Apalutamide

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Apalutamide is a weak inducer of CYP2C9 and strong inducer of CYP2C19 and may significantly decrease concentrations of phenytoin. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with phenytoin. Moreover, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of apalutamide may decrease due to CYP3A4 induction. A decrease in exposure can lead to decreased efficacy. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is clinically necessary, closely monitor both phenytoin and apalutamide efficacy. Monitor phenytoin and apalutamide plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Apalutamide

Phytomenadione (Vitamin K)

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not inhibit or induce CYP4F2.

Description:

See Summary

Do Not Coadminister

Apalutamide

Pimozide

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be avoided. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease pimozide concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with pimozide. Therefore, coadministration should be avoided. Furthermore, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as apalutamide.

Description:

See Summary

No Interaction Expected

Apalutamide

Pindolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolised to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Apalutamide does not interact with these metabolic or elimination pathways.

Description:

See Summary

No Interaction Expected

Apalutamide

Pioglitazone

Quality of Evidence: Low

Summary:

Coadministration has been studied and a clinically significant interaction is unlikely. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Apalutamide is a moderate inhibitor of CYP2C8 in vitro, a strong inducer of CYP3A4 and a weak inducer of CYP2C9. In prostate cancer patients (n=23), coadministration of pioglitazone (15 mg single dose, day 8 and 50) with apalutamide (240 mg once daily, day 15 to 42) decreased pioglitazone AUC by 18%. Therefore, no clinically relevant effect on pioglitazone exposure is expected.

Description:

See Summary

Potential Interaction

Apalutamide

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Apalutamide does not inhibit or induce CYP2D6 at clinically relevant concentrations. However, caution should be taken when using pipotiazine with drugs that are known to prolong the QT interval. Apalutamide and pipotiazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Interaction

Apalutamide

Piroxicam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Piroxicam is primarily metabolised by CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease piroxicam concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with piroxicam. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of piroxicam efficacy is recommended. A dose increase of piroxicam may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Pitavastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pitavastatin is metabolised by UGT1A3 and UGT2B7 with minimal metabolism by CYP2C9 and CYP2C8. Pitavastatin is also a substrate of OATP1B1. Apalutamide is a weak inducer of CYP2C9 and OATP1B1 and may be an inducer of UGT, and may decrease concentrations of pitavastatin. The clinical relevance of UGT induction is unknown. Coadministration of rosuvastatin (a BCRP and OATP1B1 substrate) with apalutamide decreased rosuvastatin AUC by 41%. Similar effects may occur after coadministration with pitavastatin. If coadministration is clinically necessary, monitoring of pitavastatin efficacy is recommended. A dose increase of OATP1B1 may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Apalutamide is an inducer of P-gp and may be an inducer of UGT and may decrease concentrations of posaconazole. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with posaconazole. In addition, posaconazole is a strong inhibitor of CYP3A4 and may increase apalutamide concentrations. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and posaconazole potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

No Interaction Expected

Apalutamide

Potassium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on limited data available an interaction appears unlikely. Potassium is eliminated renally. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Prasugrel

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but 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. Apalutamide is a strong inducer of CYP3A4, CYP2C19 and a weak inducer of CYP2C9. In addition, apalutamide is a moderate inducer and inhibitor of CYP2B6. Concentrations of the active metabolite of prasugrel may increase due to induction of CYPs 3A4, 2C19, 2C9 and 2B6 by apalutamide. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with prasugrel. Therefore, a supratherapeutic effect may occur and coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Pravastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Apalutamide is a weak inducer of OATP1B1 and may decrease pravastatin concentrations. Coadministration of rosuvastatin (a BCRP and OATP1B1 substrate) with apalutamide decreased rosuvastatin AUC by 41%. A similar effect may occur after coadministration with pravastatin. If coadministration is clinically necessary, monitoring of pravastatin efficacy is recommended. A dose increase of pravastatin may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Prazosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prazosin is extensively metabolised, primarily by demethylation and conjugation. Apalutamide may be an inducer of UGT and may decrease exposure to prazosin. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with prazosin. Monitoring of prazosin efficacy may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Prednisolone undergoes hepatic metabolism via CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease prednisolone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with prednisolone. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Prednisone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease prednisolone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with prednisolone. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Pregabalin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pregabalin is cleared mainly by glomerular filtration (90% as unchanged drug). Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Apalutamide is a strong inducer of CYP2C19 and may decrease prochlorperazine concentrations. Coadministration of omeprazole (a sensitive CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur after coadministration of prochlorperazine. Furthermore, apalutamide and prochlorperazine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Interaction

