Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. After ingestion of acarbose, the majority of active unchanged drug remains in the lumen of the gastrointestinal tract to exert its pharmacological activity and is metabolised by intestinal enzymes and by the microbial flora. 

Coadministration has not been studied. Acenocoumarol is mainly metabolized by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. A clinical adverse event (increased coagulation times) reported in a RCC patient receiving concomitant cabozantinib and warfarin was attributed to cabozantinib related inhibition of CYP-mediated warfarin metabolism. However, this event may reflect displacement of plasma protein-bound warfarin by cabozantinib. The same adverse event may occur when cabozantinib is combined with coumarins. Close monitoring of INR/PT is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aspirin is rapidly deacetylated to form salicylic acid and then further metabolized by glucuronidation (by several UGTs, major UGT1A6). Cabozantinib does not inhibit or induce UGTs.

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%). Cabozantinib does not inhibit or induce CYPs.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as alfuzosin is metabolized by CYP3A. Cabozantinib 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. P-gp is a major determinant of aliskiren bioavailability. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on aliskiren exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug-drug interaction is unlikely as allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Cabozantinib 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 metabolized by CYPs 2C9, 3A4 and 1A2. Cabozantinib does not inhibit of induce these CYP. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as antacids. 

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. Cabozantinib is a weak inhibitor of P-gp in vitro but no clinically relevant effect on ambrisentan exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as amikacin is eliminated by glomerular filtration.

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. Cabozantinib is unlikely to significantly inhibit amiloride renal elimination.

Coadministration has not been studied. Amiodarone is metabolised by CYP3A4 and CYP2C8. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on amiodarone exposure is not expected. However, 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). Cabozantinib concentrations may increase due to CYP3A4 inhibition. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary. Due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone. Furthermore, cabozantinib should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amisulpride is weakly metabolized and is primarily eliminated renally (possibly via OCT). Cabozantinib is unlikely to significantly impair amisulpride elimination. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is coadministered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised but is eliminated to a large extent in the bile. Cabozantinib does not interfere with this elimination pathway. However, the European SPC for amphotericin B states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension. Monitoring may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Renal clearance of ampicillin occurs partly by glomerular filtration and partly by tubular secretion. About 20-40% 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. In vitro data indicate that ampicillin is a substrate of OAT1. Metabolites of cabozantinib may inhibit OAT1, which may increase ampicillin concentrations and thus slow down ampicillin renal elimination. However, this is unlikely to be clinically relevant.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as antacids. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Apixaban is metabolized by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on apixaban exposure is not expected.

Coadministration has not been studied but should be approached with caution. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Cabozantinib does not inhibit or induce these CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of cabozantinib during the three days of coadministration. The clinical relevance of this interaction is unknown. Coadministration is not recommended. If coadministration is unavoidable, monitor closely for cabozantinib toxicity. The dose of cabozantinib may also need to be reduced by approximately 50% during the few days of coadministration. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of cabozantinib may decrease due to weak induction of CYP3A4 and CYP2C9, but this is not considered to be clinically relevant.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aripiprazole is metabolized by CYP3A4 and CYP2D6. Cabozantinib does not inhibit or induce CYPs 3A4 and 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 (minor), 2D6 (minor)). Cabozantinib 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 as astemizole is metabolized by CYPs 2D6, 2J2 and 3A4. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Atorvastatin is metabolised by CYP3A4 and is a substrate of P-gp and OATP1B1. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on atorvastatin exposure is expected.

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 metabolized analogously to natural purines. Cabozantinib does not interfere with this metabolic pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Azithromycin is mainly eliminated via biliary excretion with animal data suggesting this may occur via P-gp and MRP2. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on azithromycin exposure is expected. Azithromycin is also an inhibitor of P-gp, but the clinical relevance of P-gp inhibition is unknown. Cabozantinib is not a substrate of P-gp. However, caution should be taken when using azithromycin with drugs that are known to prolong the QT interval. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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. Cabozantinib does not interact with beclomethasone metabolism. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as bedaquiline is metabolised by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, bedaquiline prolongs the QTc interval. When bedaquiline is coadministered with cabozantinib an additive or synergistic effect on QT prolongation cannot be excluded. If coadministration is necessary, close monitoring including ECG assessment is recommended. 

Coadministration has not been studied. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. Secretion of bendoflumethiazide into the urinary tract by these transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit OAT1/OAT3 in vitro and may decrease bendroflumethiazide secretion and therapeutic effect. In vitro data indicate that bendroflumethiazide inhibits OAT1/OAT3 but a clinically significant interaction is unlikely in the range of observed clinical concentrations. In addition, there is no evidence that bendroflumethiazide inhibits or induces CYP450 enzymes and therefore is unlikely to impact cabozantinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bepridil is metabolized by CYP2D6 (major) and 3A4. Cabozantinib does not inhibit or induce CYP2D6 and 3A4. However, caution is needed when co-administering cabozantinib with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as half of bezafibrate dose is eliminated unchanged in the urine. In vitro data suggest that bezafibrate inhibits the renal transporter OAT1. In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3, but a clinically significant interaction is unlikely as bezafibrate has a wide therapeutic range.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bisoprolol is partly metabolised by CYP3A4 and CYP2D6, and partly eliminated unchanged in the urine. Bisoprolol is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on bisoprolol exposure is expected.

Coadministration has not been studied. Bosentan is a substrate and inducer of CYP3A4 and CYP2C9. Bosentan could potentially decrease cabozantinib exposure. Imatinib concentrations, on average, decreased by 33% in the presence of bosentan in a phase III clinical study and a similar effect may be expected with cabozantinib. If the combination of cabozantinib and bosentan appears necessary, close monitoring is needed.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromazepam undergoes oxidative biotransformation. Drug-drug interaction studies indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may play a role. Cabozantinib 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 metabolized by CYP3A4. Cabozantinib 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). Cabozantinib 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 metabolized by CYP2B6. Cabozantinib does not inhibit or induce CYP2B6.

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

Coadministration has not been studied but a clinically significant pharmacokinetic interaction is unlikely. Calcium is eliminated through faeces, urine and sweat. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Candesartan is mainly eliminated unchanged via urine and bile. The role of OAT1/3 in renal secretion of angiotensin II receptor blockers appears limited, because these compounds are mostly excreted through the biliary route. Therefore, cabozantinib is unlikely to significantly inhibit renal elimination of angiotensin II receptor blockers.

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. Cabozantinib does not interfere with capreomycin renal elimination.

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. In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as captopril has a wide therapeutic range.

