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.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolized by glucuronidation (by several UGTs, major UGT1A6). Lenvatinib 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. Agomelatine is metabolized predominantly via CYP1A2 (90%), with a small proportion metabolized by CYP2C9 and CYP2C19 (10%). Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied. Alendronate is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, alendronate should be separated from food or other medicinal products and patients must wait at least 30 minutes after taking alendronate before taking any other oral medicinal product. Osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients since the use of combined therapies consisting of nitrogen-containing bisphosphonates and antiangiogenic targeted agents. This suggests that angiogenesis suppression might increase the risk of osteonecrosis of the jaw when coadministered with bisphosphonates.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfentanil undergoes extensive CYP3A4 metabolism. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as alfuzosin is metabolized by CYP3A. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aliskiren is minimally metabolized and is mainly excreted unchanged in faeces. P-gp is a major determinant of aliskiren bioavailability, but this is not affected by lenvatinib.

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. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that alosetron is metabolized by CYPs 2C9, 3A4 and 1A2. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alprazolam is mainly metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Lenvatinib is unlikely to interfere with this metabolic pathway. Furthermore, aluminium hydroxide is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Lenvatinib does not inhibit or induce UGTs, CYPs or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amikacin is eliminated by glomerular filtration therefore no pharmacokinetic interaction is expected with lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amiloride is eliminated unchanged in the kidney. In vitro data indicate that amiloride is a substrate of OCT2. Lenvatinib is unlikely to significantly inhibit amiloride renal elimination.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amiodarone is metabolised by CYP3A4 and CYP2C8. Lenvatinib does not inhibit or induce CYPs. 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). Although lenvatinib is a substrate of CYP3A4, no clinically relevant effect on lenvatinib exposure is expected. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline. 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 clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally (possibly via OCT). Lenvatinib is unlikely to significantly impair amisulpride elimination. 

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. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amlodipine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Lenvatinib is unlikely to interfere with amoxicillin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolized but is eliminated to a large extent in the bile. Lenvatinib 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 clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20 to 40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60 to 80% is excreted in the urine within 6 hours. Lenvatinib is unlikely to significantly inhibit ampicillin renal elimination.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Apixaban is metabolized by CYP3A4 and to a lesser extent by CYP1A2, CYP2C8, CYP2C9 and CYP2C19. Lenvatinib does not inhibit or induce CYPs. Apixaban is a substrate of P-gp and BCRP which are not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Lenvatinib does not inhibit or induce CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Although lenvatinib is a substrate of CYP3A4, CYP3A4 mediated metabolism is only a minor pathway and a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Asenapine is metabolised by glucuronidation (UGT1A4) and oxidative metabolism (CYPs 1A2 (major), 3A4 (minor), 2D6 (minor)). Lenvatinib does not inhibit or induce UGTs or CYPs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Astemizole is metabolized by CYPs 2D6, 2J2 and 3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atorvastatin is metabolized by CYP3A4 and is a substrate of P-gp and OATP1B1. Lenvatinib does not inhibit or induce CYPs, P-gp or OATP1B1.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Azithromycin is also an inhibitor of P-gp. The clinical relevance of P-gp inhibition by azithromycin is unknown and no clinically relevant effect on lenvatinib exposure is expected. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. Lenvatinib does not interact with beclomethasone metabolism. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bedaquiline is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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 relevant drug interaction is unlikely in the range of observed clinical concentrations. In addition, there is no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes and therefore is unlikely to impact lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Betamethasone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as half of bezafibrate dose is eliminated unchanged in the urine. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1. Lenvatinib does not interact with this pathway. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolized by CYP3A4 and CYP2D6 and partly eliminated unchanged in the urine. Lenvatinib does not inhibit or induce CYPs. Bisoprolol is a substrate for P-gp which is not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9 and may decrease lenvatinib exposure. However, since CYP3A4 mediated metabolism is only a minor pathway for lenvatinib, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromazepam undergoes oxidative biotransformation. Drug-drug interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may play a role. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Budesonide is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buprenorphine undergoes both N-dealkylation to form norbuprenorphine (via CYP3A4) and glucuronidation (via UGT2B7 and UGT1A1). Lenvatinib does not inhibit or induce CYPs or UGTs. Buprenorphine is a substrate of P-gp which is not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolized by CYP2B6 and is a strong inhibitor of CYP2D6. Lenvatinib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Buspirone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Captopril is largely excreted in the urine by OAT1. Lenvatinib does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Lenvatinib does not inhibit or induce CYPs. Carbamazepine is also an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4. After coadministration with rifampicin, a strong CYP3A4 inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with carbamazepine. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent CYPs 2C9 and 1A2. Carvedilol is a substrate for P-gp. Lenvatinib does not inhibit or induce UGTs or CYPs and does not affect P-gp. 