Apalutamide

Promethazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Promethazine is metabolised by CYP2D6. Apalutamide does not inhibit or induce CYP2D6. However, caution should be taken when using promethazine with drugs that are known to prolong the QT interval. Apalutamide and promethazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Interaction

Apalutamide

Propafenone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease propafenone concentrations. Since CYP3A4 is a minor pathway, the clinical relevance of this interaction is unknown. Therefore, coadministration is not recommended. If coadministration is unavoidable, close monitoring of propafenone efficacy is recommended. A dose increase of propafenone may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Propranolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but 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). Apalutamide is a strong inducer of CYP2C19 and may be an inducer of UGT, and concentrations of propranolol may significantly decrease. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with propranolol. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Prucalopride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Prucalopride is minimally metabolised and mainly eliminated renally, partly by active secretion by renal transporters. Prucalopride is also a substrate of P-gp. Apalutamide is a weak inducer of P-gp and may decrease concentrations of prucalopride. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with prucalopride. Care should be taken. Monitoring of prucalopride efficacy is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Pyrazinamide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Pyridoxine (Vitamin B6)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Quetiapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Quetiapine is primarily metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease quetiapine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with quetiapine. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Quinapril

Quality of Evidence: Very Low

Summary:

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. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on quinapril exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and P-gp, which may decrease quinidine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with quinidine. In addition, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Apalutamide concentrations may increase due to CYP3A4 inhibition, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. No clinically relevant effect on apalutamide exposure is expected after coadministration with quinidine. Apalutamide and quinidine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Interaction

Apalutamide

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Apalutamide is a strong inducer of CYP3A4 and CYP2C19 and may decrease rabeprazole concentrations. The clinical relevance of this interaction is unknown as CYP-mediated metabolism is not the major pathway in rabeprazole metabolism. Therefore, coadministration is not recommended. Note: No clinically significant effect of gastric pH increasing drugs on apalutamide exposure is expected.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Ramipril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Apalutamide may be an inducer of UGT and may decrease exposure to prazosin. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with prazosin. Monitoring of ramipril efficacy may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Ranitidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on ranitidine exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Ranolazine

Quality of Evidence: Very Low

Summary:

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. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of apalutamide may increase due to inhibition of CYP3A4, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease concentrations of ranolazine. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide, decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with ranolazine. Furthermore, apalutamide and ranolazine potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Reboxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Reboxetine is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease reboxetine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with reboxetine. Therefore, coadministration should be avoided. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4, but in vivo data showed no inhibitory effect on CYP3A4. No effect on apalutamide exposure is expected.

Description:

See Summary

Do Not Coadminister

Apalutamide

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. In vitro data indicate that apalutamide is a moderate inhibitor of CYP2C8, however this is clinically non relevant. In addition, apalutamide is a strong inducer of CYP3A4 and a weak inducer of OATP1B1 and repaglinide concentrations may decrease. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with repaglinide. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Retinol (Vitamin A)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. 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. Apalutamide may be an inhibitor of UGT and may decrease exposure to retinol. However, the clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with retinol. Monitoring for retinol efficacy may be required.

Description:

See Summary

No Interaction Expected

Apalutamide

Riboflavin (Vitamin B2)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Apalutamide is a strong CYP3A4 inducer and may significantly decrease rifabutin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with rifabutin. In addition, rifabutin is a strong CYP3A4 and P-gp inducer and may decrease concentrations of apalutamide. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Coadministration should be avoided. If coadministration is unavoidable, closely monitor apalutamide efficacy and apalutamide plasma concentrations, if available. Dose increments of apalutamide should be considered.