Coadministration has not been studied but is contraindicated. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on carbamazepine exposure is not expected. However, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Concentrations of cabozantinib may significantly decrease due to induction of CYP3A4 and CYP2C9. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable an increase in the dosage of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib plasma concentrations, if available. After discontinuation of carbamazepine treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYP2C9 and CYP1A2. Carvedilol is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on carvedilol exposure is expected.

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. Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied. Cefalexin is predominantly renally eliminated unchanged by glomerular filtration and tubular secretion via OAT1 and MATE1. Cabozantinib and its metabolites possibly inhibit OAT1 and MATE1, which may increase cefalexin concentrations. The clinical relevance of this interaction is unknown. Since cefalexin is nephrotoxic, renal function should be monitored periodically.

Coadministration has not been studied. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Metabolites of cabozantinib possibly inhibit OAT3 which may increase cefazolin concentrations. The clinical significance of this interaction is unknown. 

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

Coadministration has not been studied. Cefotaxime is partially metabolized by non-specific esterases. Most of a dose of cefotaxime is excreted in the urine - about 60% as unchanged drug and a further 24% as desacetyl-cefotaxime, an active metabolite. In vitro studies indicate that OAT3 participates in the renal elimination of cefotaxime. Metabolites of cabozantinib possibly inhibit OAT3 which may increase cefotaxime concentrations. The clinical significance of this interaction is unknown. However, since cefotaxime is nephrotoxic, renal function should be monitored periodically.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolized by CYP2C9. Cabozantinib 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 (possibly via OCT2). In vitro data indicate that cetirizine inhibits OCT2. Cabozantinib is unlikely to interact with cetirizine’s renal elimination.

Coadministration has not been studied. Chloramphenicol is predominantly glucuronidated. Cabozantinib does not inhibit or induce UGTs. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Concentrations of cabozantinib may increase due to CYP3A4 inhibition, increasing the risk of adverse events. The clinical relevance of this interaction is unknown and close monitoring for cabozantinib toxicity is recommended. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolized mainly by CYP2D6, but also by CYP1A2. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit renal transporters OAT1/OAT3 and may decrease chlortalidone secretion and therapeutic effect. Monitoring for chlortalidone toxicity and blood pressure may be required.

Coadministration has not been studied. Ciclosporin is a substrate of CYP3A4 and P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on ciclosporin exposure is expected. Ciclosporin is also an inhibitor of CYP3A4 and OATP1B1, and may increase cabozantinib concentrations. Close monitoring is recommended. No a priori dosage adjustment is recommended for cabozantinib.

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 (possibly via OATs). In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as cilazapril has a wide therapeutic range.

Coadministration has not been studied. Cimetidine is metabolised by CYP450 enzymes. Although cabozantinib is an in vitro inhibitor of CYP2C8, no clinically relevant effect on cimetidine exposure is expected. However, cimetidine is a weak inhibitor of several CYP-enzymes (CYPs 3A4, 1A2, 2D6 and 2C19, among others). Concentrations of cabozantinib may increase due to CYP3A4 inhibition. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary. Cimetidine may also decrease the renal excretion of drugs due to competition for the active tubular secretion. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Cabozantinib does not interact with this pathway. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as cimetidine.

Coadministration has not been studied but care should be taken. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. Ciprofloxacin is also metabolised and partially cleared through the bile and intestine. Metabolites of cabozantinib potentially inhibit OAT3 which may increase ciprofloxacin concentrations, and thus may slow down ciprofloxacin renal elimination. Monitoring of ciprofloxacin toxicity and renal function may be required. Although ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2, no clinically relevant effect on cabozantinib exposure is expected. However, caution should be taken when using ciprofloxacin with drugs that are known to prolong the QT interval. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Cisapride is metabolised by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Citalopram is metabolized by CYP2C19 (38%), 2D6 (31%) and 3A4 (31%). Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but should be approached with caution. Clarithromycin is metabolised by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. Clarithromycin is an inhibitor of CYP3A4 (strong) and P-gp and may increase cabozantinib concentrations. Concurrent use of potent CYP3A4 inhibitors should be avoided as cabozantinib is relatively toxic and can cause dose-related QT-prolongation. If coadministration is unavoidable, monitor closely for cabozantinib toxicity and reduce the cabozantinib dose. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor. Furthermore, cabozantinib and clarithromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clavulanic acid is extensively metabolized (likely non CYP mediated pathway) and excreted in the urine by glomerular filtration. Cabozantinib 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 metabolized in the liver via CYP2D6. Cabozantinib does not interact with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolized by CYP3A4. Cabozantinib 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 clobetasol.

Coadministration has not been studied. Clofazimine is largely excreted unchanged in the faeces. Cabozantinib does not interfere with this elimination pathway. In vitro data suggest that clofazimine is a CYP3A4 inhibitor and may increase cabozantinib concentrations. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary. Furthermore, in patients therapeutic doses of cabozantinib have been shown to prolong the QTc interval. Caution should be taken when using clofazimine with drugs that are known to prolong the QT interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clofibrate is hydrolyzed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as clofibrate has a wide therapeutic range.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clomipramine is metabolized by CYP3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolized by CYP2D6. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

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

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 metabolized to oxazepam by CYP3A4. Oxazepam is mainly glucuronidated. Cabozantinib does not inhibit or induce CYPs or UGTs.

Coadministration has not been studied. 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, probably via OAT1/3. Metabolites of cabozantinib possibly inhibit OAT1/3 which may increase cloxacillin concentrations. The clinical significance of this interaction is unknown. 

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. Cabozantinib does not inhibit or induce CYPs. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered. Furthermore, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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. Furthermore, codeine is converted via CYP3A4 to norcodeine, an inactive metabolite. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

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

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. Cabozantinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dabigatran is a substrate of P-gp and is renally excreted. Cabozantinib is a weak inhibitor of P-gp in vitro and may increase concentrations of dabigatran. However, no clinically relevant effect on dabigatran exposure is expected.