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. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefalexin is predominantly eliminated unchanged renally by glomerular filtration and tubular secretion via OAT1 and MATE1. Lenvatinib does not interfere with cefalexin renal elimination.

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. Lenvatinib does not interfere with cefazolin renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as cefixime is renally excreted predominantly by glomerular filtration. Lenvatinib does not interfere with cefixime renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolized 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. Lenvatinib does not interfere with cefotaxime renal elimination.

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

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. Lenvatinib does not interfere with ceftriaxone renal elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolized by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine inhibits OCT2. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloramphenicol is predominantly glucuronidated. Lenvatinib does not inhibit or induce UGTs. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of lenvatinib may increase due to CYP3A4 inhibition, but a clinically relevant effect on lenvatinib exposure is not expected. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. Lenvatinib is unlikely to interfere with this elimination pathway. 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. Lenvatinib does not inhibit or induce OATs.

Coadministration has not been studied. Ciclosporin is substrate for CYP3A4 and P-gp. Lenvatinib does not inhibit or induce CYPs and does not affect P-gp. Ciclosporin inhibits CYP3A4 and OATP1B1 and could potentially increase lenvatinib concentrations, but this is unlikely to be clinically significant.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine is metabolised by CYPs. Lenvatinib does not inhibit or induce CYPs. Cimetidine is also a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, amongst others). Although cimetidine is an inhibitor of CYP3A4, no clinically relevant effect on lenvatinib exposure is expected. Cimetidine may decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine also inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Lenvatinib does not interact with this pathway.

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. Ciprofloxacin is metabolised and partially cleared through the bile and intestine. Lenvatinib does not interfere with this elimination pathway. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Lenvatinib does not interact with this pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Cisapride is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Furthermore, cisapride is unlikely to alter lenvatinib absorption. However, in a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms), but grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Citalopram is metabolized by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clarithromycin is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Clarithromycin is an inhibitor of CYP3A4 (strong) and P-gp and may slightly increase concentrations of lenvatinib, but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with clarithromycin. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolized (likely non CYP mediated pathway) and excreted in the urine by glomerular filtration. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clemastine is predominantly metabolized in the liver via CYP2D6. Lenvatinib is unlikely to interact with clemastine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In vitro data suggest that clindamycin is a CYP3A4 inhibitor and could increase lenvatinib concentrations, but this is unlikely to be clinically significant. No a priori dosage adjustment is recommended for lenvatinib. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces. Lenvatinib does not interfere with this elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor and could increase lenvatinib concentrations, but this is unlikely to be clinically relevant. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clomipramine is metabolized 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 metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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 form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2 but is unlikely to interact with lenvatinib elimination. In addition, lenvatinib does not interfere with clonidine elimination.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Lenvatinib does not inhibit or induce CYPs. Clopidogrel is also an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. The clinical relevance of CYP2C9 inhibition is unknown. Lenvatinib is not metabolised by these CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Lenvatinib 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. 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. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clozapine is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2C19 and CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline. Furthermore, 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 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). Morphine is also a substrate of P-gp. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Lenvatinib does not inhibit or induce CYPs, UGTs or P-gp.

Coadministration has not been studied but based on the metabolism and clearance a clinically significant interaction is unlikely. Colchicine is metabolized by CYP3A4 and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs and does not affect P-gp. 

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. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dabigatran is renally excreted and is a substrate of P-gp. Lenvatinib does not interact with this pathway.

