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. Tivozanib is unlikely to interfere with this metabolic pathway.

Coadministration has not been studied but should be approached with caution. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Tivozanib does not inhibit or induce CYPs 2C9, 1A2 or 2C19. However, coadministration of acenocoumarol and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolised by glucuronidation (by several UGTs, major UGT1A6). Tivozanib does not interact with this pathway. However, both aspirin and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Agomelatine is metabolised predominantly via CYP1A2 (90%), with a small proportion metabolised by CYP2C9 and CYP2C19 (10%). Tivozanib does not inhibit or induce these CYPs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Alendronate is not metabolised but 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. Furthermore, osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients, largely due to the use of combined therapies consisting of nitrogen-containing bisphosphonates (such as alendronic acid) 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. Tivozanib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Alfuzosin is metabolised by CYP3A. Tivozanib does not inhibit or induce CYP3A.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aliskiren is minimally metabolised and is mainly excreted unchanged in faeces. Furthermore, P-gp is a major determinant of aliskiren bioavailability. Tivozanib does not interact with this metabolic pathway.

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. Tivozanib not interfere 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 metabolised by CYPs 2C9, 3A4 and 1A2. Tivozanib does not inhibit or induce these CYPs.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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. Tivozanib 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. Tivozanib does not interfere with this elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amiodarone is metabolised by CYP2C8 and CYP3A4. Tivozanib is a weak inhibitor of CYP2C8 in vitro, but no clinically relevant effect on amiodarone exposure is expected. 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). Both CYP3A4 and CYP1A1 are minor pathways in tivozanib metabolism and no clinically relevant effect on tivozanib exposure is expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and amiodarone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, close ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolised and is primarily renally eliminated (possibly via OCT). Tivozanib is unlikely to interfere with this elimination pathway.

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. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and amitriptyline may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Tivozanib 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. Furthermore, both tivozanib and amphotericin B may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20-40% of an oral dose may be excreted unchanged in the urine in 6 hours. After parenteral use about 60-80% is excreted in the urine within 6 hours. Tivozanib 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. Anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperatures. Tivozanib does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Furthermore, tivozanib has low solubility across the whole physiological pH range, therefore acid reducing agents will presumably not affect the absorption of tivozanib.

Coadministration has not been studied but should be approached with caution. Apixaban is a substrate of P-gp and BCRP, and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Tivozanib is a weak inhibitor of CYP2C8 in vitro, no clinically significant effect on apixaban exposure is expected. Tivozanib is also an inhibitor of BCRP in vitro at concentrations that are likely to only effect the BCRP present in the gut. The clinical relevance of this interaction is unknown. Monitoring of signs and symptoms of increased exposure to apixaban is recommended. Furthermore, coadministration of apixaban and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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. Tivozanib does not inhibit or induce these CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of tivozanib. However, coadministration of tivozanib and the strong CYP3A4 inhibitor, ketoconazole, had no effect on tivozanib AUC or Cmax. Therefore, no clinically significant effect with aprepitant is expected. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Although tivozanib is a substrate of CYP3A4, no clinically relevant effect is expected.

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

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 and 2D6 (minor)). Tivozanib does not inhibit or induce these CYPs or UGTs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and astemizole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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

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

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. Tivozanib does not interact with this pathway. However, both tivozanib and azithromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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. Tivozanib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bedaquiline is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. However, both tivozanib and bedaquiline may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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 interaction is unlikely in the range of observed clinical concentrations. There is also no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes. Tivozanib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Tivozanib does not inhibit or induce CYP2D6 or CYP3A4. However, both tivozanib and bepridil may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Tivozanib does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Tivozanib does not inhibit or induce CYP3A4 or CYP2C9. Although tivozanib is a substrate of CYP3A4, tivozanib is not likely to be affected by CYP3A4 induction of bosentan.

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

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

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). Tivozanib does not inhibit or induce CYP3A4 or UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolised by CYP2B6. Tivozanib is a weak inhibitor of CYP2B6 in vitro but no clinically significant effect is expected on bupropion exposure.

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

Coadministration has not been studied but a clinically significant clinically significant interaction is unlikely. Calcium is eliminated through faeces, urine and sweat. Tivozanib does not interfere with these elimination pathways.