Coadministration has not been studied but based on metabolism and clearance, a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys via unsaturable glomerular filtration. Cabozantinib is unlikely to interfere with the renal excretion of dalteparin. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP P450 enzymes. Cabozantinib does not interfere with this pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as desipramine is metabolized by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied. Dexamethasone is metabolised by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, dexamethasone has been described as a weak inducer of CYP3A4 and may decrease cabozantinib plasma concentrations. The clinical relevance of this interaction is not known as the induction of CYP3A4 by dexamethasone has not yet been established.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dextropropoxyphene is mainly metabolized by CYP3A4. Cabozantinib 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 metabolized by sequential deacetylation to morphine which is then mainly glucuronidated to morphine-3-glucuronide (UGT2B7>UGT1A1) and to a lesser extent, to the pharmacologically active morphine-6-glucuronide (UGT2B7>UGT1A1). Morphine is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diazepam is metabolized to nordiazepam (by CYP3A4 and CYP2C19) and to temazepam (mainly by CYP3A4). Temazepam is mainly glucuronidated. Cabozantinib 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. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidized by CYP2C9. Cabozantinib 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. Digoxin is renally eliminated via OATP4C1 and P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on digoxin exposure is expected.

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. Cabozantinib does not inhibit or induce CYP3A4 or UGTs. 

Coadministration has not been studied. Diltiazem is metabolized by CYP3A4 and CYP2D6. Diltiazem is a moderate inhibitor of CYP3A4 and could potentially increase cabozantinib exposure. The clinical relevance of this interaction is unknown. No a priori dosage adjustment is recommended for cabozantinib. Close monitoring of cabozantinib tolerability is recommended. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Diphenhydramine is mainly metabolized by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Cabozantinib does not inhibit or induce these CYPs. Diphenhydramine is also a weak inhibitor of CYP2D6. Cabozantinib is not metabolised by CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Cabozantinib is unlikely to interfere with this pathway.

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. Cabozantinib does not interact with this metabolic or elimination pathway. However, caution is needed when co-administering cabozantinib with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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 metabolized by CYP2D6 (10-20%) and CYP3A4 (<1%). However dolasetron may prolong the QT interval and in cabozantinib has been shown to prolong the QT interval. Caution should be taken when using dolasetron with drugs that are known to prolong the QT interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Domperidone is mainly metabolized by CYP3A4. Cabozantinib does not inhibit of induce CYP3A4. However, cabozantinib should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. Cabozantinib has been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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 cabozantinib, or to be affected by cabozantinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxazosin is metabolized mainly by CYP3A4. Cabozantinib 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 metabolized to nordoxepin (a metabolite with comparable pharmacological activity as the parent compound) mainly by CYP2C19. In addition, doxepin and nordoxepin are metabolized by CYP2D6. Cabozantinib does not inhibit or induce CYP2C19 and 2D6. 

Coadministration has not been studied but based on the 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. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dronabinol is mainly metabolized by CYP2C9 and to a lesser extent by CYP3A4. Cabozantinib does not inhibit of induce CYPs 2C9 and 3A4. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as dulaglutide is degraded by endogenous endopeptidases. Dulaglutide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since cabozantinib is absorbed in approximately 5h, the clinical relevance of delayed absorption is considered to be limited.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Duloxetine is metabolized by CYP2D6 and CYP1A2. Cabozantinib does not inhibit or induce CYPs 2D6 and 1A2. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

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). Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on eltrombopag exposure is not 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 eliminated renally (possibly via OATs). In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as cilazapril has a wide therapeutic range.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as eprosartan is largely excreted in bile and urine as unchanged drug. The role of OAT1/3 in renal secretion of angiotensin II receptor blockers appears limited, because these compounds are mostly excreted through the biliary route. Therefore, cabozantinib is unlikely to significantly inhibit renal elimination of angiotensin II receptor blockers.

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

Coadministration has not been studied but should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on erythromycin exposure is expected. Erythromycin is an inhibitor of CYP3A4 (moderate) and P-gp and may increase cabozantinib concentrations. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary, but close monitoring for cabozantinib toxicity is recommended. Furthermore, cabozantinib and erythromycin may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Escitalopram is metabolized by CYP2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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 and inhibits CYP2C19. Cabozantinib does not interact with this pathway. However, the solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. Coadministration of esomeprazole (40 mg daily for 6 days) with a single dose of 100 mg cabozantinib to healthy volunteers resulted in no clinically-significant effect on cabozantinib AUC. No dose adjustment is indicated when gastric pH modifying agents are co-administered with cabozantinib. 

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

Coadministration has not been studied. Estradiol is metabolized by CYP3A4, CYP1A2 and is glucuronidated. Cabozantinib does not inhibit or induce CYP3A4 and 1A2 or UGTs and a pharmacokinetic interaction is unlikely. However, as the effect of cabozantinib on contraceptive efficacy has not been investigated, the European product label for cabozantinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethambutol is partly metabolized by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and in the urine (50%), possibly via OCT2. Cabozantinib does not interact with this route of elimination.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Although cabozantinib is an inhibitor of P-gp, no clinically significant effect on everolimus is expected. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as exenatide is cleared mainly by glomerular filtration. Exenatide delays gastric emptying and could possibly decrease the absorption rate of concomitantly administered oral drugs. Since cabozantinib is absorbed in approximately 5h, the clinical relevance of delayed absorption is considered to be limited.

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. Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Since H2 receptor antagonists have a wide therapeutic window, inhibition of OAT1/OAT3 by cabozantinib metabolites will not lead to a clinically significant interaction. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as famotidine.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Felodipine is metabolized by CYP3A4. Cabozantinib 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 hydrolyzed to an active metabolite, fenofibric acid. In vitro data suggest that fenofibric acid inhibits OAT3. In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as fenofibrate has a wide therapeutic range.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fexofenadine undergoes negligible metabolism and is mainly eliminated unchanged in the faeces. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Finasteride is metabolised by CYP3A4. Cabozantinib 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 metabolized mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also eliminated unchanged renally. Cabozantinib does not interact with this metabolic pathway. However, caution is needed when co-administered cabozantinib with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Metabolites of cabozantinib potentially inhibit OAT1 which may increase flucloxacillin concentrations. Flucloxacillin has been described as a CYP3A4 inducer and may decrease cabozantinib exposure. As the clinical relevance of this interaction is unknown, monitoring of cabozantinib efficacy may be required.

