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 microbial flora. Trametinib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Acenocoumarol is mainly metabolised by CYP2C9 and to a lesser extent by CYP1A2 and CYP2C19. Trametinib does not inhibit or induce CYPs 2C9, 1A2 and 2C19. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging 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 metabolised by glucuronidation (by several UGTs, major UGT1A6). Trametinib 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%). Trametinib does not inhibit or induce CYPs 1A2, 2C9 or 2C19.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Allopurinol is converted to oxipurinol by xanthine oxidase and aldehyde oxidase. Trametinib does not interfere with this metabolic pathway. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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. Trametinib does not inhibit or induce UGTs, CYPs or P-gp.

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

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

Coadministration has not been studied but should be approached with caution. Amiodarone is metabolised by CYP3A4 and CYP2C8. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase amiodarone concentrations. The clinical relevance of this interaction is unknown. Moreover, the major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYP3A4 (weak), CYP2C9 (moderate), CYP2D6 (moderate), CYP2C19 (weak), CYP1A1 (strong), CYP2B6 (moderate) and P-gp (strong). This does not affect trametinib. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with amiodarone is necessary, close monitoring including ECG assessment is recommended. Note: due to the long half-life of amiodarone, interactions can be observed for several months after discontinuation of amiodarone.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amitriptyline and its active metabolite nortriptyline are metabolised predominantly by CYPs 3A4, 2D6 and 2C19. Trametinib does not inhibit or induce CYPs 3A4, 2D6 or 2C19. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with amitriptyline 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 metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Trametinib does not interfere with this elimination pathway. However, the European SPC for amphotericin states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension and so monitoring may be required. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with amphotericin B 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. 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. Trametinib is unlikely to interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Anidulafungin is not metabolised hepatically but undergoes chemical degradation at physiological temperatures. Trametinib does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Apixaban is transported by P-gp and metabolised predominantly by CYP3A4, and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase apixaban concentrations. This is unlikely to be clinically relevant as CYP2C8 is only a minor metabolic pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Trametinib does not inhibit or induce these CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. No clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aripiprazole is metabolised by CYP3A4 and CYP2D6. Trametinib does not inhibit or induce CYP3A4 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 and 2D6 (minor)). Trametinib does not inhibit or induce these CYPs or UGTs.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Trametinib does not interact with this metabolic pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with astemizole 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. Atenolol is mainly eliminated unchanged in the kidney, predominantly by glomerular filtration. Trametinib does not interfere with this elimination pathway.

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

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

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. Trametinib does not interact with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with azithromycin 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. Trametinib does not interact with this metabolic pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bedaquiline is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with bedaquiline 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. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. Trametinib does not interact with this metabolic or elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Trametinib does not inhibit or induce CYP2D6 and CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with bepridil 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 metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Half of a bezafibrate dose is eliminated unchanged in the urine. Trametinib does not interact with this elimination pathway.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosentan is metabolised by CYP3A4 and CYP2C9. Trametinib does not inhibit or induce CYP3A4 or CYP2C9. Bosentan is an inducer of CYP3A4 and could potentially decrease trametinib concentrations. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 mediated metabolism is a minor pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bromazepam undergoes oxidative biotransformation. Data indicate that CYP3A4 plays a minor role in bromazepam metabolism, but other cytochromes such as CYP2D6 or CYP1A2 may also play a role. Trametinib does not inhibit or induce CYPs 3A4, 2D6 and 1A2.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bupropion is primarily metabolised by CYP2B6. Trametinib 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 metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbamazepine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2C8. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase carbamazepine plasma concentrations. However, a clinical relevant effect is not expected since CYP2C8 is a minor pathway. Furthermore, carbamazepine is an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. No clinically significant effect is expected on trametinib exposure since CYP3A4 is a minor pathway in trametinib metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and metabolism via CYP2D6 and to a lesser extent CYP2C9 and CYP1A2. Trametinib does not inhibit or induce these UGTs or CYPs.