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. Tivozanib does not 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. Tivozanib 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. Tivozanib does not inhibit or induce OATs.

Coadministration has not been studied but should be approached with caution. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Although tivozanib is a weak inhibitor of CYP2C8 in vitro, no clinically significant effect on carbamazepine exposure is expected. However, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of tivozanib may decrease due to CYP3A4 induction. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with carbamazepine. Therefore, coadministration should be approached with caution. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

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 metabolism via CYP2D6 and to a lesser extent by CYPs 2C9 and 1A2. Carvedilol is also a substrate of P-gp. Tivozanib does not inhibit or induce these UGTs, CYPs or 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. Tivozanib 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. Tivozanib does not interfere with this elimination pathway.

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. Tivozanib does not interfere with this elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefotaxime is partially metabolised by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates in the renal elimination of cefotaxime. Tivozanib does not interfere with this elimination pathway.

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

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

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

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. Tivozanib is unlikely to interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloramphenicol is predominantly glucuronidated. Tivozanib does not inhibit or induce UGTs. Furthermore, in vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlordiazepoxide is extensively metabolised by CYP3A4 but does not inhibit or induce cytochromes. Tivozanib 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 metabolised in the liver via CYP2D6. Tivozanib does not inhibit or induce CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Tivozanib does not inhibit or induce CYP2D6 or CYP1A2. However, both tivozanib and chlorpromazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlortalidone is mainly excreted unchanged in the urine and faeces.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ciclosporin is a substrate of CYP3A4 and P-gp, and inhibits CYP3A4 and OATP1B1. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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. Tivozanib does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cimetidine is also a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Furthermore, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, caution should be taken when using ciprofloxacin with drugs that are known to prolong the QT interval. In patients, therapeutic doses of tivozanib have been shown to prolong the QTc interval. If coadministration is necessary, monitoring including ECG assessment may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Cisapride is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib. However, both tivozanib and cisapride may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and citalopram may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clarithromycin is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Clarithromycin is also a strong inhibitor of CYP3A4 and P-gp. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. In vitro data suggest that clindamycin is a CYP3A4 inhibitor. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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, both as unabsorbed drug and via biliary excretion. Tivozanib does not interact with this pathway. However, both tivozanib and clofazimine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolised by CYP2D6. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and clomipramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Coadministration has not been studied but should be approached with caution. Clopidogrel is a prodrug and is converted to its active metabolite mainly through CYP2C19 with CYPs 3A4, 2B6 and 1A2 playing a minor role. Tivozanib is a weak inhibitor of CYP2B6 in vitro, but no clinically relevant effect on clopidogrel exposure is expected. Furthermore, clopidogrel is an inhibitor of CYP2C8 (strong), CYP2B6 (weak) and of CYP2C9 (in vitro) at high concentrations. Tivozanib is not metabolised by these CYPs. However, coadministration of clopidogrel and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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. Tivozanib does not inhibit or induce CYP3A4.

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. Tivozanib does not interact with this metabolic or elimination 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. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and clozapine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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 metabolised by conjugation with glucuronic acid to morphine-3-glucuronide (inactive) and morphine-6-glucuronide (active). Morphine is also a substrate of P-gp. Codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Tivozanib does not inhibit or induce CYP2D6, CYP3A4 or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Colchicine is metabolised by CYP3A4 and is a substrate of P-gp. Tivozanib does not inhibit or induce CYP3A4 or 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. Tivozanib does not interact with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Dabigatran is a substrate of P-gp and is renally excreted. Tivozanib does not interact with this pathway. However, coadministration of dabigatran and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied should be approached with caution. Dalteparin is excreted largely unchanged via the kidneys. Tivozanib does not interfere with the renal excretion of dalteparin. However, coadministration of dalteparin and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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 CYPs. Tivozanib is a weak inhibitor of CYP2B6 and CYP2C8 in vitro but no clinically relevant effect on dapsone exposure is expected in vivo.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Desipramine is metabolised by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and desipramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Tivozanib does not inhibit or induce these CYPs. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dexamethasone is a known substrate of CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Dexamethasone has also been described as a CYP3A4 inducer. However, the CYP3A4 induction effect of dexamethasone has yet to be established. Although tivozanib is a substrate of CYP3A4, no clinically relevant effect on tivozanib exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diamorphine is rapidly metabolised by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and, to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Tivozanib 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). Tivozanib does not inhibit or induce CYP3A4 or CYP2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Tivozanib does not inhibit or induce UGTs or CYP2C9.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Digoxin is renally eliminated via OATP4C1 and P-gp. Tivozanib does not inhibit or induce OATP4C1 or P-gp.