Coadministration has not been studied but should be approached with caution. Fluconazole is renally excreted. Cabozantinib is unlikely to interact with this elimination pathway. However, fluconazole is an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Concentrations of cabozantinib may increase due to inhibition of CYP3A4 and CYP2C9. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary, but close monitoring for cabozantinib toxicity is recommended. Furthermore, cabozantinib and fluconazole may cause QTc interval prolongation. Coadministration is not recommended. If coadministration is unavoidable, monitor ECG.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase to an inactive metabolite. Cabozantinib does not interfere with this elimination pathway. However, 5-FU binds to the enzyme thymidylate synthase resulting in DNA damage. This mechanism occurs in all fast dividing cells including bone marrow cells, resulting in haematological toxicity. Cabozantinib also induces haematological toxicity which could be enhanced by the use of flucytosine. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fludrocortisone is metabolized in the liver to inactive metabolites, possibly via CYP3A. Cabozantinib 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 metabolized mainly via CYP3A4 and 2C19. Cabozantinib does not inhibit or induce CYPs 3A4 and 2C19.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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. Cabozantinib does not interfere with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluticasone is metabolized by CYP3A4. Cabozantinib 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%). Cabozantinib is an inhibitor of CYP2C8 in vitro, but no clinically relevant effect on fluvastatin exposure is expected. Fluvastatin also potentially inhibits CYP2C9. However, the clinical relevance of CYP2C9 inhibition is unknown. Since CYP2C9 is a minor pathway in cabozantinib metabolism, a clinically relevant interaction is not expected.

Coadministration has not been studied. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Cabozantinib does not inhibit or induce these CYPs. However, fluvoxamine is an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Cabozantinib concentrations may increase due to CYP3A4 inhibition. The clinical relevance of this interaction is unknown. No a priori dose adjustment is necessary, but close monitoring for cabozantinib toxicity is recommended.

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

Coadministration has not been studied but should be approached with caution. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Cabozantinib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Cabozantinib does not inhibit or induce these CYPs. However, during treatment aprepitant is a moderate inhibitor of CYP3A4 and may increase concentrations of cabozantinib during the three days of coadministration. The clinical relevance of this interaction is unknown. Coadministration is not recommended. If coadministration is unavoidable, monitor closely for cabozantinib toxicity. The dose of cabozantinib may also need to be reduced during the few days of coadministration by approximately 50%. Furthermore, after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Concentrations of cabozantinib may decrease due to weak induction of CYP3A4 and CYP2C9, but this is not considered to be clinically relevant.

Coadministration has not been studied but should be avoided. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Cabozantinib does not inhibit or induce these CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of cabozantinib may decrease due to induction of CYP3A4. Therefore, coadministration should be avoided. If coadministration is unavoidable, the dose of cabozantinib should be increased. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib plasma concentrations, if available. After discontinuation of fosphenytoin treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also renally eliminated unchanged (via OATs). In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/3. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit OAT1/3 in vitro and may decrease furosemide secretion and therapeutic effect. Monitoring for furosemide toxicity and blood pressure may be required. In vitro data suggest that cabozantinib is a substrate of MRP2. Furosemide possibly inhibits MRP2 which may lead to increased plasma concentrations of cabozantinib. Care should be taken if coadministered. Monitoring for cabozantinib toxicity may be required.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gemfibrozil is metabolised by UGT2B7. Cabozantinib does not inhibit or induce UGTs. Gemfibrozil is also an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9 but in vivo data showed no clinically relevant effect on CYP2C9. Since CYP2C9 is only a minor pathway in cabozantinib metabolism, a clinically relevant interaction is not expected.

Coadministration has not been studied. Gentamicin is eliminated unchanged predominantly via glomerular filtration. There is little potential for interaction with cabozantinib via competition for active renal transport mechanisms. However, since gentamicin is nephrotoxic, renal function should be monitored periodically as changes in the renal function may impair cabozantinib elimination. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glibenclamide is mainly metabolized by CYP3A4 and to a lesser extent by CYP2C9. Cabozantinib does not inhibit or induce CYPs 3A4 and 2C9.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gliclazide is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C19. Cabozantinib does not inhibit or induce CYPs 2C9 and 2C19.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Glimepiride is mainly metabolized by CYP2C9. Cabozantinib 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 metabolized by CYP2C9. Cabozantinib 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. Granisetron is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on granisetron exposure is expected. However, granisetron may prolong the QT interval and cabozantinib has been shown to prolong the QTc interval. Caution should be taken when using granisetron with drugs that are known to prolong the QT interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied and should be approached with caution. Grapefruit juice is known to inhibit CYP3A4 enzymes and could potentially increase cabozantinib concentrations. Increased cabozantinib exposure may increase the risk of exposure-related toxicity. 

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

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

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 (UGT2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4, 2D6). Cabozantinib does not inhibit or induce these CYPs or UGTs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Heparin is thought to be eliminated via the reticuloendothelial system. Cabozantinib does not interact with this metabolic pathway.

Coadministration has not been studied. Hydralazine is metabolised via primary oxidative metabolism and acetylation. 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 cabozantinib. 

Coadministration has not been studied. Hydrochlorothiazide is not metabolized but is cleared by the kidneys via OAT1. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit OAT1/3 in vitro and may decrease hydrochlorothiazide secretion and therapeutic effect. Monitoring for hydrochlorothiazide toxicity and blood pressure may be required.

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. Cabozantinib does not inhibit or induce these CYPs. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyurea is not a substrate of CYP enzymes or P-gp. However, coadministration may increase risk of gastro-intestinal toxicity, haematological toxicity or mucositis. Monitor haematological parameters if used concurrently.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolized by alcohol dehydrogenase and partly by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Ibandronic acid is not metabolised and is cleared from the plasma by uptake into bone and elimination via renal excretion. Although no pharmacokinetic interaction is expected, ibandronic acid should be taken after an overnight fast (at least 6 hours) and before the first food or drink of the day. Medicinal products and supplements should be similarly avoided prior to taking ibandronic acid. Fasting should be continued for at least 30 minutes after taking ibandronic acid. Osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients since the use of combined therapies consisting of nitrogen-containing bisphosphonates and antiangiogenic targeted agents. This suggests that angiogenesis suppression might increase the risk of osteonecrosis of the jaw when coadministered with bisphosphonates. 

Coadministration has not been studied. Ibuprofen is metabolized mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Cabozantinib does not inhibit or induce these CYPs or UGTs. However, ibuprofen inhibits MRP2 in renal cells, which may increase cabozantinib concentrations in plasma and renal cells. The clinical relevance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Iloperidone is metabolized by CYP3A4 and CYP2D6. Cabozantinib does not inhibit or induce CYPs 3A4 and 2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipenem/cilastatin are eliminated by glomerular filtration and to a lesser extent, active tubular secretion via OAT3. Metabolites of cabozantinib possibly inhibit OAT1/3 which may increase imipenem/cilastatin concentrations. The clinical significance of this interaction is unknown. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Imipramine is metabolized by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolized by CYP2D6. Cabozantinib does not inhibit or induce these CYPs. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but should be approached with caution. Indapamide is extensively metabolised by CYP450. Cabozantinib is an in vitro inhibitor of CYP2C8, but no clinically significant effect on indapamide exposure is expected. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit OAT1/3 in vitro and may decrease indapamide secretion and therapeutic effect. Monitoring for indapamide toxicity and blood pressure may be required. Furthermore, cabozantinib has been shown to prolong the QTc interval and the use of indapamide in patients treated with QT prolonging medicinal products should be avoided. If coadministration appears necessary, close monitoring including ECG assessment 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 pharmacokinetic interaction is unlikely. However, coadministration may increase risk of neutropenia, fatigue, and thrombocytopenia. Monitor haematological parameters if used concurrently.