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. Lenvatinib does not interfere with the renal excretion of dalteparin. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP450 enzymes. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Desipramine is metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possible CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Lenvatinib does not inhibit or induce these CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Dexamethasone is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Furthermore, dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease lenvatinib plasma concentrations. However, the induction of CYP3A4 by dexamethasone has not yet been established. Since CYP3A4 mediated metabolism is only a minor pathway in lenvatinib metabolism, this interaction is unlikely to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dextropropoxyphene is mainly metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diamorphine is rapidly metabolized by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Lenvatinib does not inhibit or induce UGTs or P-gp.

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. Lenvatinib 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. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidized by CYP2C9. Lenvatinib 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. Digoxin is eliminated renally via the renal transporters OATP4C1 and P-gp, which are not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dihydrocodeine undergoes predominantly direct glucuronidation, with CYP3A4 mediated metabolism accounting for only 5-10% of the overall metabolism. Lenvatinib 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. Diltiazem is metabolized by CYP3A4 and CYP2D6. Lenvatinib does not inhibit or induce CYPs. Diltiazem is also a moderate inhibitor of CYP3A4 and may slightly increase concentrations of lenvatinib. However, since CYP3A4 mediated metabolism is only a minor pathway for lenvatinib, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Diphenhydramine is mainly metabolized by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is also a weak inhibitor of CYP2D6. Lenvatinib does not interact with this pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Lenvatinib does not induce or inhibit UGTs. Although dipyridamole is an inhibitor of P-gp, no clinically significant effect on lenvatinib is expected

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. Lenvatinib does not interact with this metabolic pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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 metabolized by CYP2D6 (10-20%) and CYP3A4 (<1%). Lenvatinib does not inhibit or induce UGTs or CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Domperidone is mainly metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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 lenvatinib, or to be affected if co-administered with lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxazosin is metabolized mainly by CYP3A4. Lenvatinib 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 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. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40%-60% of an administered dose can be accounted for in the urine. Lenvatinib does not inhibit or induce CYPs. Therefore, a clinically significant pharmacokinetic interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied. Drospirenone is metabolized to a minor extent via CYP3A4. Lenvatinib does not inhibit or induce CYP3A4 and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is degraded by endogenous endopeptidases. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dutasteride is mainly metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied. Dydrogesterone is metabolized to dihydrodydrogesterone (possibly via CYP3A4). Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Lenvatinib 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. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1, UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Lenvatinib does not induce or inhibit UGTs or CYPs.

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). Lenvatinib does not interfere with this pathway.

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 excreted predominantly renally. Lenvatinib does not interact with this metabolic pathway.

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

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

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. Lenvatinib does not inhibit or induce CYPs or P-gp. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp and may slightly increase concentrations of lenvatinib, but this is unlikely to be clinically relevant. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Escitalopram is metabolized by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4, and is an inhibitor of CYP2C19. Lenvatinib does not interact with this pathway. Furthermore, esomeprazole is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estazolam is metabolized to its major metabolite 4-hydroxyestazolam via CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Lenvatinib does not inhibit or induce CYPs and UGTs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

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

Coadministration has not been studied. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Lenvatinib does not inhibit or induce CYPs and UGTs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method. 

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

Coadministration has not been studied. Etonogestrel is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYP3A4 or P-gp. In patients with metastatic renal cell carcinoma, coadministration of lenvatinib and everolimus showed increased progression free survival and manageable toxicity compared to everolimus alone. In another study with patients with metastatic renal cell carcinoma, coadministration of the maximum tolerated dose of lenvatinib and everolimus showed manageable toxicity in 18 patients. Since everolimus as an immunosuppressive drug is dosed much lower than as anticancer therapy no tolerability issues at reduced doses are expected. 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 clinically significant interaction is unlikely as exenatide is cleared mainly by glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ezetimibe is glucuronidated by UGTs 1A1 and 1A3 and to a lesser extent by UGTs 2B15 and 2B7. Lenvatinib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Lenvatinib does not inhibit or induce OATs. Furthermore, famotidine is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Felodipine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolyzed to an active metabolite, fenofibric acid. In vitro data suggest that fenofibric acid inhibits OAT3. Lenvatinib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl undergoes extensive CYP3A4 metabolism. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fexofenadine is a substrate of P-gp which is not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Finasteride is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flecainide is metabolized mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. Lenvatinib does not interact with this metabolic pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. Lenvatinib does not interact with this metabolic pathway. Flucloxacillin has been described as an inducer of CYP3A4, but this is unlikely to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluconazole is renally excreted. Lenvatinib does not interact with this elimination pathway. Fluconazole is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4 but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur with fluconazole. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase to an inactive metabolite. Lenvatinib does not interfere with this elimination pathway. However, 5-FU binds to the enzyme thymidylate synthase resulting in DNA damage. This mechanism occurs in all fast dividing cells including bone marrow cells, resulting in haematological toxicity. Lenvatinib also induces haematological toxicity which could be enhanced by the use of flucytosine. 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 clinically significant interaction is unlikely. Fludrocortisone is metabolized in the liver to inactive metabolites, possibly via CYP3A. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flunitrazepam is metabolized mainly via CYPs 3A4 and 2C19. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolised by CYP2D6 and CYP2C9 and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Fluoxetine is a strong inhibitor of CYP2D6 and CYP2C19. Lenvatinib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of flurazepam is most likely CYP-mediated. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Lenvatinib does not interact with this pathway.