Description:

See Summary

Potential Interaction

Apalutamide

Rifampicin

Quality of Evidence: Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifampicin is metabolised via deacetylation. Apalutamide is unlikely to interact with this metabolic pathway. However, rifampicin is also a strong CYP3A4 and P-gp inducer, which may decrease apalutamide concentrations. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Therefore, coadministration should be approached with caution. If coadministration is unavoidable, closely monitor apalutamide efficacy and apalutamide plasma concentrations, if available. Dose increments of apalutamide should be considered.

Description:

See Summary

Potential Interaction

Apalutamide

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifapentine is metabolised via deacetylation. Apalutamide is unlikely to interact with this pathway. However, rifapentine is also a strong CYP3A4, CYP2C8 and P-gp inducer. Significant decreases in apalutamide plasma concentrations may occur due to induction of CYP3A4 and CYP2C8 by rifapentine. A decrease in exposure can lead to decreased efficacy. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. The clinical relevance of this interaction is unknown. Coadministration should be approached with caution. Selection of an alternate concomitant medicinal product, with no or minimal potential to induce CYP3A4 and CYP2C8 should be considered. If coadministration is unavoidable, closely monitor apalutamide efficacy and apalutamide plasma concentrations, if available. Dose increments of apalutamide should be considered.

Description:

See Summary

No Interaction Expected

Apalutamide

Rifaximin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Apalutamide

Risperidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Furthermore, risperidone is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease risperidone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased AUC by 30%. A similar effect may occur with risperidone. Due to induction, CYP3A4 may become a more prominent pathway at steady state. However, the clinical relevance of this interaction is unknown. Caution should be taken if coadministered. If coadministration is clinically necessary, monitoring of risperidone efficacy is recommended. A dose increase of risperidone may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is also a substrate of P-gp and BCRP. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease rivaroxaban concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with rivaroxaban. Therefore, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of anti-Xa activity is recommended.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Rosiglitazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. In vitro data indicate that apalutamide is a moderate inhibitor of CYP2C8, however this is considered to not be clinically relevant. In addition, apalutamide is a weak inducer of CYP2C9 and may decrease rosiglitazone concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with rosiglitazone. Care should be taken if coadministered. No a priori dose adjustment is necessary. However, monitoring of blood glucose levels should be considered.

Description:

See Summary

Potential Interaction

Apalutamide

Rosuvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has been studied should be approached with caution. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Apalutamide is a weak inducer of OATP1B1 and BCRP. In prostate cancer patients (n=23), coadministration of rosuvastatin (10 mg single dose, day 9 and 51) with apalutamide (240 mg once daily, day 15 to 42) decreased rosuvastatin AUC by 41%. If coadministration is clinically necessary, monitoring of rosuvastatin efficacy is recommended. A dose increase of rosuvastatin may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Salbutamol

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Salmeterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease salmeterol concentrations. However, the systemic exposure of salmeterol is low. Therefore, no clinically relevant effect is expected on salmeterol exposure.

Description:

See Summary

Do Not Coadminister

Apalutamide

Saxagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Saxagliptin is mainly metabolised by CYP3A4 and is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease saxagliptin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92% Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with saxagliptin. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Senna

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 the faeces, and also in other secretions. No clinically significant interactions are known.

Description:

See Summary

Do Not Coadminister

Apalutamide

Sertindole

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Sertindole is metabolised by CYP2D6 and CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease sertindole concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with sertindole. Furthermore, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as apalutamide

Description:

See Summary

Potential Interaction

Apalutamide

Sertraline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9 and may decrease sertraline concentrations. Apalutamide is also a moderate inducer and inhibitor of CYP2B6 in vitro. The clinical relevance of CYP2B6 induction and inhibition is unknown. Coadministration is not recommended. If coadministration is clinically necessary, close monitoring of sertraline efficacy is recommended. A dose increase of sertraline may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Sildenafil is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may significantly decrease sildenafil concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with sildenafil. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Simvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Simvastatin is metabolised by CYP3A4. Simvastatin is also a substrate of BCRP, and the active metabolite is a substrate of OATP1B1. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of OATP1B1 and BRCP, and and may decrease concentrations of simvastatin. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of rosuvastatin (a BCRP and OATP1B1 substrate) with apalutamide decreased rosuvastatin AUC by 41%. Similar effects may occur after coadministration with simvastatin. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Sirolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may significantly decrease everolimus exposure. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. Similar effects may occur with sirolimus. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Sitagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents a minor metabolic pathway. Apalutamide is an inhibitor of OAT3 in vitro, but no clinically significant effect on sitagliptin exposure due to OAT3 inhibition is expected. However, apalutamide is a strong CYP3A4 inducer and weak inducer of P-gp and may decrease sitagliptin exposure. Since CYP3A4 is a minor metabolic pathway, the clinical relevance of this interaction is unknown. Care should be taken, and monitoring of blood glucose levels is recommended.

Description:

See Summary

No Interaction Expected

Apalutamide

Sodium nitroprusside

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Sotalol

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is not recommended. Sotalol is excreted unchanged via renal elimination. Apalutamide is unlikely to interact with this elimination pathway. However, the product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval, such as apalutamide.

Description:

See Summary

No Interaction Expected

Apalutamide

Spectinomycin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Spironolactone

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Stanozolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Stanozolol undergoes hepatic metabolism. Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYPs 3A4 and 2C19. Stanozolol concentrations may significantly decrease due to the induction of these CYPs by apalutamide. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of stanozolol efficacy is recommended. A dose increase of stanozolol may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

St John's Wort

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. St John’s wort is a P-gp and CYP3A4 inducer and may decrease apalutamide concentrations. A decrease in exposure can lead to decreased efficacy. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. A simulation study predicted that coadministration with rifampicin (a strong CYP3A4 inducer) would decrease apalutamide steady-state AUC by 34%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC decreased by 19%. As the clinical relevance of this interaction is unknown, coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for apalutamide efficacy and apalutamide plasma concentrations, if available. Dose increments of apalutamide should be considered.

Description:

See Summary

No Interaction Expected

Apalutamide

Streptokinase

Quality of Evidence: Very Low

Summary:

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 apalutamide, or to be affected if coadministered with apalutamide.

Description:

See Summary

No Interaction Expected

Apalutamide

Streptomycin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Apalutamide

Sulfadiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Apalutamide is a weak inducer of CYP2C9 and may decrease sulfadiazine concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with sulfadiazine. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of sulfadiazine efficacy is recommended. A dose increase of sulfadiazine may be necessary to achieve comparable efficacy.

Description:

See Summary

Potential Interaction

Apalutamide

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Apalutamide does not interact with this elimination pathway. However, caution should be taken when using sulpiride with drugs that are known to prolong the QT interval. Apalutamide and sulpiride potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tacrolimus is metabolised mainly by CYP3A4. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Concentrations of apalutamide may increase due to CYP3A4 inhibition, but this is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and may significantly decrease tacrolimus exposure. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with tacrolimus. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tadalafil is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease tadalafil concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ranolazine. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Tamsulosin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tamsulosin is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease tamsulosin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with tamsulosin. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Tazobactam

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease telithromycin concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with telithromycin. Therefore, coadministration should be avoided. Furthermore, telithromycin is an inhibitor of CYP3A4 (strong) and may increase apalutamide concentrations. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolites. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increase was 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Telithromycin is also an inhibitor of P-gp, however no clinically relevant on apalutamide exposure is expected.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Telmisartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Telmisartan is mainly glucuronidated by UGT1A3. Apalutamide may be an inducer of UGT and may decrease exposure to telmisartan. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with telmisartan. Monitoring of telmisartan efficacy may be required.

Description:

See Summary

Potential Weak Interaction

Apalutamide

Temazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Temazepam is mainly glucuronidated. Apalutamide may be an inducer of UGT and may decrease exposure to temazepam. The clinical relevance of this interaction is unknown. Care should be taken when apalutamide is coadministered with temazepam. Monitoring of temazepam efficacy may be required.