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. 

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. Cabozantinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolized by glucuronidation and oxidation (mainly CYP2C9). Metabolites are excreted via bile (~80%) and urine (~20%). Significant interactions are not expected with cabozantinib. 

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. Cabozantinib 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. Cabozantinib does not inhibit or induce CYP3A4. As renal elimination of unchanged drug is a minor pathway, there is little potential for an interaction.

Coadministration has not been studied but should be approached with caution. Itraconazole is metabolised primarily by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, itraconazole is an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Concentrations of cabozantinib may increase due to inhibition of CYP3A4 and CYP2C9. Coadministration of cabozantinib and ketoconazole, a strong CYP3A4 inhibitor, decreased total cabozantinib clearance by 29% and increased cabozantinib AUC by 38%. The effect of itraconazole is expected to be comparable. Concurrent use of CYP3A4 inhibitors should be avoided as cabozantinib has a relatively narrow therapeutic window and can cause dose-related QT-prolongation. If coadministration is unavoidable, monitor closely for cabozantinib toxicity. Monitor cabozantinib plasma concentrations, if available. The dose of cabozantinib should be reduced if coadministration is unavoidable. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ivabradine is metabolized by CYP3A4. Cabozantinib does not inhibit or induce CYPs. However, cabozantinib has been shown to prolong the QTc interval and the use of ivabradine in patients treated with QT prolonging medicinal products should be avoided. If the combination appears necessary, close monitoring including ECG assessment is needed.

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

Coadministration has not been studied but should be approached with caution. Ketoconazole is metabolised by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, ketoconazole is an inhibitor of CYP3A4 (strong) and P-gp. Coadministration of cabozantinib and ketoconazole decreased total cabozantinib clearance by 29% and increased cabozantinib AUC by 38%. Therefore, coadministration should be approached with caution as cabozantinib has a relatively narrow therapeutic index and can cause dose-related QT-prolongation. If coadministration is unavoidable, monitor closely for cabozantinib toxicity, including ECG assessment. Monitor cabozantinib plasma concentrations, if available. The dose of cabozantinib should be reduced if coadministration is unavoidable. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lacidipine is metabolized by CYP3A4. Cabozantinib 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. 

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. Cabozantinib does not interact with this pathway. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as lansoprazole.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion (possibly via OCT2.

Coadministration has not been studied but based on metabolism and clearance, a pharmacokinetic interaction is unlikely. Levofloxacin is eliminated renally mainly by glomerular filtration and active secretion (possibly OCT2). Cabozantinib does not interact with this metabolic pathway. However, cabozantinib should be used with caution when co-administered with a drug with a known risk of QTc interval prolongation. In patients therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levomepromazine is metabolized by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Cabozantinib does not interact with this metabolic pathway and a pharmacokinetic interaction is unlikely. However, as the effect of cabozantinib on contraceptive efficacy has not been investigated, the European product label for cabozantinib recommends the use of an additional contraceptive method, such as a barrier method.

Coadministration has not been studied Levonorgestrel is metabolized by CYP3A4 and is glucuronidated to a minor extent. Cabozantinib does not interact with this metabolic pathway and a pharmacokinetic interaction is unlikely. However, the effect of cabozantinib on contraceptive efficacy has not been investigated.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. CYP1A2 is the predominant enzyme involved in lidocaine metabolism in the range of therapeutic concentrations with a minor contribution from CYP3A4. Cabozantinib does not inhibit or induce CYPs 1A2 and 3A4. 

Coadministration has not been studied. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on linagliptin exposure is expected. However, linagliptin is an inhibitor of CYP3A4 and may increase cabozantinib concentrations. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is eliminated unchanged renally via glomerular filtration. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate therefore no pharmacokinetic interaction is expected. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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. If coadministration is judged clinically necessary, use with extreme caution since generalized infections can occur.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolized by CYP3A4 and CYP2C8. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on loperamide exposure is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loratadine is metabolized mainly by CYP3A4 and to a lesser extent by CYP2D6. Cabozantinib does not inhibit or induce CYPs 3A4 and 2D6.

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 and no effect on plasma concentrations is expected when coadministered with cabozantinib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant drug-drug interaction is unlikely. Lormetazepam is mainly glucuronidated. Cabozantinib does not interact with this metabolic pathway. 

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. Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lovastatin is metabolised by CYP3A4. Cabozantinib 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 metabolized mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on macitentan exposure is not expected.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolized by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Cabozantinib 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 (probably via OCT2). 

Coadministration has not been studied. Meropenem is primarily eliminated by the kidney and in vitro data suggest that it is a substrate of the renal transporters OAT3>OAT1. Metabolites of cabozantinib possibly inhibit OAT1/3 which may increase meropenem concentrations. The clinical significance of this interaction is unknown.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mesalazine is metabolized to N-acetyl-mesalazine by N-acetyltransferase. Cabozantinib does not interfere with this 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%). Cabozantinib does not interact with this metabolic pathway. However, metamizole is an inducer of CYP3A4 and may decrease cabozantinib concentrations. As the clinical relevance of this interaction is unknown, monitoring of cabozantinib efficacy may be required.

Coadministration has not been studied. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Cabozantinib may inhibit MATE1 and MATE2 which may increase metformin concentrations. 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 pharmacokinetic interaction is unlikely. Methadone is demethylated by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. However, cabozantinib should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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 cabozantinib, or to be altered by co-administration with cabozantinib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylprednisolone is metabolized by CYP3A4. Cabozantinib 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 metabolized by CYP450 system (mainly CYP2D6). Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Cabozantinib metabolites inhibit renal transporters OAT1/3 in vitro and may decrease metolazone secretion and therapeutic effect. Monitoring for metolazone toxicity and blood pressure may be required.