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. Tivozanib does not inhibit or induce UGTs or CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diltiazem is metabolised by CYP3A4 and CYP2D6. Tivozanib does not inhibit or induce these CYPs. Furthermore, diltiazem is a moderate inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is also a weak inhibitor of CYP2D6. Tivozanib does not interact with this pathway. However, both tivozanib and diphenhydramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but should be approached with caution. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Tivozanib does not inhibit or induce UGTs. However, coadministration of dipyridamole and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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. Tivozanib does not interact with this metabolic or elimination pathway. However, both tivozanib and disopyramide may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Dolasetron is converted by carbonyl reductase to its active metabolite, hydrodolasetron, which is mainly glucuronidated (60%) and metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). Tivozanib does not interact with this metabolic pathway. However, both tivozanib and dolasetron may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Domperidone is mainly metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. However, both tivozanib and domperidone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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. Tivozanib does not interact with the elimination of doxycycline.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolised to a minor extent via CYP3A4. Tivozanib does not inhibit or induce CYP3A4. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Tivozanib does not inhibit or induce CYP3A4.

Coadministration has not been studied but should be approached with caution. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Tivozanib does not inhibit or induce CYP3A4 or P-gp. However, coadministration of edoxaban and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Tivozanib is a weak inhibitor of CYP2C8 in vitro, but no clinically significant effect on eltrombopag exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Enalapril is hydrolysed to enalaprilat which is renally eliminated (possibly via OATs). Tivozanib does not interfere with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Enoxaparin does not undergo cytochrome metabolism but is desulphated and depolymerised in the liver, and is excreted predominantly renally. Tivozanib does not interact with this metabolic pathway. However, coadministration of enoxaparin and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ertapenem is mainly eliminated through the kidneys by glomerular filtration with tubular secretion playing a minor role. Tivozanib does not interact with this elimination 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. Tivozanib does not inhibit or induce CYP3A4 or P-gp. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and erythromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and escitalopram may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Esomeprazole is also an inhibitor of CYP2C19. Tivozanib does not interact with this pathway. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Tivozanib does not inhibit or induce CYP3A4, CYP1A2 or UGTs. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Tivozanib does not inhibit or induce CYP3A4 or P-gp. Furthermore, in patients with metastatic colorectal cancer (n=40), coadministration of tivozanib (1 mg daily for 3 of 4 weeks) and everolimus (10 mg daily continuously) was well tolerated. Since everolimus as an immunosuppressive drug is dosed much lower than as anticancer therapy, no tolerability issues at reduced dose are expected.

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

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. Tivozanib 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. Tivozanib does not inhibit or induce OATs. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. In vitro data suggest that fenofibric acid inhibits OAT3. Tivozanib 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. Tivozanib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fexofenadine is a substrate of P-gp. Tivozanib does not inhibit or induce P-gp.

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

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 metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Tivozanib does not interact with this metabolic pathway. However, both tivozanib and flecainide may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flucloxacillin is mainly eliminated renally partly by glomerular filtration and partly by active secretion via OAT1. Tivozanib does not interact with this elimination pathway. Flucloxacillin was also shown to induce CYP3A4 and P-gp. Although tivozanib is a CYP3A4 substrate, no effect on tivozanib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluconazole is cleared primarily by renal excretion. Tivozanib does not interact with this elimination pathway. Furthermore, fluconazole is an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and fluconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludrocortisone is metabolised in the liver to inactive metabolites, possibly via CYP3A. Tivozanib does not inhibit or induce CYP3A.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flunitrazepam is metabolised mainly via CYP3A4 and CYP2C19. Tivozanib does not inhibit or induce CYP3A4 or CYP2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluoxetine is metabolised by CYP2D6 and CYP2C9, and to a lesser extent by CYP2C19 and CYP3A4 to form norfluoxetine. Tivozanib does not inhibit or induce these CYPs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and fluphenazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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. Although tivozanib is a weak inhibitor of CYP2C8 and CYP2B6 in vitro, a clinically relevant interaction is not expected.