Description:

See Summary

Do Not Coadminister

Apalutamide

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Apalutamide is a strong inducer of CYP3A4 and CYP2C19, a weak inducer of CYP2C9 in vivo and an inhibitor of CYP2C8 in vitro. Concentrations of terbinafine may decrease significantly due to induction CYP2C9 and CYP3A4. Coadministration should be avoided. If coadministration is clinically necessary, close monitoring of terbinafine efficacy is recommended. A dose increase of terbinafine may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Testosterone

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Testosterone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease testosterone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with testosterone. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Tetracycline

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Theophylline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Theophylline is mainly metabolised by CYP1A2. Apalutamide does not inhibit or induce CYP1A2.

Description:

See Summary

No Interaction Expected

Apalutamide

Thiamine (Vitamin B1)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Apalutamide

Thioridazine

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease thioridazine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Since CYP3A4 may become more important due to induction in the metabolism of thioridazine, a similar effect may occur with thioridazine. Furthermore, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as apalutamide.

Description:

See Summary

Potential Interaction

Apalutamide

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tiapride is excreted largely unchanged in urine. Apalutamide is unlikely to interact with this elimination pathway. However, caution should be taken when using tiapride with drugs that are known to prolong the QT interval. Apalutamide and tiapride potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ticagrelor is a substrate of CYP3A4 and P-gp. Ticagrelor is also a weak inhibitor of CYP3A4 and may increase apalutamide concentrations. This is unlikely to be clinically significant since strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of P-gp and may decrease ticagrelor concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur with ticagrelor. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Timolol

Quality of Evidence: Very Low

Summary:

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. Apalutamide does not inhibit or induce CYP2D6.

Description:

See Summary

No Interaction Expected

Apalutamide

Tinzaparin

Quality of Evidence: Very Low

Summary:

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. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

Potential Interaction

Apalutamide

Tolbutamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C8 and CYP2C19. In vitro data indicate that apalutamide is a moderate inhibitor of CYP2C8, however this is considered not to be clinically relevant. Apalutamide is also a weak inducer of CYP2C9 and a strong inducer of CYP2C19 and may decrease tolbutamide concentrations. Therefore, coadministration is not recommended. 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.

Description:

See Summary

Do Not Coadminister

Apalutamide

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Apalutamide does not inhibit or induce CYP2D6. However, apalutamide is a strong inducer of CYP3A4 and may significantly decrease tolterodine concentrations. Therefore, coadministration should be avoided. In addition, apalutamide and tolterodine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Potential Interaction

Apalutamide

Torasemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Torasemide is metabolised mainly by CYP2C9. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Apalutamide is an inhibitor of OAT3 in vitro, but no clinically significant effect on torasemide exposure is expected. However, apalutamide is a weak inducer of CYP2C9 and may decrease torasemide concentrations. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with torasemide. Therefore, coadministration is not recommended. If coadministration is clinically necessary, close monitoring of torasemide efficacy is recommended. A dose increase of torasemide may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Apalutamide is a strong inducer of CYP3A4 and a moderate inducer and inhibitor of CYP2B6 in vitro. Apalutamide may decrease tramadol concentrations due to CYP3A4 and CYP2B6 induction and may increase tramadol concentrations due to CYP2B6 inhibition. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with tramadol. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Apalutamide

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trandolapril is hydrolysed to trandolaprilat. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Tranexamic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Apalutamide

Tranylcypromine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tranylcypromine is hydroxylated and acetylated. Apalutamide does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Apalutamide

Trazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Trazodone is primarily metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease trazodone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with trazodone. Furthermore, apalutamide and trazodone potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

See Summary

Do Not Coadminister

Apalutamide

Triamcinolone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Triamcinolone is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease triamcinolone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with triamcinolone. Therefore, coadministration should be avoided.

Description:

See Summary

Do Not Coadminister

Apalutamide

Triazolam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Triazolam is metabolised by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease triazolam concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with triazolam. Therefore, coadministration should be avoided.

