Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amiodarone is metabolised by CYP3A4 and CYP2C8. 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). 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of amitriptyline. However, no formal interaction studies have been conducted. The clinical relevance of this interaction is unknown, but since CYP2C9 is a minor pathway no clinically relevant effect on amitriptyline exposure is expected. 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. 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 pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised but is eliminated to a large extent in the bile. 5-fluorouracil does not interfere with this elimination pathway. However, the European SPC for amphotericin B states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension. Monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. 5-fluorouracil does not inhibit or induce these CYPs. 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 pharmacokinetic interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Azithromycin is also an inhibitor of P-gp, but the clinical relevance of P-gp inhibition by azithromycin is unknown. 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Bedaquiline is metabolised by CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4 or CYP2D6. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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. Chloramphenicol is predominantly glucuronidated. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). 5-fluorouracil does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. 5-fluorouracil does not inhibit or induce CYP2D6 or CYP1A2. 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 pharmacokinetic 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. 5-fluorouracil is unlikely to interfere with this elimination pathway. However, in patients receiving cyclophosphamide, methotrexate and 5-fluorouracil, addition of thiazide diuretics resulted in a more pronounced decrease in the number of granulocytes when compared to patients not receiving thiazides. Therefore, care should be taken and due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is metabolised and partially cleared through the bile and intestine. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 should be approached with caution. Cisapride is metabolised by CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4. However, coadministration with other drugs that prolong the QTc interval should be avoided. 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. If coadministration is unavoidable monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). 5-fluorouracil does not inhibit or induce these CYPs. 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 pharmacokinetic interaction is unlikely. Clarithromycin is metabolised by CYP3A4 and is also an inhibitor of CYP3A4 (strong) and P-gp. 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces. In vitro data suggest that clofazimine is a CYP3A4 inhibitor. 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-fluorouracil. However, 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 pharmacokinetic interaction is unlikely. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce these CYPs. 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 should be avoided. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. 5-fluorouracil does not inhibit or induce these CYPs. However, due to the risk of additive haematological toxicity (especially agranulocytosis), coadministration should be avoided. If coadministration is unavoidable, closely monitor the haematological parameters. Furthermore, 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 if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Codeine is converted via CYP2D6 to morphine, an active metabolite with analgesic and opioid properties. Morphine is further metabolized by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Additionally, the metabolite morphine is a substrate of P-gp. 5-fluorouracil does not inhibit or induce these CYPs, UGTs or P-gp.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Desipramine is metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 is contraindicated if 5-fluorouracil is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but care should be taken. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase desogestrel concentrations and decrease etonogestrel concentrations. However, no formal interaction studies have been conducted. The clinical relevance of this interaction is unknown. No a priori dose adjustment is needed but monitoring of etonogestrel efficacy should be considered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of diphenhydramine. However, no formal interaction studies have been conducted. The clinical relevance of this interaction is unknown, but since CYP2C9 is a minor pathway, no clinically relevant effect on diphenhydramine exposure is expected. Diphenhydramine is also a weak inhibitor of CYP2D6. 5-fluorouracil does not interact with this pathway. 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. 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 pharmacokinetic interaction is unlikely. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. 5-fluorouracil does not interact with this metabolic or elimination pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. 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%). 5-fluorouracil does not interact with this metabolic pathway. 