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

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 is also a potential inhibitor of CYP2C9. Tivozanib 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. Tivozanib does not inhibit or induce CYP2D6 or CYP1A2. Furthermore, fluvoxamine is an inhibitor of CYPs 1A2, 2C19, 3A4, 2C9. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

Coadministration has not been studied but should be approached with caution. Fondaparinux does not undergo cytochrome metabolism but is eliminated predominantly renally. Tivozanib does not interact with this metabolic pathway. However, coadministration of fondaparinux and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Formoterol is eliminated primarily by direct glucuronidation, with O-demethylation (by CYPs 2D6, 2C19, 2C9, and 2A6) followed by further glucuronidation. As multiple CYP450 and UGT enzymes catalyse the transformation, the potential for a pharmacokinetic interaction is low. Tivozanib does not inhibit or induce these CYPs or UGTs.

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. Tivozanib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Tivozanib does not inhibit or induce these CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of tivozanib. However, coadministration of tivozanib and the strong CYP3A4 inhibitor, ketoconazole, had no effect on tivozanib AUC or Cmax. Therefore, no clinically significant effect with aprepitant is expected. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Although tivozanib is a substrate of CYP3A4, no clinically relevant effect is expected.

Coadministration has not been studied but should be approached with caution. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Tivozanib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a strong inducer of CYP3A4, UGT and P-gp. Concentrations of tivozanib may decrease due to CYP3A4 induction. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with phenytoin. Therefore, coadministration should be approached with caution. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

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 eliminated unchanged renally (via OATs). In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/OAT3. Tivozanib does not interfere 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. Tivozanib does not 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 and is 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. Tivozanib 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. Tivozanib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Tivozanib does not inhibit or induce these CYPs. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Tivozanib does not inhibit or induce CYP3A4 or P-gp. However, both tivozanib and granisetron may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Grapefruit juice is a known inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Tivozanib 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. However, hepatic metabolism is only a minor pathway for tivozanib, therefore no clinically significant effect on tivozanib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction, as well as oxidative metabolism (CYP3A4 and CYP2D6). Tivozanib does not interact with this metabolic pathway. However, both tivozanib and haloperidol may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but should be approached with caution. Heparin is thought to be eliminated via the reticuloendothelial system. Tivozanib does not interact with this metabolic pathway. However, coadministration of heparin and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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. Tivozanib does not interfere with this metabolic pathway. Although 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 tivozanib.

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. In vitro data indicate that hydrochlorothiazide is unlikely to inhibit OAT1 in the range of clinically relevant drug concentrations. A clinically significant interaction is not expected with tivozanib.

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. Tivozanib does not inhibit or induce CYP2D6 or CYP3A4.

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

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. Tivozanib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyurea is metabolised in the liver and cleared via the lungs and kidneys. Tivozanib is unlikely to interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. However, both tivozanib and hydroxyzine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ibandronic acid is not metabolised but 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. Furthermore, osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients, largely due to the use of combined therapies consisting of nitrogen-containing bisphosphonates (such as ibandronic acid) 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. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on ibuprofen exposure is expected. However, tivozanib coadministration with ibuprofen may increase the risk of haemorrhage. Therefore monitoring for bleeding may be required.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Iloperidone is metabolised by CYP3A4 and CYP2D6. Tivozanib does not inhibit or induce CYP3A4 or CYP2D6. However, both tivozanib and iloperidone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Tivozanib does not inhibit or induce these CYPs. However, both tivozanib and imipramine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Indapamide is extensively metabolised by CYPs. Tivozanib is a weak inhibitor of CYP2B6 and CYP2C8 in vitro but no clinically significant effect on indapamide exposure is expected. However, both tivozanib and indapamide may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. A small proportion of an inhaled ipratropium dose is systemically absorbed (6.9%). Metabolism is via ester hydrolysis and conjugation. Tivozanib 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 metabolised by glucuronidation and oxidation (mainly CYP2C9). Tivozanib does not inhibit or induce UGTs or CYP2C9.