Description:

See Summary

Potential Interaction

Apalutamide

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP-enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may decrease trimethoprim concentrations. Since metabolism by CYP enzymes is a minor pathway, no clinically significant effect is expected. Trimethoprim is also a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Concentrations of apalutamide may increase due to inhibition of CYP2C8 but this is unlikely to be clinically significant since strong CYP2C8 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. However, sulfamethoxazole is metabolised by and is a weak inhibitor of CYP2C9. Apalutamide is a weak inducer of CYP2C9 and may decrease concentrations of sulfamethoxazole. Coadministration of single dose S-warfarin (a sensitive CYP2C9 substrate) with apalutamide decreased S-warfarin AUC by 46%. A similar effect may occur after coadministration with sulfamethoxazole. Coadministration is not recommended. If coadministration is clinically necessary, close monitoring of sulfamethoxazole efficacy is recommended when coadministered with apalutamide. A dose increase of sulfamethoxazole may be necessary to achieve comparable efficacy.

Description:

See Summary

No Interaction Expected

Apalutamide

Trimipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trimipramine is metabolised mainly by CYP2D6. Apalutamide does not inhibit or induce CYP2D6.

Description:

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Potential Interaction

Apalutamide

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Tropisetron is a substrate of P-gp and is metabolised mainly by CYP2D6. Apalutamide is a weak inducer of P-gp and may decrease concentrations of fexofenadine. Coadministration of fexofenadine (a P-gp substrate) with apalutamide resulted in a decreased AUC by 30%. A similar effect may occur with tropisetron. Furthermore, apalutamide and tropisetron potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Description:

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Do Not Coadminister

Apalutamide

Ulipristal

Quality of Evidence: Very Low

Summary:

If apalutamide is used for treatment of hormone-sensitive cancer coadministration is contraindicated. If used for hormone insensitive tumours the following information is applicable: Coadministration has not been studied but should be avoided. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease ulipristal concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with ulipristal. Therefore, coadministration should be avoided.

Description:

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Potential Interaction

Apalutamide

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Valproic acid is primarily metabolised by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolised by CYP2C9 and CYP2C19. Apalutamide is a strong inducer of CYP2C19, a weak inducer of CYP2C9 and a potential inducer of UGT and may decrease concentrations of valproic acid. The clinical relevance of this interaction is unknown as metabolism via CYP2C9 and CYP2C19 are only minor pathways. Monitoring of valproic acid efficacy and plasma concentrations is recommended. In addition, valproic acid is an inhibitor of CYP2C9. Apalutamide is not metabolised by CYP2C9.

Description:

See Summary

No Interaction Expected

Apalutamide

Valsartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valsartan is eliminated unchanged mostly through biliary excretion. Apalutamide is unlikely to interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Apalutamide

Vancomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vancomycin is excreted unchanged via glomerular filtration. Apalutamide is unlikely to interact with this elimination pathway.

Description:

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Potential Interaction

Apalutamide

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but is not recommended. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Apalutamide is a weak inducer of CYP2C9 and a strong inducer of CYP2C19 and CYP3A4. Concentrations of venlafaxine may significantly decrease due to induction of CYPs 2C9, 2C19 and 3A4 by apalutamide. Therefore, coadministration is not recommended. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYPs 2C19, 2C9 and 3A4 should be considered. If coadministration is clinically necessary, close monitoring of venlafaxine efficacy is recommended. A dose increase of venlafaxine may be necessary to achieve comparable efficacy.

Description:

See Summary

Do Not Coadminister

Apalutamide

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong). Apalutamide and the active moiety N-desmethyl apalutamide are in vitro substrates for P-gp, but no clinically relevant effect of P-gp inhibtion on apalutamide exposure is expected. Furthermore, strong CYP3A4 inhibitors only have a minor effect on the sum exposure of apalutamide and its active metabolite. Therefore, no clinically relevant effect on apalutamide exposure is expected. However, apalutamide is a strong inducer of CYP3A4 and a weak inducer of CYP2C9 and may decrease concentrations of verapamil. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with verapamil. Therefore, coadministration should be avoided.

Description:

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Potential Weak Interaction

Apalutamide

Vildagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Apalutamide is a weak inducer of P-gp and may decrease vildagliptin concentrations. Coadministration of fexofenadine (a P-gp substrate) with apalutamide decreased fexofenadine AUC by 30%. A similar effect may occur after coadministration with vildagliptin. Care should be taken, and monitoring of blood glucose levels is recommended.