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

Coadministration has not been studied. Metronidazole is eliminated via glomerular filtration. Cabozantinib is unlikely to interfere with this elimination pathway. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, cyclosporine) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with cabozantinib cannot be excluded. Monitoring for cabozantinib toxicity is recommended. Monitoring of cabozantinib plasma concentrations should be considered, if available.

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

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

Coadministration has not been studied but should be approached with caution. Miconazole is extensively metabolized by the liver. Cabozantinib is unlikely to interact with this unspecified metabolic pathway. However, miconazole is an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong) and may increase concentrations of cabozantinib. Coadministration of cabozantinib and ketoconazole, a strong CYP3A4 inhibitor, decreased total cabozantinib clearance by 29% and increased cabozantinib AUC by 38%. The effect of miconazole is expected to be comparable. Concurrent use of CYP3A4 inhibitors should be avoided as cabozantinib has a relatively narrow therapeutic index and can cause dose-related QT-prolongation. If coadministration is unavoidable, monitor closely for cabozantinib toxicity, including ECG assessment. Monitor cabozantinib plasma concentrations, if available. The dose of cabozantinib should be reduced if coadministration is unavoidable. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor. Dermal application: No a priori dosage adjustment is recommended for cabozantinib, since miconazole is used topically and systemic exposure is limited.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Midazolam is metabolized by CYP3A4. Cabozantinib 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 metabolized by CYP3A4. Cabozantinib 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%). Cabozantinib is unlikely to interfere with this pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mirtazapine is metabolised to 8-hydroxymirtazapine by CYP2D6 and CYP1A2, and to N-desmethylmirtazapine mainly by CYP3A4. Cabozantinib 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 metabolized by CYP3A4. Cabozantinib 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 metabolized by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on montelukast exposure is not 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. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Moxifloxacin is predominantly glucuronidated by UGT1A1. Cabozantinib does not inhibit or induce UGTs. However, the product labels for moxifloxacin contraindicate its use in the presence of other drugs that prolong the QT interval, such as cabozantinib. If coadministration is unavoidable, use with extreme caution including ECG monitoring.

Coadministration has not been studied, but based on metabolism and clearance a clinically significant interaction is unlikely. Mycophenolate is mainly glucuronidated by UGT1A9 and 2B7. Mycophenolate glucuronide is excreted via OAT1/3 renal transporters. Cabozantinib metabolites inhibit renal transporters OAT1/OAT3 in vitro and could possibly increase mycophenolate glucuronide concentrations but this is unlikely to be clinical relevant since mycophenolate glucuronide is an inactive metabolite. In addition, inhibition of OAT1/OAT3 renal transporters by mycophenolic acid (active metabolite) is unlikely to interfere with cabozantinib elimination. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Cabozantinib does not inhibit or induce CYPs 2C9 and 1A2 or UGTs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nateglinide is mainly metabolized by CYP2C9 (70%) and to a lesser extent CYP3A4 (30%). Cabozantinib does not inhibit or induce CYP2C9 and 3A4.

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

Coadministration has not been studied but should be approached with caution. Nefazodone is metabolized mainly by CYP3A4 and is a strong inhibitor of CYP3A4. Concentrations of cabozantinib may increase due to CYP3A4 inhibition. Increased cabozantinib exposure may increase the risk of exposure-related toxicity. If coadministration is unavoidable, monitor closely for cabozantinib toxicity and monitor cabozantinib concentrations, if available. The cabozantinib dose should also be reduced. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

Coadministration has not been studied. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on nicardipine exposure is not expected. However, nicardipine is a weak inhibitor of CYP3A4 and may increase cabozantinib concentrations. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nifedipine is metabolised mainly by CYP3A4. Cabozantinib 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 metabolized in the liver following multiple pathways including CYP2C9. Cabozantinib 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 metabolized by CYP3A4. Cabozantinib 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 metabolized mainly by CYP3A4. Cabozantinib 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 metabolized in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). As renal excretion is not the predominant mechanism of elimination, there is little potential for a significant interaction with cabozantinib and metabolites via competition for renal elimination pathways. 

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolized mainly by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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. Ofloxacin is eliminated unchanged renally by glomerular filtration and active tubular secretion via both cationic and anionic transport systems (OAT/OCT). Metabolites of cabozantinib possibly inhibit OAT1/3 which may increase ofloxacin concentrations. The clinical significance of this interaction is unknown. Cabozantinib should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. In patients therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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). Cabozantinib 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. Olmesartan medoxomil is de-esterified to the active metabolite olmesartan which is eliminated in the faeces and urine. The role of OAT1/3 in renal secretion of angiotensin II receptor blockers appears limited, because these compounds are mostly excreted through the biliary route. Therefore, cabozantinib is unlikely to significantly inhibit renal elimination of angiotensin II receptor blockers.

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 induces CYP1A2 and inhibits CYP2C19. Cabozantinib does not interact with this pathway. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as omeprazole.

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. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on ondansetron exposure is expected. However, ondansetron may prolong the QT interval dose dependently and cabozantinib has been shown to prolong the QTc interval. Caution should be taken when using ondansetron with drugs that are known to prolong the QT interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxazepam is mainly glucuronidated. Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied but should be avoided. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Cabozantinib does not interact with this metabolic pathway. However, both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Cabozantinib concentrations may decrease due to CYP3A4 induction. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable increasing the dose of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib concentrations, if available. After discontinuation of oxcarbazepine treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxprenolol is largely metabolized via glucuronidation cabozantinib does not interact with this metabolic pathway. 

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. Cabozantinib does not inhibit or induce CYPs 3A and 2D6. 

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 3A4. Cabozantinib does not inhibit or induce CYPs 2D6 and 3A4.

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. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on palonosetron exposure is expected.

Osteonecrosis of the jaw has been reported in an increasing number of renal cell cancer patients since the use of combined therapies consisting of nitrogen-containing bisphosphonates and antiangiogenic targeted agents. This suggests that angiogenesis suppression might increase the risk of osteonecrosis of the jaw when coadministered with bisphosphonates. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4, 2D6 and 2C9. Cabozantinib does not interact with this pathway. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as pantoprazole.

Coadministration has not been studied. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. An interaction with cabozantinib cannot be excluded as the renal transporters involved in tubular secretion of para-aminosalicylic acid have not been identified.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolized 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). Cabozantinib 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. Paroxetine is mainly metabolised by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. Paroxetine is also an inhibitor of CYP2D6 (strong) and CYP2C9. Since CYP2C9 is only a minor pathway in cabozantinib metabolism, a clinically relevant interaction is not expected.