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. Lenvatinib does not inhibit or induce CYPs. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4. However, no clinically relevant effect on lenvatinib exposure is expected.

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 eliminated predominantly renally. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation being another pathway. As multiple CYP450 and UGT enzymes catalyze the transformation the potential for a pharmacokinetic interaction is low. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Lenvatinib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Lenvatinib does not inhibit or induce CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Although lenvatinib is a substrate of CYP3A4, CYP3A4 mediated metabolism is only a minor pathway and a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Lenvatinib does not interact with this pathway. Phenytoin is also a potent inducer of CYP3A4, UGT and P-gp. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4 and P-gp. After coadministration with rifampicin, a strong CYP3A4 inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with fosphenytoin. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also renally eliminated unchanged (via OATs). 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. Lenvatinib does not inhibit or induce UGTs or OATs. In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3. Lenvatinib does not interact with this pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7. Gemfibrozil is also an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9 but in vivo data showed no clinically relevant effect on CYP2C9. Lenvatinib does not interact with this pathway.

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. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied. Gestodene is metabolized by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glibenclamide is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C19. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is mainly metabolized by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glipizide is mainly metabolized by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Granisetron is metabolized by CYP3A4 and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied. Grapefruit juice is known to inhibit CYP3A4 and may slightly increase concentrations of lenvatinib. However, since CYP3A4 mediated metabolism is only a minor pathway for lenvatinib, this is unlikely to be clinically relevant. Additionally, 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 has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely.

Coadministration has not been studied. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Lenvatinib does not interfere with this elimination pathway. However, griseofulvin is a liver microsomal enzyme inducer and may lower plasma levels, and therefore reduce the efficacy of concomitantly administered medicinal products that are metabolized by CYP3A4, such as lenvatinib.

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 and 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Lenvatinib does not inhibit or induce UGTs or CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. Lenvatinib does not interact with this metabolic pathway.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocodone is metabolised by CYP2D6 to hydromorphone and by CYP3A4 to norhydrocodone, both of which have analgesic effects. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocortisone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydromorphone is eliminated via glucuronidation, mainly by UGT2B7. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyurea is metabolized in the liver and cleared via the lungs and kidneys. Lenvatinib is unlikely to interact with this metabolic pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolized by alcohol dehydrogenase and partly by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied. 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. Osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients since the use of combined therapies consisting of nitrogen-containing bisphosphonates and antiangiogenic targeted agents. This suggests that angiogenesis suppression might increase the risk of osteonecrosis of the jaw when coadministered with bisphosphonates.