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. Tivozanib 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. Tivozanib does not inhibit or induce CYP3A4, and as renal elimination of the unchanged drug is a minor pathway, there is little potential for an interaction.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Itraconazole is primarily metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Furthermore, itraconazole is an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and itraconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ivabradine is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. However, both tivozanib and ivabradine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ketoconazole is a substrate of CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Furthermore, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and ketoconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Tivozanib 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 metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4.

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. Tivozanib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Tivozanib does not inhibit or induce CYP2C19 or CYP3A4. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Tivozanib does not interfere 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). Tivozanib does not interact with this elimination pathway. However, both tivozanib and levofloxacin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levomepromazine is metabolised by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and levomepromazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Tivozanib does not inhibit or induce CYP3A4 or UGTs. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Tivozanib does not inhibit or induce CYP3A4 or UGTs.

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

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. Tivozanib does not inhibit or induce CYP1A2 or CYP3A4.

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 metabolic pathway. Linagliptin is also a substrate of P-gp. Tivozanib does interact with this metabolic or elimination pathway. Furthermore, linagliptin is a weak inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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

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

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. Tivozanib does not interfere with this elimination pathway.

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. However, both tivozanib and lithium may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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. However, tivozanib is not an immunosuppressant, immunomodulatory or bone marrow toxic drug. Therefore, no pharmacodynamic interaction is expected with live vaccines.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolised by CYP3A4 and CYP2C8, and is a substrate of P-gp. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on loperamide exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loratadine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6. Tivozanib does not inhibit or induce CYP3A4 or CYP2D6.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lormetazepam is mainly glucuronidated. Tivozanib 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. Tivozanib does not inhibit or induce CYP2C9.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on macitentan exposure is expected.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Tivozanib does not inhibit or induce CYP2C9 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. Tivozanib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Meropenem is primarily eliminated by the kidney with in vitro data suggesting it is a substrate of OAT3>OAT1. Tivozanib 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 metabolised to N-acetyl-mesalazine by N-acetyltransferase. Tivozanib does not interfere with this metabolic pathway.

Coadministration has not been studied. 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%). Tivozanib does not interact with this metabolic pathway. However, metamizole may decrease tivozanib concentrations due to induction of CYP3A4. As the clinical relevance of this interaction is unknown, monitoring may be required.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Methadone is demethylated by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. However, both tivozanib and methadone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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 tivozanib, or to be altered by coadministration with tivozanib.

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

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

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

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. Tivozanib does not interfere with this elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metronidazole is eliminated via glomerular filtration. Tivozanib does not interfere with this elimination pathway. Furthermore, elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Miconazole is extensively metabolised by the liver. Tivozanib is unlikely to interact with this unspecified metabolic pathway. Furthermore, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and miconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended. Note: No a priori dosage adjustment is recommended for tivozanib with dermal administration of miconazole, since systemic exposure of miconazole is limited when used topically.

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

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

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%). Tivozanib is unlikely to interfere with this pathway.

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. Tivozanib does not inhibit or induce these CYPs.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on montelukast exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. Tivozanib does not inhibit or induce UGTs. However, both tivozanib and moxifloxacin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3. Tivozanib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nadroparin is renally excreted by a nonsaturable mechanism. Tivozanib does not interact with this elimination pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nandrolone is metabolised in the liver by alpha-reductase. Tivozanib does not interact with this 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. Tivozanib does not inhibit or induce CYP2C9, CYP1A2 or UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nateglinide is mainly metabolised by CYP2C9 (70%) and to a lesser extent by CYP3A4 (30%). Tivozanib does not inhibit or induce CYP2C9 or CYP3A4.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nefazodone is metabolised mainly by CYP3A4. Tivozanib does not inhibit or induce CYP3A4. Furthermore, nefazodone is a strong inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and nefazodone may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on nicardipine exposure is expected. Furthermore, nicardipine is a weak inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected.

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

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

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Tivozanib does not inhibit or induce CYP3A4. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Tivozanib does not interact with this metabolic pathway. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Tivozanib does not interact with this metabolic pathway. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Tivozanib does not inhibit or induce CYP3A4 or UGTs. It is currently unknown whether tivozanib may reduce the effectiveness of hormonal contraceptives. Based on the pharmacology of tivozanib no interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolised mainly by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and nortriptyline may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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 eliminated unchanged renally by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Tivozanib is unlikely to interfere with this pathway. However, both tivozanib and ofloxacin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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). Tivozanib does not inhibit or induce CYP1A2, CYP2D6 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. Tivozanib does not interfere with this pathway.