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. Trametinib does not interact with this metabolic pathway. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Trametinib does not interfere with this elimination pathway.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Celecoxib is primarily metabolised by CYP2C9. Trametinib 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. Data indicate that cetirizine inhibits OCT2 in vitro. Trametinib is unlikely to interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chloramphenicol is predominately glucuronidated. Trametinib does not inhibit or induce UGTs. In vitro studies have shown that chloramphenicol inhibits CYP3A4. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 is a minor pathway in trametinib metabolism. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the concentrations used are unlikely to cause a clinically significant interaction.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2 and CYP3A4. Trametinib does not inhibit or induce CYPs 2D6, 1A2 or 3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with chlorpromazine 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. Chlortalidone is mainly excreted unchanged in the urine and faeces. Trametinib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ciclosporin is a substrate of CYP3A4 and P-gp, and inhibits CYP3A4 and OATP1B1. Concentrations of trametinib may increase due to CYP3A4 inhibition but this is unlikely to be clinically relevant as CYP3A4 mediated metabolism is only a minor pathway. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ciclosporin 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. Cilazapril is mainly eliminated unchanged by the kidneys. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Additionally, cimetidine is an inhibitor of CYP3A4. However, no clinically significant effect on trametinib exposure is expected since CYP3A4-mediated metabolism is only a minor pathway. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is also metabolised and partially cleared through the bile and intestine. Furthermore, ciprofloxacin is a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2, but no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ciprofloxacin 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. Trametinib does not inhibit or induce CYP3A4. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with cisapride 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 metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Trametinib does not inhibit or induce CYPs 2C19, 2D6 and 3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with citalopram 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. Clarithromycin is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. Clarithromycin is also an inhibitor of CYP3A4 and P-gp. However, no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clindamycin is metabolised by CYP3A4. Trametinib 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 but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clofazimine is largely excreted unchanged in the faeces, both as unabsorbed drug and via biliary excretion. Trametinib does not interfere with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with clofazimine 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 hydrolysed to an active metabolite, clofibric acid. Excretion of clofibric acid glucuronide is possibly performed via OAT1. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. In addition, clomipramine and desmethylclomipramine are metabolised by CYP2D6. Trametinib does not inhibit or induce CYPs 3A4, 1A2, 2C19 or 2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with clomipramine 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. Approximately 70% of administered clonidine is excreted in the urine, mainly in the form of the unchanged parent drug (40-60% of the dose). Clonidine is a weak inhibitor of OCT2. Trametinib is not a substrate of OCT2 and does not interfere with the elimination of clonidine.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clopidogrel is a prodrug and is converted to its active metabolite via CYPs 3A4, 2B6, 2C19 and 1A2. Trametinib does not inhibit or induce these CYPs. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clorazepate is rapidly converted to nordiazepam which is then metabolised to oxazepam by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cloxacillin is metabolised to a limited extent, and the unchanged drug and metabolites are excreted in the urine by glomerular filtration and renal tubular secretion. Trametinib does not interact with this metabolic or elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Clozapine is metabolised mainly by CYP1A2 and CYP3A4 and to a lesser extent by CYP2C19 and CYP2D6. Trametinib does not inhibit or induce these CYPs. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are coadministered with a drug with a known risk of Torsade de Pointes. If coadministration with clozapine is necessary, close monitoring including ECG assessment is recommended. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with dabrafenib plus trametinib.

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. Trametinib does not inhibit or induce CYP2D6, CYP3A4, UGTs or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Colchicine is metabolised by CYP3A4 and transported by P-gp. Trametinib does not inhibit or induce CYP3A4 or P-gp.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cycloserine is predominantly renally excreted via glomerular filtration. Trametinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Dabigatran is transported via P-gp and is renally excreted. Trametinib does not inhibit or induce P-gp. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys. Trametinib does not interfere with this elimination pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP450 enzymes. Trametinib is a weak inhibitor of CYP2C8 in vitro but a clinically relevant interaction is unlikely.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Desipramine is metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with desipramine 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. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Trametinib does not inhibit or induce CYPs 2C9, 2C19 and 3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dexamethasone has been described as a weak inducer of CYP3A4 and could possibly decrease trametinib plasma concentrations. However, the clinical relevance of CYP3A4 induction by dexamethasone has not been established yet. No clinically significant effect is expected on trametinib concentrations as CYP3A4 mediated metabolism is only a minor pathway.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Digoxin is renally eliminated via the renal transporters OATP4C1 and P-gp. Trametinib does not interact with this elimination pathway.