Coadministration has not been studies. However, based on metabolism and clearance a clinically significant interaction is unlikely. Ibuprofen is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Lenvatinib does not inhibit or induce CYPs or UGTs. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Iloperidone is metabolized by CYP3A4 and CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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, active tubular secretion. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Imipramine is metabolized by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Indapamide is extensively metabolised by CYPs. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Lenvatinib does not inhibit or induce CYPs or OATs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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

Coadministration has not been studied but based on metabolism and clearance a 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. Interleukin-2 is mainly eliminated by glomerular filtration. Lenvatinib is unlikely to interfere with this elimination pathway. 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 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. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolized by glucuronidation and oxidation (mainly CYP2C9). Significant interactions are not expected with lenvatinib. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest that CYP3A4 has a role in nitric oxide formation from isosorbide dinitrate. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Itraconazole is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYP3A4. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4 but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with itraconazole.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ivabradine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline. According to the product labels, the use of ivabradine in patients treated with QT prolonging medicinal products, like lenvatinib, should be avoided.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely as kanamycin is eliminated unchanged predominantly via glomerular filtration 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ketoconazole is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Furthermore, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4 but this is unlikely to be clinically relevant. Coadministration with ketoconazole increased lenvatinib AUC by 15%. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and 2B7). Lenvatinib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lacidipine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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. Lenvatinib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolized by CYP2C19 and to a lesser extent by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Furthermore, lansoprazole is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lercanidipine is mainly metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as 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. Lenvatinib does not interact with this elimination pathway.

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). Lenvatinib does not interact with this metabolic pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levomepromazine is metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied. Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Lenvatinib does not inhibit or induce CYPs and UGTs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Lenvatinib does not inhibit or induce CYPs or UGTs and a pharmacokinetic interaction is unlikely. However, the effect of lenvatinib on contraceptive efficacy has not been investigated.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levothyroxine is metabolized by deiodination (by enzymes of deiodinase family) and glucuronidation. Lenvatinib does not interact with levothyroxine metabolism. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. Furthermore, linagliptin is a weak inhibitor of CYP3A4 and may slightly increase concentrations of lenvatinib. However, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Linezolid undergoes non CYP mediated metabolism. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely as liraglutide is degraded by endogenous endopeptidases. 

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.

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, therefore no pharmacokinetic interaction is expected. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. If coadministration is judged clinically necessary, use with extreme caution since generalized infections can occur.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolized by CYP3A4 and CYP2C8 and is a substrate of P-gp. Lenvatinib 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. Loratadine is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Based on non-CYP-mediated elimination pathways for lorazepam, no effect on plasma concentrations is expected upon coadministration with lenvatinib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated. Lenvatinib does not inhibit or induce UGTs.

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. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lovastatin is metabolised by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Macitentan is metabolized mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Magnesium is eliminated in kidney, mainly by glomerular filtration. 

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

Coadministration has not been studied. Medroxyprogesterone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Medroxyprogesterone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolized by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Lenvatinib 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. Megestrol acetate is mainly eliminated in the urine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney and in vitro data suggest that it is a substrate of the renal transporters OAT3>OAT1. Lenvatinib does not interfere with this elimination pathway. 

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

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%). Lenvatinib is unlikely to interfere with this elimination pathway. Metamizole is also an inducer of CYP3A4 and may decrease lenvatinib concentrations. However, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Methadone is demethylated by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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. It is unlikely to affect the disposition of lenvatinib, or to be altered by coadministration with lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent and does not inhibit cytochrome P450s. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylprednisolone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metoclopramide is partially metabolized by CYP450 system (mainly CYP2D6). Lenvatinib does not interact with this metabolic pathway. 

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. Lenvatinib does not interact with this pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metronidazole is eliminated via glomerular filtration. Lenvatinib does not interfere with this elimination pathway. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, cyclosporine) with metronidazole, but metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with lenvatinib cannot be excluded. However, a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mexiletine is metabolized mainly by CYP2D6 and to a lesser extent CYP1A2. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mianserin is metabolized by CYPs 2D6 and 1A2, and to a lesser extent by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Miconazole is extensively metabolised by the liver. Lenvatinib is unlikely to interact with this unspecified metabolic pathway. However, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4 but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with miconazole. Dermal application: No a priori dosage adjustment is recommended for lenvatinib, since miconazole is used topically and systemic exposure is limited.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Midazolam is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Midazolam is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mometasone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Montelukast is mainly metabolized by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but morphine is mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Lenvatinib does not interact with this metabolic pathway. Morphine is a substrate of P-gp which is not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. Lenvatinib 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, such as lenvatinib. If coadministration is unavoidable, use with caution. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied, but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and 2B7. Lenvatinib does not interact with this metabolic pathway. In addition, inhibition of OAT1/OAT3 renal transporters by mycophenolic acid (active metabolite) is unlikely to interfere with lenvatinib elimination. 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 clinically significant interaction is unlikely. Nadroparin is renally excreted by a nonsaturable mechanism. Lenvatinib does not interact with this elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Lenvatinib 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. Nateglinide is mainly metabolized by CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Lenvatinib does not inhibit or induce CYPs. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nefazodone is metabolised mainly by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Nefazodone is also a strong inhibitor of CYP3A4 and may slightly increase concentrations of lenvatinib, but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with nefazodone.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Lenvatinib does not inhibit or induce CYPs. Nicardipine is also a weak inhibitor of CYP3A4 and may increase concentrations of lenvatinib. However, no clinically relevant effect on lenvatinib exposure is expected.