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. Tivozanib does not interact with this pathway. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ondansetron is metabolised mainly by CYP1A2 and CYP3A4, and to a lesser extent by CYP2D6. Ondansetron is also a substrate of P-gp. Tivozanib does not inhibit or induce these CYPs or P-gp. However, both tivozanib and ondansetron may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated. Tivozanib 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 metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5, and are inhibitors of CYP2C19. Tivozanib exposure is not affected by moderate induction of CYP3A or inhibition of CYP2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolised via glucuronidation. Tivozanib 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. Tivozanib does not inhibit or induce CYP3A or CYP2D6.

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 CYP2D6 and CYP3A4. Tivozanib does not inhibit or induce OCTs, CYP2D6 or CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Palonosetron is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP1A2. Palonosetron is also a substrate of P-gp. Tivozanib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Pamidronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, pamidronic 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 pamidronic acid. Fasting should be continued for at least 30 minutes after taking pamidronic acid. Furthermore, osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients, largely due to the use of combined therapies consisting of nitrogen-containing bisphosphonates (such as pamidronic acid) 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. Tivozanib does not inhibit or induce these CYPs. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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. Tivozanib does not interact with this elimination 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). Tivozanib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paroxetine is mainly metabolised by CYP2D6 and CYP3A4. Tivozanib does not inhibit or induce CYP2D6 or CYP3A4.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Tivozanib does not interfere with the 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. Tivozanib does not inhibit or induce these 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. Tivozanib does not inhibit or induce CYP2D6.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Perphenazine is metabolised by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and perphenazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pethidine is metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Tivozanib is a weak inhibitor of CYP2B6 in vitro. However, no clinically significant effect on pethidine exposure is expected.

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

Coadministration has not been studied but should be approached with caution. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major), and to a lesser extent by CYP2E1. Tivozanib does not inhibit or induce these CYPs. However, phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Concentrations of tivozanib may decrease due to CYP3A4 induction. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with phenobarbital. Therefore, selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

Coadministration has not been studied but should be approached with caution. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Tivozanib does not inhibit or induce CYP2C9 or CYP3A4. However, coadministration of phenprocoumon and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but should be approached with caution. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Tivozanib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a strong inducer of CYP3A4, UGT and P-gp. Concentrations of tivozanib may decrease due to CYP3A4 induction. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with phenytoin. Therefore, coadministration should be approached with caution. Selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

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. Tivozanib does not inhibit or induce CYP4F2.

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Pimozide is mainly metabolised by CYP3A4 and CYP2D6 and to a lesser extent by CYP1A2. Tivozanib does not inhibit or induce these CYPs. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as tivozanib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on pioglitazone exposure is expected.

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. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and pipotiazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on pitavastatin exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Tivozanib does not inhibit or induce UGTs or P-gp. Furthermore, posaconazole is a strong inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and posaconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

Coadministration has not been studied but should be approached with caution. 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. Tivozanib is a weak inhibitor of CYP2B6 in vitro, but no clinically significant effect on prasugrel exposure is expected. However, coadministration of prasugrel and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised (via CYP3A4) and is a substrate of OATP1B1. Tivozanib does not inhibit or induce CYP3A4 or OATP1B1.

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

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

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 metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4.

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). Tivozanib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Tivozanib does not inhibit or induce CYP2D6 or CYP2C19. However, both tivozanib and prochlorperazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Promethazine is metabolised by CYP2D6. Tivozanib does not inhibit or induce CYP2D6. However, both tivozanib and promethazine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propafenone is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2 and CYP3A4. Tivozanib does not inhibit or induce CYPs 2D6, 1A2 or 3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolised by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Tivozanib 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. No clinically relevant interactions were observed when prucalopride was coadministered with inhibitors of renal P-gp, OAT and OCT transporters. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pyrazinamide is mainly metabolised by xanthine oxidase. Tivozanib 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 metabolised by CYP3A4. Tivozanib does not inhibit or induce CYP3A4.

