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

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

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

Coadministration has not been studied, but grapefruit juice is known to inhibit CYP3A4 and could potentially increase everolimus concentrations. However, the magnitude of this potential interaction is difficult to predict as the effect of grapefruit juice is concentration, dose and preparation dependent and varies widely across brands. Coadministration is not recommended. For patients with renal cell carcinoma, neuroendocrine tumour, mammacarcinoma or renal angiomyolipoma, consider a dose reduction from 10 mg/day to 5 mg/day and monitor everolimus trough plasma concentration to maintain a minimal trough concentration of ~14 µg/L. For patients with SEGA, consider a dose reduction of approximately 50%. The everolimus trough concentration should be assessed at least 1 week later. Dosing should be titrated to attain trough concentrations of 5-15 ng/ml.

Grapefruit juice is known to inhibit CYP3A4 enzymes and could potentially increase pazopanib concentrations. However, the magnitude of this potential interaction is difficult to predict as the effect of grapefruit juice is concentration-, dose- and preparation-dependent and varies widely across brands. The US product label for pazopanib advise to avoid coadministration with grapefruit juice.

Coadministration has not been studied. Tropisetron is metabolised mainly by CYP2D6 and is a substrate of P-gp. Enzalutamide is a moderate inducer of CYP2D6 and an inhibitor of P-gp in vitro. Concentrations of tropisetron may decrease due to induction of CYP2D6 but concentrations may also increase due to inhibition of P-gp. Therefore, coadministration should be avoided. If possible, selection of an alternate concomitant medicinal product, with no or minimal metabolism via CYP2D6 and P-gp should be considered. If coadministration is clinically necessary, close monitoring of tropisetron efficacy is recommended. A dose increase of tropisetron may be necessary to achieve comparable efficacy.

Coadministration has not been studied. Tropisetron is metabolized mainly by CYP2D6 and is a substrate of P-gp. Pazopanib is a weak inhibitor of CYP2D6 and may increase tropisetron concentrations. The clinical relevance of this interaction is unknown. Moreover, tropisetron may prolong the QT interval and pazopanib has been shown to prolong the QTc interval. Caution should be taken when using tropisetron with drugs that are known to prolong the QT interval. If coadministration is necessary, clinical monitoring including ECG assessment is recommended.

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

Coadministration has not been studied. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Capecitabine is an inhibitor of CYP2C9 and may increase concentrations of losartan, thus decreasing concentrations of the active metabolite. However, no formal interaction studies have been conducted. Therefore, the clinical relevance of this interaction is unknown. No a priori dose adjustment is needed, but monitoring for losartan toxicity may be required. Furthermore, losartan can cause renal insufficiency and may impair capecitabine elimination. Due to the risk of capecitabine toxicity, renal function should be monitored if coadministered.

Coadministration has not been studied. Tropisetron is metabolized mainly by CYP2D6. Everolimus does not inhibit of induce CYPs. However, tropisetron is substrate of P-gp and concentrations may potentially increase due to inhibition of P-gp by everolimus. No effect on everolimus concentrations is expected.

Coadministration has not been studied. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Pazopanib is a weak inhibitor of CYP2D6 and may increase concentrations of doxepine and nordoxepine. The clinical relevance of this interaction is unknown and monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tropisetron is metabolised mainly by CYP2D6. Tropisetron is also a substrate of P-gp. 5-fluorouracil does not inhibit or induce CYP2D6 or P-gp. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of fluorouracil. A thorough QT study has not been performed and the mechanism for the cardiotoxic effect is not fully understood. Therefore, it is unknown whether a warning is in place. ECG monitoring should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Both of these metabolic pathways are not affected by lorlatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4). Pazopanib is a weak inhibitor of CYP3A4 and may increase diazepam concentrations. However, since diazepam does not have a narrow therapeutic index, this is unlikely to be of clinical significance.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Pazopanib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Everolimus does not inhibit or induce CYPs. 

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolized to nordiazepam (by CYP3A4 and 2C19) and to temazepam (mainly by CYP3A4). Everolimus does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Everolimus does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. Doxepin and nordoxepin are also metabolised by CYP2D6. Cetuximab does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Cetuximab does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tropisetron is metabolised mainly by CYP2D6. Tropisetron is also a substrate of P-gp. Cetuximab does not inhibit or induce CYPs or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Grapefruit juice is a known inhibitor of CYP3A4. Cetuximab is not metabolised by CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Losartan is converted to its active metabolite mainly by CYP2C9 in the range of clinical concentrations. Cetuximab does not inhibit or induce CYP2C9.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxepin is metabolised to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. Doxepin and nordoxepin are also metabolised by CYP2D6. Capecitabine does not inhibit or induce CYP2C19 or CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolised to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Capecitabine does not inhibit or induce CYP3A4 or CYP2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tropisetron is metabolised mainly by CYP2D6 and is a substrate of P-gp. Capecitabine does not inhibit or induce CYP2D6 or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Grapefruit juice is a known inhibitor of CYP3A4. Capecitabine does not interact with this pathway.