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 metabolized by xanthine oxidase and aldehyde oxidase. Lenvatinib does not interact with this metabolic pathway. In addition, nicotinic acid and its metabolites do not inhibit CYP-mediated reactions in vitro and therefore are unlikely to impact lenvatinib exposure.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nifedipine is metabolised mainly by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nimesulide is extensively metabolized in the liver following multiple pathways including CYP2C9. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nisoldipine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nitrendipine is extensively metabolized mainly by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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

Coadministration has not been studied. Norelgestromin is metabolized to norgestrel (possibly by CYP3A4). Lenvatinib does not inhibit or induce CYPs and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Lenvatinib does not interact with this metabolic pathway and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolized via CYP450. Lenvatinib does not interact with this metabolic pathway and a pharmacokinetic interaction is unlikely. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Lenvatinib does not inhibit or induce CYPs or UGTs. However, as the effect of lenvatinib on contraceptive efficacy has not been investigated, the European product label for lenvatinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolized mainly by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Lenvatinib is unlikely to interfere with this pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). Lenvatinib 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. Olmesartan medoxomil is de-esterified to the active metabolite olmesartan which is eliminated in the faeces and urine. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Omeprazole is also an inducer of CYP1A2 and inhibits CYP2C19. Lenvatinib does not interact with this pathway. Furthermore, omeprazole is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ondansetron is metabolized mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated. Lenvatinib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxcarbazepine is extensively metabolized to the active metabolite, monohydroxyderivate, through cystolic enzymes. Lenvatinib does not interact with this pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4. After coadministration with rifampicin, a strong CYP3A4 inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with oxcarbazepine. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolized via glucuronidation. Lenvatinib does not inhibit or induce UGTs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxycodone is metabolised principally to noroxycodone via CYP3A and oxymorphone via CYP2D6. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paliperidone is primarily eliminated renally (possibly via OCT) with minimal metabolism occurring via CYPs 2D6 and 3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Palonosetron is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2, and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs and does not affect P-gp. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients since the use of combined therapies consisting of nitrogen-containing bisphosphonates and antiangiogenic targeted agents. This suggests that angiogenesis suppression might increase the risk of osteonecrosis of the jaw when coadministered with bisphosphonates.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Lenvatinib does inhibit or induce CYPs. Furthermore, pantoprazole is unlikely to alter lenvatinib absorption.

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. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15) sulfation and to a lesser extent by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Lenvatinib 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. Paroxetine is mainly metabolised by CYP2D6. Paroxetine is an inhibitor of CYP2D6 (strong) and CYP2C9. Lenvatinib does not interact with this pathway.

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 clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Lenvatinib does not interfere with elimination of penicillins.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Lenvatinib does not inhibit or induce CYPs or FMO3.

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. Lenvatinib does not inhibit or induce CYPs.

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 metabolized to other inactive metabolites. Elimination occurs predominantly via the urine. Lenvatinib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Perphenazine is metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pethidine is metabolized mainly by CYP2B6 and to a lesser extent by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major) and to a lesser extent by CYP2E1. Lenvatinib does not inhibit or induce CYPs. Phenobarbital is also a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4. After coadministration with rifampicin, a strong CYP3A4 inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with phenobarbital. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Lenvatinib does not inhibit or induce CYPs. Phenytoin is also a potent inducer of CYP3A4, UGT and P-gp. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4 and P-gp. After coadministration with rifampicin, a strong CYP3A4 inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with phenytoin. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

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. Lenvatinib does not interact with this metabolic pathway. 