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. Trametinib does not inhibit or induce UGTs or CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diltiazem is metabolised by CYP3A4 and CYP2D6. Trametinib does not inhibit or induce CYP3A4 or CYP2D6. Diltiazem is a moderate inhibitor of CYP3A4 and may increase trametinib concentrations. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 mediated metabolism is only a minor pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with diphenhydramine 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. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Trametinib does not inhibit or induce UGTs. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

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. Trametinib does not inhibit or induce CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with disopyramide 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 metabolised by CYP2D6 (10-20%) and CYP3A4 (<1%). Trametinib does not interact with these metabolic pathways. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with dolasetron 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 metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with domperidone 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 trametinib, or to be affected if coadministered with trametinib.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40-60% of an administered dose can be accounted for in urine. Trametinib does not interact with this elimination pathway. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Drospirenone is metabolised to a minor extent via CYP3A4. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Trametinib does not inhibit or induce CYP3A4 or P-gp. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase eltrombopag concentrations. The clinical relevance of this interaction is unknown.

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). Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Enoxaparin does not undergo cytochrome metabolism but is desulphated and depolymerised in the liver, and is predominantly renally excreted. Trametinib does not interact with this metabolic or elimination pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

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

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

Coadministration has not been studied. Erythromycin is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. Erythromycin is an inhibitor of CYP3A4 but no clinically relevant effect on trametinib exposure is expected as CYP3A4 is only a minor pathway in trametinib metabolism. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with erythromycin 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. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Trametinib does not inhibit or induce CYPs 2C19, 2D6 and 3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with escitalopram is necessary, close monitoring including ECG assessment is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant effect is unlikely. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Trametinib does not interact with this pathway. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Trametinib does not inhibit or induce CYP3A4, CYP1A2 or UGTs. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation, and glucuronidation (UGT1A1). Trametinib does not interfere with this metabolic pathway. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Etonogestrel is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration should be approached with caution. Everolimus is mainly metabolised via CYP3A4 and is a substrate of P-gp. Trametinib does not inhibit or induce CYP3A4 or P-gp. Coadministration of trametinib (2 mg once daily) and everolimus (5 mg once daily) did not show a clinically relevant pharmacokinetic interaction. However, coadministration did lead to intolerability and monitoring for increased toxicity is recommended. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

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

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. Trametinib does not inhibit or induce UGTs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Trametinib does not inhibit or induce OAT1/OAT3. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. Trametinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fentanyl undergoes extensive CYP3A4 metabolism. Trametinib 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. Trametinib does not interfere with this metabolic or elimination pathway. 

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated as unchanged drug. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with flecainide 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. Flucloxacillin is predominately renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Trametinib does not interact with this elimination pathway. Flucloxacillin was also shown to induce CYP3A4 and P-gp. However, no clinically relevant effect on trametinib exposure is expected as CYP3A4 is a minor pathway and P-gp is not clinical relevant in trametinib metabolism and clearance.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluconazole is cleared primarily by renal excretion and is an inhibitor of CYPs 3A4 (moderate), 2C9 and 2C19. Trametinib does not interfere with this elimination pathway and no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with fluconazole 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. Flucytosine is metabolised to 5-fluorouracil (5-FU). 5-FU is further metabolised by dihydropyrimidine dehydrogenase (DPD) to an inactive metabolite. Trametinib does not interfere with flucytosine elimination. 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. Trametinib plus dabrafenib 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 flucytosine is coadministered with trametinib plus dabrafenib.

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fluphenazine is metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with fluphenazine is necessary, close monitoring including ECG assessment is recommended. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should also be monitored if coadministered with trametinib and dabrafenib.