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 pharmacokinetic interaction is unlikely. Domperidone is mainly metabolised by CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4. 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 pharmacokinetic interaction is unlikely. Erythromycin is a substrate of CYP3A4 and P-gp. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp. 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. 5-fluorouracil does not inhibit or induce these CYPs. 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 pharmacokinetic interaction is unlikely. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. 5-fluorouracil does not inhibit or induce CYP2D6. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Fluconazole is cleared primarily by renal excretion and is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). 5-fluorouracil does not interact with this pathway. 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 pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 should be approached with caution. Fosphenytoin is rapidly converted to the active metabolite phenytoin. 5-fluorouracil does not interact with this metabolic pathway. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of phenytoin. No formal interaction studies have been conducted but two case reports observed an increased exposure to phenytoin after coadministration with 5-fluorouracil. If coadministration is unavoidable, monitor closely for phenytoin toxicity. Monitor phenytoin plasma concentrations, if available. Phenytoin is also a potent inducer of CYP3A4, UGT and P-gp. 5-fluorouracil is not a substrate of CYP3A4, UGT or P-gp.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. 5-fluorouracil does not inhibit or induce CYP3A4 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 pharmacokinetic interaction is unlikely. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). 5-fluorouracil does not inhibit or induce CYP3A4, CYP2D6 or UGTs. 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. Heparin is thought to be eliminated via the reticuloendothelial system. 5-fluorouracil does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydrochlorothiazide is not metabolised but is cleared by the kidneys via OAT1. 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. 5-fluorouracil does not inhibit or induce OATs. However, in patients receiving cyclophosphamide, methotrexate and 5-fluorouracil, addition of thiazide diuretics resulted in a more pronounced decrease in the number of granulocytes when compared to patients not receiving thiazides. Therefore, care should be taken and due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. 5-fluorouracil does not interact with this metabolic pathway. 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 pharmacokinetic interaction is unlikely. Iloperidone is metabolised by CYP3A4 and CYP2D6. 5-fluorouracil does not inhibit or induce CYP3A4 or CYP2D6. 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 pharmacokinetic interaction is unlikely. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce these CYPs. 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 pharmacokinetic interaction is unlikely. 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. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of indapamide. However, no formal interaction studies have been conducted. The clinical relevance of CYP2C9 inhibition is unknown but since indapamide is metabolized by multiple CYPs, no clinically relevant effect on indapamide exposure is expected. In patients receiving cyclophosphamide, methotrexate and 5-fluorouracil, addition of thiazide diuretics resulted in a more pronounced decrease in the number of granulocytes when compared to patients not receiving thiazides. Care should be taken and due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered. 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. 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 pharmacokinetic interaction is unlikely. Ivabradine is metabolised by CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4. 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 pharmacokinetic interaction is unlikely. Ketoconazole is a substrate of CYP3A4 and an inhibitor of CYP3A4 (strong) and P-gp. 5-fluorouracil does not interact with this pathway. 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 pharmacokinetic interaction is unlikely. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). 5-fluorouracil is unlikely to interfere with this elimination pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-fluorouracil. However, 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 pharmacokinetic interaction is unlikely. Levomepromazine is metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 is contraindicated if 5-fluorouracil is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. 5-fluorouracil does not inhibit or induce CYP3A4 or UGTs.

Coadministration is contraindicated if 5-fluorouracil is used for treatment of hormone-sensitive cancer. However, the use of levonorgestrel as emergency contraception is a relative contraindication due to the risk of a pregnancy while having a hormone sensitive tumour. Therefore, the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. 5-fluorouracil does not inhibit or induce CYP3A4 or UGTs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate and no pharmacokinetic interaction is expected. 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. Mesalazine is metabolised to N-acetyl-mesalazine by N-acetyltransferase. 5-fluorouracil does not interact with this metabolic pathway.