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. Tivozanib does not interfere with this pathway.

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. Furthermore, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and quinidine may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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 CYP2C19 and CYP3A4. Tivozanib does not interact with this metabolic pathway. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

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 metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Tivozanib is not expected to interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Tivozanib does not inhibit or induce OAT1/OAT3. Furthermore, tivozanib has low solubility across the whole physiological pH range therefore acid reducing agents will presumably not affect the absorption of tivozanib.

Coadministration has not been studied but is not recommended. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Tivozanib does not inhibit or induce these CYPs or P-gp. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. In healthy volunteers (n=25), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. Therefore, no clinically significant effect on tivozanib is expected after coadministration with ranolazine. However, tivozanib and ranolazine potentially cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Reboxetine is metabolised by CYP3A4. In vitro data indicate reboxetine to be a weak inhibitor of CYP3A4 but in vivo data showed no inhibitory effect on CYP3A4. Tivozanib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolised by CYP2C8 and CYP3A4 with clinical data indicating it is a substrate of OATP1B1. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on repaglinide exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver, but retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Tivozanib 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 should be approached with caution. Rifabutin is metabolised by CYP3A and via deacetylation. Tivozanib does not interact with this metabolic pathway. However, rifabutin is a strong CYP3A4 and P-gp inducer. Concentrations of tivozanib may decrease due to induction of CYP3A4. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with rifabutin. Therefore, selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

Coadministration should be approached with caution. Rifampicin is metabolised via deacetylation. Tivozanib does not interfere with this metabolic pathway. However, rifampicin is a strong CYP3A4 and P-gp inducer. Concentrations of tivozanib may decrease due to induction of CYP3A4. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and rifampicin (600 mg once daily for 28 days) decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. Therefore, selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

Coadministration has not been studied but should be approached with caution. Rifapentine is metabolised via deacetylation. Tivozanib does not interfere with this metabolic pathway. However, rifapentine is a strong CYP3A4, CYP2C8 and P-gp inducer. Concentrations of tivozanib may decrease due to induction of CYP3A4. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with rifabutin. Therefore, selection of an alternative concomitant medication with no or minimal enzyme induction potential is recommended. If coadministration is unavoidable, monitor closely for decreased tivozanib efficacy.

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. Tivozanib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Tivozanib does not inhibit or induce CYP3A4 or CYP2D6.

Coadministration has not been studied but should be approached with caution. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine (by P-gp and BCRP). Tivozanib is an in vitro inhibitor of BCRP at concentrations that are likely to only effect the BCRP present in the gut. The systemic exposure of tivozanib is too low to inhibit systemic BCRP, therefore no effect is expected on the renal elimination of rivaroxaban. However, the absorption of rivaroxaban may be increased. Monitoring for signs and symptoms of increased exposure to rivaroxaban is recommended. Furthermore, coadministration of rivaroxaban and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on rosiglitazone exposure is expected.

Coadministration has not been studied but should be approached with caution. Rosuvastatin is largely excreted unchanged in the faeces via OATP1B1 and is a substrate of BCRP. Tivozanib is an inhibitor of BCRP in vitro at concentrations that are likely to only effect the BCRP present in the gut. As the clinical relevance of this interaction is unknown, monitoring of signs and symptoms of increased exposure to rosuvastatin is recommended. If coadministration is unavoidable, it is recommended to start with the lowest dose of rosuvastatin and titrate up to the desired clinical effect while monitoring for safety. Separate rosuvastatin administration at least 2 hours from the tivozanib administration.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Senna glycosides are hydrolysed by colonic bacteria in the intestinal tract and the active anthraquinones liberated into the colon. Excretion occurs in the urine and the faeces, and also in other secretions. No clinically significant drug interactions are known.