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. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase the plasma concentrations of flurazepam. However, flurazepam does not have a narrow therapeutic index and CYP2C8 mediated metabolism is unlikely to be a major pathway. Therefore, a clinically relevant interaction is unlikely.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvoxamine is metabolised mainly by CYP2D6 and to a lesser extent by CYP1A2. Trametinib does not inhibit or induce CYP2D6 or CYP1A2. Furthermore, fluvoxamine is an inhibitor of CYPs 1A2, 2C19, 3A4, 2C9. However, no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is predominantly renally eliminated. Trametinib does not interact with this elimination pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosaprepitant is rapidly, almost completely, converted to the active metabolite aprepitant. Trametinib does not interact with this metabolic pathway. Aprepitant is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. Trametinib does not inhibit or induce these CYPs. Furthermore, during treatment aprepitant is a moderate inhibitor of CYP3A4, but after treatment aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. No clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Trametinib does not interact with this pathway. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. No clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also eliminated unchanged renally (via OATs). Trametinib does not inhibit or induce UGT1A9, UGT1A1 or OATs.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gabapentin is cleared mainly by glomerular filtration. Trametinib does not interact 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. Trametinib does not inhibit or induce UGT2B7. 

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Trametinib does not inhibit or induce CYPs 3A4, 2C9 and 2C19. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Granisetron is metabolised by CYP3A4 and is a substrate of P-gp. Trametinib does not inhibit or induce CYP3A4 or P-gp. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with granisetron 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. Grapefruit juice is a known inhibitor of CYP3A4. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 mediated metabolism is a minor 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. Less than 1% of a griseofulvin dose is excreted unchanged via the kidneys. Trametinib does not interfere with this elimination pathway. However, griseofulvin is a liver microsomal enzyme inducer and may lower plasma levels, reducing the efficacy of concomitantly administered medicinal products metabolised by CYP3A4, such as trametinib. However, CYP3A4-mediated metabolism is only a minor pathway. Therefore, no clinically significant interaction is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4 and 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Trametinib does not inhibit or induce UGTs, CYP3A4 and CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with haloperidol 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. Heparin is thought to be eliminated via the reticuloendothelial system. Trametinib does not interact with this metabolic pathway. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrochlorothiazide is not metabolised and is cleared by the kidneys via OAT1. Trametinib does not interfere with this metabolic or elimination pathway.

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. Trametinib does not inhibit or induce CYP2D6 or CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydrocortisone is metabolised by CYP3A4. Trametinib 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. Trametinib 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 with trametinib and dabrafenib may increase risk of gastro-intestinal toxicity, haematological toxicity or mucositis. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Trametinib does not interact with these metabolic pathways. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with hydroxyzine 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. 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. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase ibuprofen concentrations. However, a clinically relevant interaction is unlikely since CYP2C8 is only a minor pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Iloperidone is metabolised by CYP3A4 and CYP2D6. Trametinib does not inhibit or induce CYP3A4 or CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with iloperidone 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 and cilastatin are eliminated by glomerular filtration and to a lesser extent by active tubular secretion. Trametinib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Trametinib does not inhibit or induce these CYPs. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with imipramine 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. Indapamide is extensively metabolised by CYP450s. Trametinib is a weak inhibitor of CYP2C8 in vitro but as multiple CYP450 enzymes catalyse the transformation, a clinically significant interaction is unlikely. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with indapamide 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.

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. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

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. Trametinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. A small proportion of an inhaled ipratropium dose is systemically absorbed (6.9%). Metabolism is via ester hydrolysis and conjugation. Trametinib does not interact with this metabolic pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Irbesartan is metabolised by glucuronidation and oxidation (mainly CYP2C9). Trametinib does not inhibit or induce UGTs or CYP2C9.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Trametinib 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. Trametinib does not inhibit or induce CYP3A4.