Coadministration has been studied but care should be taken. Metronidazole is eliminated via glomerular filtration. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. Metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). 5-fluorouracil does not interact with this pathway. However, after coadministration metronidazole increased the exposure of 5-fluorouracil due to decreased clearance, leading to increased haematological toxicity. If coadministration is unavoidable, haematological parameters should be monitored.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. 5-fluorouracil does not inhibit or induce UGTs. However, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval. 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-fluorouracil. However, 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 is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolised mainly by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 pharmacokinetic interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. 5-fluorouracil is unlikely to interfere with this elimination pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. 5-fluorouracil does not inhibit or induce these CYPs 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 pharmacokinetic interaction is unlikely. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Perphenazine is metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 should be approached with extreme caution. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. 5-fluorouracil does not inhibit or induce these CYPs. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval. 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. Extreme caution is advised if coadministered. Monitor ECG closely if coadministration is unavoidable.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. The metabolism of pipotiazine has not been well described but may involve CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 pharmacokinetic interaction is unlikely. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Posaconazole is also a strong inhibitor of CYP3A4. 5-fluorouracil does not interact with this pathway. 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. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. 5-fluorouracil does not inhibit or induce OATP1B1.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. 5-fluorouracil does not inhibit or induce CYP2D6 or CYP2C19. 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 pharmacokinetic interaction is unlikely. Promethazine is metabolised by CYP2D6. 5-fluorouracil does not inhibit or induce CYP2D6. 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 pharmacokinetic interaction is unlikely. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is a substrate of P-gp. Quinidine is also an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). 5-fluorouracil does not interact with this pathway. However, 5-fluorouracil showed significant QTc prolongation at high doses especially with continuous infusions of 5-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 pharmacokinetic interaction is unlikely. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is a substrate of P-gp and also a weak inhibitor of P-gp, CYP3A4 and CYP2D6. 5-fluorouracil does not interact with this pathway. 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 should be approached with extreme caution. Sertindole is metabolised by CYP2D6 and CYP3A4. 5-fluorouracil does not inhibit or induce CYP2D6 or CYP3A4. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval. 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. Extreme caution is advised if coadministered. Monitor ECG closely if coadministration is unavoidable.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sotalol is excreted unchanged via renal elimination. 5-fluorouracil is unlikely to interfere with this elimination pathway. However, the product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval. 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. Caution is advised if coadministered. Monitor ECG closely if coadministration is unavoidable.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. 5-fluorouracil is unlikely to interfere with this elimination pathway. 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. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of terbinafine. However, no formal interaction studies have been conducted. The clinical relevance of this interaction is unknown, but since multiple CYP enzymes are involved in this metabolic pathway, no clinically relevant effect on terbinafine exposure is expected. Terbinafine is also a moderate-strong inhibitor of CYP2D6. 5-fluorouracil is not metabolised by CYPs.

Coadministration has not been studied but should be approached with extreme caution. Thioridazine is metabolised by CYP2D6 and to a lesser extent by CYP3A4. 5-fluorouracil does not inhibit or induce CYP2D6 or CYP3A4. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval. 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. Extreme caution is advised if coadministered. Monitor ECG closely if coadministration is unavoidable.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tiapride is excreted largely unchanged in urine. 5-fluorouracil is unlikely to interfere with this elimination pathway. 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 pharmacokinetic interaction is unlikely. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. 5-fluorouracil does not inhibit or induce CYP2D6 or CYP3A4. 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 pharmacokinetic interaction is unlikely. Trazodone is primarily metabolised by CYP3A4. 5-fluorouracil does not inhibit or induce CYP3A4. 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 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 is contraindicated if 5-fluorouracil is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. 5-fluorouracil does not inhibit or induce these CYPs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Voriconazole is metabolised by CYP2C19 (major) and to a lesser extent by CYP3A4 and CYP2C9. 5-fluorouracil may be an inhibitor of CYP2C9 and may, therefore, increase concentrations of voriconazole. However, no formal interaction studies have been conducted. The clinical relevance of this interaction, but since CYP2C9 is a minor pathway no clinically relevant effect on voriconazole exposure is expected. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. 5-fluorouracil is not metabolised by CYPs. 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. It is unknown whether a warning is in place. ECG monitoring should be considered.

Coadministration has not been studied but should be approached with extreme caution. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). 5-fluorouracil does not interact with this pathway. However, the product labels for ziprasidone contraindicate its use in the presence of other drugs that prolong the QT interval. 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. Extreme caution is advised if coadministered. Monitor ECG closely if coadministration is unavoidable.