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sertindole is metabolised by CYP2D6 and CYP3A4. Tivozanib does not inhibit or induce CYP2D6 or CYP3A4. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as tivozanib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Tivozanib is a weak inhibitor of CYP2B6 in vitro but no clinically significant effect on sertraline exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Simvastatin is metabolised by CYP3A4 and the active metabolite is a substrate of OATP1B1. Simvastatin is also a substrate of BCRP. Tivozanib is an inhibitor of BCRP in vitro at concentrations that are likely to only effect the BCRP present in the gut. As the clinical relevance of this interaction is unknown, monitoring for signs and symptoms of increased exposure to simvastatin should be considered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Tivozanib does not inhibit or induce CYPs or P-gp. Furthermore, coadministration of tivozanib (escalating doses from 0.5-1.5 mg/d for 3 of 4 weeks) and temsirolimus (the water soluble ester of sirolimus, 15 or 25 mg/week) showed no dose limiting toxicities. Additionally, an acceptable tolerability and no synergistic toxicity was observed.

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 elimination pathway. Tivozanib does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. 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 tivozanib, or to be affected if co-administered with tivozanib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sotalol is excreted unchanged via renal elimination. Tivozanib does not interfere with this elimination pathway. However, coadministration is not recommended due to the potential for life threatening arrhythmias such as torsade de pointes and sudden death. The product labels for sotalol advise extreme caution if given with other drugs that prolong the QT interval, such as tivozanib.

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. Tivozanib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spironolactone is partly metabolised by the flavin containing monooxygenases. Tivozanib 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. Tivozanib is unlikely to interact with this pathway.

Coadministration has not been studied but is contraindicated. St John’s wort is a P-gp and CYP3A4 inducer. Concentrations of tivozanib may unpredictably and significantly decrease due to CYP3A4 induction. Coadministration should be approached with caution. In healthy volunteers (n=28), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inducer, rifampicin (600 mg once daily for 28 days), decreased tivozanib AUC and t_1/2 by 52% and 55%, respectively. A similar effect may occur with St John’s Wort. If a patient is already taking St John’s Wort, this should be stopped before starting tivozanib treatment. The inducing effect of St John’s Wort may persist for at least 2 weeks after cessation of treatment with St John’s Wort.

Coadministration has not been studied but should be approached with caution. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Streptokinase is unlikely to affect the disposition of tivozanib, or to be affected if coadministered with tivozanib. However, coadministration of streptokinase and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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

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. Tivozanib does not inhibit or induce CYP2C9.

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. Tivozanib does not interfere with this elimination pathway. However, both tivozanib and sulpiride may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tacrolimus is metabolised mainly by CYP3A4 and is a substrate of P-gp. Tivozanib does not inhibit or induce CYP3A4 or P-gp. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and tacrolimus may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

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

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. Tivozanib does not inhibit or induce CYP3A4 or CYP2D6.

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. Tivozanib 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. Tivozanib does not interact with this metabolic pathway. Telithromycin is also a strong inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. However, both tivozanib and telithromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telmisartan is mainly glucuronidated by UGT1A3. Tivozanib does 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. Tivozanib 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 CYPs 2C8 and 2C19. Tivozanib is a weak inhibitor of CYP2C8 in vitro but no clinically significant effect on terbinafine exposure is expected.

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

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. Tivozanib does not interfere with this elimination pathway.

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

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 metabolised by CYP2D6 and to a lesser extent by CYP3A4. Tivozanib does not inhibit or induce CYP2D6 or CYP3A4. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as tivozanib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tiapride is excreted largely unchanged in urine. Tivozanib does not interfere with this elimination pathway. However, coadministration of tivozanib and tiapride may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, ECG monitoring is recommended.

Coadministration has not been studied but should be approached with caution. Ticagrelor undergoes extensive CYP3A4 metabolism and is a substrate of P-gp. Tivozanib does not inhibit or induce CYP3A4 or P-gp. Furthermore, ticagrelor is a weak inhibitor of CYP3A4. Although tivozanib is a CYP3A4 substrate, a clinically relevant effect on tivozanib exposure is not expected. In healthy volunteers (n=26), coadministration of tivozanib (1.5 mg single dose) and the strong CYP3A4 inhibitor, ketoconazole (400 mg once daily for 25 days), increased tivozanib AUC by 12%. Cmax was unaffected. Therefore, no clinically significant effect on tivozanib is expected. However, coadministration of ticagrelor and tivozanib may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

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. Tivozanib does not inhibit or induce CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tinzaparin is renally excreted as unchanged or almost unchanged drug. Tivozanib does not interact with this elimination pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for signs of bleeding.