Coadministration has not been studied. Itraconazole is primarily metabolised by CYP3A4 and is an inhibitor of CYP3A4 (strong) and CYP2C9. Trametinib does not inhibit or induce CYP3A4. Although, itraconazole is an inhibitor of CYP3A4, no clinically significant effect on trametinib exposure is expected as CYP3A4-mediated metabolism is a minor pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with itraconazole 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. Ivabradine is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ivabradine 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. Kanamycin is eliminated unchanged predominantly via glomerular filtration. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied. Ketoconazole is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. Ketoconazole is also an inhibitor of CYP3A4 but no clinically significant effect on trametinib exposure is expected as CYP3A4-mediated metabolism is only a minor pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ketoconazole 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. Labetalol is mainly glucuronidated (via UGT1A1 and UGT2B7). Trametinib does not inhibit or induce UGT1A1 and UGT2B7.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lacidipine is metabolised by CYP3A4. Trametinib 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. Trametinib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Trametinib does not inhibit or induce CYP2C19 and CYP3A4. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Less than 14% of a dose of levocetirizine is metabolised. Levocetirizine is mainly eliminated unchanged in the urine through both glomerular filtration and tubular secretion. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Trametinib does not interact with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with levofloxacin 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 metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with levomepromazine 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. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Trametinib does not inhibit or induce CYP3A4 or UGTs. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Levonorgestrel is metabolised by CYP3A4 and is glucuronidated to a minor extent. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor pathway. Trametinib does not inhibit or induce CYP3A4. Furthermore, linagliptin is an inhibitor of CYP3A4 but no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linezolid undergoes non-CYP mediated metabolism. Trametinib 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. Liraglutide is degraded by endogenous endopeptidases. Trametinib is unlikely to interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lisinopril is eliminated unchanged renally via glomerular filtration. Trametinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Lithium is mainly eliminated unchanged by the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate, therefore no pharmacokinetic interaction is expected with trametinib. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with lithium 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 metabolised by CYP3A4 and CYP2C8. Trametinib is a weak inhibitor of CYP2C8 in vitro. However, due to the wide therapeutic index of loperamide, this interaction is unlikely to be clinically relevant.

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

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Macitentan is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C19, 2C9 and 2C8. Trametinib is a weak inhibitor of CYP2C8 in vitro but since CYP2C8 mediated metabolism is only a minor pathway, a clinically significant interaction is unlikely.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Trametinib 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 urine. Trametinib does not interact with this elimination pathway. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metamizole is metabolised by hydrolysis to the active metabolite MMA in the gastrointestinal tract. Subsequently, metamizole is metabolised by CYPs. Metamizole is excreted via urine (90%) and faeces (10%) as metabolites. In addition, metamizole is an inducer of CYP3A4. However, no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Methadone is demethylated by CYP3A4. Trametinib does not inhibit or induce CYP3A4. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with methadone 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. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Methylphenidate is not metabolised by CYP450s to a clinically relevant extent and does not inhibit or induce CYP450s. 

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metolazone is largely excreted unchanged in the urine. Trametinib does not interact with the renal elimination of metolazone.

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

Coadministration has not been studied but elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. However, metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Since the mechanism of the interaction with CYP3A has not yet been identified, an interaction with trametinib cannot be excluded. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 is a minor pathway in trametinib metabolism.

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

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

Coadministration has not been studied. Miconazole inhibits CYP2C9 and CYP3A4, potentially increasing trametinib concentrations. Oromucosal coadministration may increase trametinib concentrations due to inhibition of CYP3A4. However, since CYP3A4-mediated metabolism is only a minor pathway, no clinically significant effect is expected on trametinib exposure. No dosage adjustment is recommended for trametinib with dermal administration of miconazole, since systemic exposure of miconazole is limited when used topically. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with miconazole 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. Midazolam is metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Midazolam is metabolised by CYP3A4. Trametinib 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%). Trametinib is unlikely to interfere with these 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. Trametinib does not inhibit or induce CYPs 2D6, 1A2 and 3A4.

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

Coadministration has not been studied. Montelukast is mainly metabolised by CYP2C8 and to a lesser extent by CYPs 3A4 and 2C9. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase montelukast concentrations. As the clinical relevance of this interaction is unknown, monitoring for toxicity may be required.

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). Trametinib does not inhibit or induce UGTs.

Coadministration has not been studied but should be avoided. Moxifloxacin is predominantly glucuronidated by UGT1A1. Trametinib does not inhibit or induce UGT1A1. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with moxifloxacin 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. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Trametinib does not inhibit or induce UGTs. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nandrolone is metabolised in the liver by alpha-reductase. Trametinib does not interact with this 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. Trametinib does not inhibit or induce UGT2B7, CYP2C9 or CYP1A2.

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nefazodone is a substrate and inhibitor of CYP3A4. Trametinib does not inhibit or induce CYP3A4 and no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with nefazodone 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. Nicardipine is metabolised mainly by CYP3A4 and to a lesser extent by CYP2D6 and CYP2C8. Trametinib is a weak inhibitor of CYP2C8 in vitro but since CYP2C8 mediated metabolism is a minor pathway, a clinically significant interaction is unlikely. Furthermore, nicardipine is an inhibitor of CYP3A4 and may increase trametinib concentrations. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 mediated metabolism is only a minor pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nicotinamide is converted to N-methylnicotinamide by nicotinamide methyltransferase which in turn is metabolised by xanthine oxidase and aldehyde oxidase. Trametinib does not interact with this metabolic pathway. 