Coadministration has not been studied, but based on metabolism and clearance a pharmacokinetic interaction is unlikely. However, coadministration may increase risk of neutropenia, fatigue, and thrombocytopenia. Monitor haematological parameters if used concurrently.

Coadministration has not been. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Metabolites of cabozantinib possibly inhibit OAT1/3 which may increase concentrations of penicillins. The clinical significance of this interaction is unknown. 

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. Cabozantinib 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. Cabozantinib 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 metabolized to other inactive metabolites. Elimination occurs predominantly via the urine (possibly via OAT). In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as perindopril has a wide therapeutic range.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Perphenazine is metabolized by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pethidine is metabolized mainly by CYP2B6 and to a lesser extent by CYP3A4. Cabozantinib does not inhibit or induce CYPs 2B6 and 3A4. 

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

Coadministration has not been studied but should be avoided. Phenobarbital is metabolised by CYP2C19 and CYP2C9 (major) and to a lesser extent by CYP2E1. Cabozantinib does not inhibit or induce these CYPs. Furthermore, phenobarbital is a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Cabozantinib concentrations may decrease due to CYP3A4 induction. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable, increasing the dose of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib concentrations, if available. After discontinuation of phenobarbital treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Cabozantinib does not inhibit or induce these CYPs. A clinical adverse event (increased coagulation times) reported in a RCC patient receiving concomitant cabozantinib and warfarin was attributed to cabozantinib-related inhibition of CYP-mediated warfarin metabolism. However, this event may reflect displacement of plasma protein-bound warfarin by cabozantinib. The same adverse event may occur when cabozantinib is combined with coumarins. Close monitoring of INR/PT is recommended.

Coadministration has not been studied but should be avoided. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Cabozantinib does not inhibit or induce these CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of cabozantinib may decrease due to induction of CYP3A4. Therefore, coadministration should be avoided. If coadministration is unavoidable, the dose of cabozantinib should be increased. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib plasma concentrations, if available. After discontinuation of phenytoin treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

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. Cabozantinib does not interact with this metabolic pathway. 

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. Cabozantinib does not inhibit or induce these CYPs. However, the labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as cabozantinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pindolol is partly metabolized to hydroxymetabolites (possibly via CYP2D6) and partly eliminated unchanged in the urine (possibly via OCT2). Cabozantinib is not expected to interfere with pindolol elimination. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pioglitazone is metabolized mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Although cabozantinib is an in vitro inhibitor of CYP2C8, data with rosiglitazone suggest this is unlikely to be of clinical relevance.

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. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Piroxicam is primarily metabolized by CYP2C9. Cabozantinib 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. Cabozantinib is an inhibitor of CYP2C8 in vitro, but no clinically relevant effect on pitavastatin exposure is expected.

Coadministration has not been studied but should be approached with caution. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro may increase concentrations of posaconazole. However, this is unlikely to be clinically relevant. Posaconazole is also a strong inhibitor of CYP3A4 and may increase concentrations of cabozantinib. Coadministration of cabozantinib and ketoconazole, a strong CYP3A4 inhibitor, decreased total cabozantinib clearance by 29% and increased cabozantinib AUC by 38%. The effect of posaconazole is expected to be comparable. Concurrent use of CYP3A4 inhibitors should be avoided as cabozantinib has a relatively narrow therapeutic index and can cause dose-related QT-prolongation. If coadministration is unavoidable, monitor closely for cabozantinib toxicity, including ECG assessment. Monitor cabozantinib plasma concentrations, if available. The dose of cabozantinib should be reduced if coadministration is unavoidable. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

Coadministration has not been studied but based on limited data available an interaction appears unlikely. Potassium is eliminated renally. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6 and to a lesser extent by CYP2C9 and CYP2C19. Cabozantinib does not inhibit or induce these CYPs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Although cabozantinib is an inhibitor of CYP2C8 in vivo, a clinically relevant interaction is not expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisolone undergoes hepatic metabolism via CYP3A4. Cabozantinib 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 metabolized by CYP3A4. Cabozantinib 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). Cabozantinib is unlikely to 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. Cabozantinib does not inhibit of induce these CYPs. However, cabozantinib should be used with caution when coadministered with a drug that has a potential risk to prolong the QT interval. Cabozantinib has been shown to prolong the QT interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Promethazine is metabolized by CYP2D6. Cabozantinib does not inhibit or induce CYP2D6. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Propranolol is metabolized by 3 routes (aromatic hydroxylation by CYP2D6, N-dealkylation followed by side chain hydroxylation via CYPs 1A2, 2C19, 2D6, and direct glucuronidation). Cabozantinib 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 eliminated renally, partly by active secretion by renal transporters (of note no clinically relevant interactions were observed when prucalopride was coadministered with inhibitors of renal P-gp, OAT and OCT transporters). 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolized by CYP3A4. Cabozantinib 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. In vitro data indicate that cabozantinib metabolites inhibit OAT1/OAT3 but a clinically significant interaction is unlikely as quinapril has a wide therapeutic range.

Coadministration has not been studied. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on quinidine exposure is expected. Quinidine is also an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Cabozantinib concentrations may increase due to CYP3A4 inhibition. As the clinical relevance of this interaction is unknown, monitoring for cabozantinib toxicity may be necessary. Cabozantinib should be used with caution when co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment 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 CYPs 2C19 and 3A4. Cabozantinib does not interact with this pathway. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as rabeprazole.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Since H2 receptor antagonists have a wide therapeutic window, inhibition of OAT1/OAT3 by cabozantinib metabolites will not lead to a clinically significant interaction. The solubility of cabozantinib is pH dependent, with very low solubility observed at pH >3. However, esomeprazole (a proton pump inhibitor) had no clinically-significant effect on cabozantinib AUC and no dose adjustment is required with gastric pH modifying agents such as ranitidine.