Coadministration has not been studied but is contraindicated. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline. The product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolized to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine. Lenvatinib is not expected to interfere with pindolol elimination. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolized mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Lenvatinib does not inhibit or induce CYPs. 

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. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piroxicam is primarily metabolized by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pitavastatin is metabolised by UGTs 1A3 and 2B7 with minimal metabolism by CYPs 2C9 and 2C8. Pitavastatin is also a substrate of OATP1B1. Lenvatinib does not inhibit or induce UGTs, CYPs or OATP1B1.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Posaconazole is metabolised primarily by UGTs and is a substrate of P-gp. Lenvatinib does not inhibit or induce UGTs or P-gp. Posaconazole is also a strong inhibitor of CYP3A4 and may slightly increase concentrations of lenvatinib, but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with posaconazole. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Lenvatinib does not inhibit or induce CYPs.

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. Lenvatinib does not inhibit or induce CYPs or OATP1B1.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prazosin is extensively metabolized, primarily by demethylation and conjugation. Lenvatinib is unlikely to interact with prazosin. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisolone undergoes hepatic metabolism via CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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). Lenvatinib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Promethazine is metabolized by CYP2D6. Lenvatinib does not inhibit or induce CYPs. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propafenone is metabolized mainly by CYP2D6 and to a lesser extent CYP1A2 and CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolized by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Lenvatinib does not interact with this metabolic pathway. 

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

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. Lenvatinib does not impact this renal transporter. 

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 also a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. Quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Although lenvatinib is a substrate of CYP3A4 and P-gp, no clinically relevant effect on lenvatinib exposure is expected. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYPs 2C19 and 3A4. Lenvatinib does not interact with this pathway. Furthermore, rabeprazole is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolized to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Lenvatinib is not expected to interfere with these metabolic pathways. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Lenvatinib does not inhibit or induce OATs. Furthermore, ranitidine is unlikely to alter lenvatinib absorption.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of ranolazine may slightly increase due to CYP3A4 inhibition, but no clinically relevant effect on lenvatinib exposure is expected. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Reboxetine is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolized by CYPs 2C8 and 3A4 and clinical data seem to indicate that it is a substrate of the hepatic transporter OATP1B1. Lenvatinib does not interact with this metabolic pathways. A human physiologically based pharmacokinetic (PBPK) model for coadministration of lenvatinib (24 mg or 32 mg once daily) and repaglinide (0.25 mg single dose) indicated no effect of lenvatinib on the AUC of repaglinide. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifabutin is metabolised by CYP3A and via deacetylation. Lenvatinib does not interact with this metabolic pathway. Rifabutin is also a strong CYP3A4 and P-gp inducer and may decrease lenvatinib concentrations. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with rifabutin. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

Rifampicin is metabolised via deacetylation and is also a strong CYP3A4 and P-gp inducer. Concentrations of lenvatinib may slightly decrease due to strong induction of CYP3A4 and P-gp. Coadministration in a phase I study showed minimal, but not clinically relevant, changes in lenvatinib exposure (lenvatinib AUC decreased by 18%).

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifapentine is metabolised via deacetylation and is also a strong CYP3A4, CYP2C8 and P-gp inducer. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4 and P-gp. After coadministration with rifampicin, a strong CYP3A4 and P-gp inducer, lenvatinib AUC decreased by 18%. A similar effect may occur after coadministration with rifapentine. Therefore, no clinically relevant effect on lenvatinib exposure is expected.

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. Rifaximin is a substrate of P-gp which is not affected by lenvatinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Risperidone is metabolized by CYP2D6 and to a lesser extent by CYP3A4 and is a substrate for P-gp. Lenvatinib does not inhibit or induce CYPs and does not affect P-gp. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Lenvatinib does not induce or inhibit CYPs, P-gp or BCRP.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosiglitazone is metabolized mainly by CYP2C8 and to a lesser extent by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Lenvatinib does not inhibit or induce OATP1B1 or BCRP.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Saxagliptin is mainly metabolized by CYP3A4 and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs and does not affect P-gp. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant pharmacokinetic 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 drug interactions are known. 