Description:

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No Interaction Expected

Apalutamide

Vitamin E

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Apalutamide

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Voriconazole is metabolised by CYP2C19 (major pathway) and to a lesser extent by CYP3A4 and CYP2C9. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9. Concentrations of voriconazole may decrease due to induction of these CYPs by apalutamide. Coadministration of omeprazole (CYP2C19 substrate) with apalutamide decreased omeprazole AUC by 85%. A similar effect may occur with voriconazole. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Apalutamide concentrations may increase due to inhibition of CYP3A4. The effect of apalutamide is caused by the sum exposure of apalutamide and its active metabolite. Coadministration of itraconazole with a single dose of apalutamide in vivo resulted in no change of the AUC of apalutamide and its active metabolite. However, a simulation study predicted coadministration with the strong CYP3A4 inhibitor ketoconazole would increase the apalutamide steady-state AUC by 51%. For the active moieties (sum of unbound apalutamide plus the potency-adjusted unbound N-desmethyl apalutamide), the predicted steady-state AUC increased by 28%. No a priori dose adjustment is recommended. Monitoring for apalutamide toxicity and, if available, apalutamide plasma concentrations may be required. Furthermore, apalutamide and voriconazole potentially cause QTc interval prolongation. Coadministration should be avoided. If coadministration is unavoidable, monitor ECG.

Description:

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Potential Interaction

Apalutamide

Warfarin

Quality of Evidence: Low

Summary:

Coadministration has been studied and is not recommended. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Apalutamide is strong inducer of CYP3A4 and a weak inducer of CYP2C9. In prostate cancer patients (n=23), coadministration of S-warfarin (10 mg single dose, day 1 and 43) with apalutamide (240 mg once daily, day 15 to 42) decreased S-warfarin AUC by 46%. Therefore, coadministration is not recommended. If coadministration is clinically necessary, additional INR monitoring should be conducted. Note: After discontinuation of apalutamide, the effect of the interaction can persist for up to several weeks.

Description:

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No Interaction Expected

Apalutamide

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). Apalutamide may be an inducer of UGT and may decrease exposure to xipamide. However, since glucuronidation is only a minor pathway in xipamide metabolism, a clinically relevant interaction is unlikely. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Apalutamide is an inhibitor of OAT3 in vitro. However, no clinically significant effect on xipamide exposure is expected.

Description:

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Do Not Coadminister

Apalutamide

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. Apalutamide is a strong inducer of CYP3A4 and may decrease zaleplon concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with zaleplon. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Ziprasidone

Quality of Evidence: Low

Summary:

Coadministration has not been studied but is contraindicated. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Apalutamide is a strong inducer of CYP3A4 and may decrease ziprasidone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. Since CYP3A4 may become more important due to induction in the metabolism of ziprasidone, a similar effect may occur with ziprasidone. Furthermore, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval, such as apalutamide.

Description:

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No Interaction Expected

Apalutamide

Zoledronic acid

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Apalutamide

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 1A2. Apalutamide is a strong inducer of CYP2C19 and CYP3A4 and a weak inducer of CYP2C9, and may significantly decrease concentrations of zolpidem. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with zolpidem. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Apalutamide is a strong inducer of CYP3A4 and may decrease zopiclone concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with zopiclone. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Zotepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zotepine is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Apalutamide is a strong inducer of CYP3A4 and may significantly decrease zotepine concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with zotepine. Therefore, coadministration should be avoided.

Description:

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Do Not Coadminister

Apalutamide

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Apalutamide is a strong inducer of CYP3A4 and may be an inducer of UGT and may decrease zuclopenthixol concentrations. Coadministration of midazolam (a CYP3A4 substrate) with apalutamide decreased midazolam AUC by 92%. A similar effect may occur with zuclopenthixol. The clinical relevance of this interaction is unknown as zuclopenthixol is metabolised via multiple routes. However, coadministration should be avoided. If coadministration is clinically necessary, close monitoring of zuclopenthixol efficacy is recommended. A dose increase of zuclopenthixol may be necessary to achieve comparable efficacy.

Description:

See Summary