Coadministration has not been studied but should be approached with caution. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro but a clinically relevant effect on ranolazine exposure is not expected. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Concentrations of cabozantinib may increase due to weak inhibition of CYP3A4, but this is unlikely to be clinically significant. However, caution is warranted when coadministering these drugs due to the risk of QT interval prolongation. If coadministration is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolized by CYP2C8 and CYP3A4 with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Although cabozantinib is an in vitro inhibitor of CYP2C8, data with rosiglitazone suggest this is unlikely to be of clinical relevance.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vitamin A esters are hydrolysed by pancreatic enzymes to retinol, which is then absorbed and re-esterified. Some retinol is stored in the liver. Retinol not stored in the liver undergoes glucuronide conjugation and subsequent oxidation to retinal and retinoic acid. Cabozantinib 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 avoided. Rifabutin is metabolised by CYP3A and via deacetylation. Cabozantinib does not interact with this metabolic pathway. However, rifabutin is a strong CYP3A4 and P-gp inducer. Concentrations of cabozantinib may significantly decrease due to CYP3A4 induction. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable a dose increase of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib concentrations, if available. After discontinuation of rifabutin treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration should be avoided. Rifampicin is metabolised via deacetylation. Cabozantinib does not interact with this metabolic pathway. Rifampicin is also a strong CYP3A4 and P-gp inducer. Concentrations of cabozantinib may significantly decrease due to CYP3A4 induction. Coadministration of cabozantinib and rifampicin increased cabozantinib clearance by 4.3-fold and decreased cabozantinib AUC by 77%. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable a dose increase of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib concentrations, if available. After discontinuation of rifampicin treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied but should be avoided. Rifapentine is metabolised via deacetylation. Cabozantinib does not interact with this metabolic pathway. Rifapentine is a strong CYP3A4, CYP2C8 and P-gp inducer. Concentrations of cabozantinib may significantly decrease due to CYP3A4 induction. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration with strong CYP3A4 inducers is unavoidable a dose increase of cabozantinib is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. Monitor cabozantinib concentrations, if available. After discontinuation of rifapentine treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

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. Cabozantinib does not interact with this metabolic 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. Risperidone is also a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rivaroxaban is partly metabolized in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is a substrate of P-gp and BCRP. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant interaction is expected.

Rosiglitazone is metabolized mainly by CYP2C8 and to a lesser extent by CYP2C9. Cabozantinib inhibits CYP2C8 in vitro and may increase rosiglitazone levels via this mechanism. However, no significant difference was observed in rosiglitazone plasma Cmax or AUC when coadministered with cabozantinib (100 mg).

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolized by CYP3A4. Cabozantinib 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. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on saxagliptin exposure is expected.

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 and is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely as sertindole is metabolized by CYP2D6 and CYP3A4 and cabozantinib does not inhibit or induce CYPs 2D6 and 3A4. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as cabozantinib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sildenafil is metabolized mainly by CYP3A4 and to a lesser extent by CYP2C9. Cabozantinib does not inhibit or induce CYPs 3A4 and 2C9. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sirolimus is metabolised by CYP3A4 and is a substrate of P-gp. Cabozantinib is a weak inhibitor of P-gp in vitro but no clinically relevant effect on sirolimus exposure is expected. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied. 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. Cabozantinib is a weak inhibitor of P-gp in vitro, but no clinically relevant effect on sitagliptin exposure is expected in vivo. However, sitagliptin concentrations may potentially increase due to inhibition of OAT3 by cabozantinib and its metabolite. 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. 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 cabozantinib, or to be affected if co-administered with cabozantinib. 

Coadministration has not been studied and is not recommended. Based on metabolism and clearance a pharmacokinetic interaction is unlikely as sotalol is excreted unchanged via renal elimination (possibly via OCT). However, coadministration is not recommended due to the potential of 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 cabozantinib.

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. Cabozantinib does not interact with this metabolic pathway. 

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

Coadministration has not been studied but should be avoided as St John’s wort, a P-gp inducer, may cause significant and unpredictable decreases in the plasma concentrations of cabozantinib due to induction of CYP3A4. Decreased cabozantinib exposure may lead to reduced efficacy. If coadministration is unavoidable, increasing the cabozantinib dose is recommended. Increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. The daily dose of COMETRIQ should not exceed 180 mg. Increase the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 80 mg daily or from 40 mg to 60 mg daily) as tolerated. The daily dose of CABOMETYX should not exceed 80 mg. After discontinuation of St John’s Wort treatment the CYP3A4 inducing effect may persist for over a week (mostly 2 weeks), so the cabozantinib dose should be decreased accordingly.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Streptokinase is unlikely to affect the disposition of tyrosine kinase inhibitors, or to be affected if co-administered with tyrosine kinase inhibitors.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as streptomycin is eliminated by glomerular filtration.

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. Cabozantinib 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. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Tacrolimus is metabolised mainly by CYP3A4. Cabozantinib does not inhibit or induce CYP3A4. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Concentrations of cabozantinib may increase due to CYP3A4 inhibition, although to a modest extent. No a priori dosage adjustment is recommended. Furthermore, caution is needed when co-administering cabozantinib with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely as tadalafil is metabolized by CYP3A4. Cabozantinib 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. Cabozantinib does not inhibit or induce CYP3A4 and 2D6. 

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. Cabozantinib does not interact with this elimination pathway.

Coadministration has not been studied but should be approached with caution. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Cabozantinib does not interact with this metabolic pathway. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. However, the clinical relevance of P-gp inhibition is unknown. Concentrations of cabozantinib may increase due to inhibition of CYP3A4. Coadministration should be approached with caution. If coadministration is unavoidable, monitor closely for cabozantinib toxicity and, if available, cabozantinib plasma concentrations. A dose reduction of cabozantinib may be required. Reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Reduce the daily CABOMETYX dose by 20 mg (for example, from 60 mg to 40 mg daily or from 40 mg to 20 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2-3 days after discontinuation of the strong inhibitor.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Temazepam is mainly glucuronidated. Cabozantinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolized by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYPs 2C8 and 2C19. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on terbinafine exposure is not expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolized by CYP3A4. Cabozantinib 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. Cabozantinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Theophylline is mainly metabolized by CYP1A2. Cabozantinib 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 and is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely as thioridazine is metabolized by CYP2D6 and to a lesser extent by CYP3A4 and cabozantinib does not inhibit or induce CYPs 2D6 and 3A4 However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as cabozantinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely as tiapride is excreted largely unchanged in urine. However, caution is needed when cabozantinib is co-administered with a drug with a known risk of Torsade de Pointes. In patients, therapeutic doses of cabozantinib have been shown to prolong the QTc interval. If coadministration is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied. Ticagrelor undergoes extensive CYP3A4 metabolism and is a mild inhibitor of CYP3A4. Coadministration is unlikely to affect ticagrelor concentrations but may slightly increase cabozantinib concentrations. The clinical relevance of this interaction is unknown and monitoring may be required. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tinzaparin is renally excreted as unchanged or almost unchanged drug. Cabozantinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tolbutamide is mainly metabolized by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Although cabozantinib is an in vitro inhibitor of CYP2C8, a clinically relevant effect on tolbutamide exposure is not expected.