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sertindole is metabolized by CYP2D6 and CYP3A4. Lenvatinib does not inhibit or induce CYPs. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as lenvatinib. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms), but grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolized by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Lenvatinib does not inhibit or induce CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sildenafil is metabolized mainly by CYP3A4 and to a lesser extent by CYP2C9. Lenvatinib does not inhibit or induce CYPs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Simvastatin is metabolised by CYP3A4. Simvastatin is also a substrate of BCRP and the active metabolite is a substrate of OATP1B1. Lenvatinib does not inhibit or induce CYPs, OATP1B1 or BCRP.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sirolimus is metabolized by CYP3A4 and is a substrate of P-gp. Lenvatinib does not inhibit or induce CYPs or P-gp. 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 clinically significant interaction is unlikely. 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. Lenvatinib does not interact with this metabolic pathway.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sotalol is excreted unchanged via renal elimination. Lenvatinib is unlikely to interfere with this elimination pathway. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline. The product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval, such as lenvatinib.

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. Lenvatinib does not interact with this metabolic pathway. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Stanozolol undergoes hepatic metabolism. Lenvatinib does not interact with stanozolol metabolic pathway.

Coadministration has not been studied. Concentrations of lenvatinib may slightly decrease due to induction of CYP3A4 by St John’s wort. However, since CYP3A4 mediated metabolism is only a minor pathway in lenvatinib metabolism, this interaction is unlikely to be clinically relevant. Although St John’s wort is an inducer of P-gp, no clinically significant effect on lenvatinib is expected. 

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. Lenvatinib is unlikely to interfere with this pathway.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Streptomycin is eliminated by glomerular filtration therefore no pharmacokinetic interaction is expected with lenvatinib. 

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Lenvatinib does not interfere with sulfadiazine metabolism.

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. Lenvatinib is unlikely to significantly impair sulpiride elimination. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tacrolimus is metabolised mainly by CYP3A4. Lenvatinib does not inhibit or induce CYPs. Tacrolimus inhibits CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Concentrations of lenvatinib may slightly increase due to CYP3A4 inhibition, but this is unlikely to be clinically relevant. 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 clinically significant interaction is unlikely as tadalafil is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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. Lenvatinib does not inhibit or induce CYPs. 

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. Lenvatinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Lenvatinib does not inhibit or induce CYPs. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp, but the clinical relevance of P-gp inhibition is unknown. Concentrations of lenvatinib may slightly increase due to inhibition of CYP3A4 and P-gp, but this is unlikely to be clinically relevant. Coadministration with ketoconazole, a strong CYP3A4 and P-gp inhibitor, increased lenvatinib AUC by 15%. A similar effect may occur after coadministration with telithromycin. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated. Lenvatinib does not inhibit or induce UGTs.

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. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Lenvatinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolized by CYP3A4. Lenvatinib does not inhibit or induce CYPs. 

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. Lenvatinib does not interact with this metabolic pathway.

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

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

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Thioridazine is metabolized by CYP2D6 and to a lesser extent by CYP3A4. Lenvatinib does not inhibit or induce CYPs. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as lenvatinib. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms), but grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tiapride is excreted largely unchanged in urine. Lenvatinib is unlikely to significantly impair tiapride elimination. In a thorough QT study in healthy volunteers lenvatinib did not show relevant QT prolongation (upper bound of 90% CI <5 ms). However, grade 3 QT interval prolongation was reported in 2% of patients treated with lenvatinib compared to no reports in patients treated with placebo. Therefore, close monitoring of ECG and electrolyte disturbances is recommended when lenvatinib is used concomitantly with a drug that is known to prolong the QT interval. Lenvatinib should be withheld in the event of a QT interval >500 ms. Subsequently, lenvatinib should be resumed at a reduced dose when QT prolongation is resolved to a QT interval <480 ms or baseline.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ticagrelor undergoes extensive CYP3A4 metabolism and is a substrate of P-gp. Lenvatinib does not induce or inhibit CYPs and does not affect P-gp. Although ticagrelor is an inhibitor of CYP3A4, no clinically significant effect on lenvatinib is expected. 

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. Lenvatinib does not inhibit or induce CYPs.

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. Lenvatinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug interaction is unlikely. Tolbutamide is mainly metabolized by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Lenvatinib does not inhibit or induce CYPs.