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

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Trametinib does not interact with these metabolic pathways. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase norgestimate concentrations. However, since norgestimate does not have a narrow therapeutic index and multiple enzymes are involved in the metabolism of norgestimate, a clinically relevant interaction is unlikely. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

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. Trametinib does not inhibit or induce CYP3A4. However, it is currently unknown if hormonal contraceptives are affected by trametinib. To prevent pregnancy, female patients using hormonal contraception are advised to use an additional or alternative method during treatment and for 4 months following discontinuation of trametinib.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Nortriptyline is metabolised mainly by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with nortriptyline 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 interactions are expected. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Trametinib is unlikely to interact with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ofloxacin 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 and CYP2D6, but also by glucuronidation (UGT1A4). Trametinib does not inhibit or induce CYP1A2, CYP2D6 or UGT1A4. 

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. Trametinib does not interact with these pathways. 

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. Trametinib does not inhibit or induce CYP2C19 or CYP3A4. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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 a substrate of P-gp. Trametinib does not inhibit or induce these CYPs or P-gp. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ondansetron 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. Trametinib does not inhibit or induce UGTs. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxcarbazepine is extensively metabolised to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Trametinib does not interact with this pathway. Both oxcarbazepine and MHD are inducers of CYP3A4 (strong) and CYP3A5 and inhibitors of CYP2C19. However, no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paliperidone is primarily renally eliminated (possibly via OCT) with minimal metabolism occurring via CYP2D6 and CYP3A4. Trametinib does not interact with this metabolic or elimination pathway.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pamidronic acid is not metabolised and is cleared as unchanged drug via urine. Trametinib does not interfere with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Trametinib does not inhibit or induce CYPs 3A4, 2D6 or 2C9. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Trametinib does not interact with this elimination pathway. 

Coadministration has not been but based on metabolism and clearance a clinically significant interaction is unlikely. Paracetamol is mainly metabolised by glucuronidation (via UGTs 1A9 (major), 1A6, 1A1, and 2B15), sulfation, and to a lesser extent by oxidation (CYPs 2E1 (major), 1A2, 3A4 and 2D6). Trametinib 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 and CYP3A4. Trametinib does not inhibit or induce CYP2D6 or CYP3A4. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. However, coadministration with trametinib and dabrafenib may increase risk of neutropenia, fatigue, and thrombocytopenia. Due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perazine is metabolised mainly by CYPs 1A2, 3A4 and 2C19, and to a lesser extent by CYPs 2C9, 2D6 and 2E1, with oxidation via FMO3. Trametinib does not inhibit or induce these CYPs and 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. Trametinib 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 probably via CYP3A4 and is metabolised to other inactive metabolites. Elimination occurs predominantly via urine. Trametinib does not interfere with these pathways. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Perphenazine is metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with perphenazine 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 metabolised mainly by CYP2B6 and to a lesser extent by CYP3A4. Trametinib does not inhibit or induce CYP2B6 and CYP3A4.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenobarbital is metabolised in the liver by CYP2C19 and CYP2C9 and to a lesser extent by CYP2E1. Trametinib does not inhibit or induce these CYPs. Phenobarbital is also a potent inducer of CYP3A4 but no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Phenprocoumon is metabolised by CYP2C9 and CYP3A4. Trametinib does not inhibit or induce these CYPs. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, monitor closely for haemorrhage.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenytoin is mainly metabolised by CYP2C9 and to a lesser extent by CYP2C19. Trametinib does not inhibit or induce CYP2C9 or CYP2C19. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. No clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway.

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. Trametinib does not inhibit or induce CYP4F2. 

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Pimozide is mainly metabolised by CYP3A4 and to a lesser extent by CYP2D6. Trametinib does not inhibit or induce CYP3A4 or CYP2D6. However, the product labels for pimozide contraindicate its use in the presence of other drugs that prolong the QT interval, such as trametinib coadministered with dabrafenib. The incidences of QTc ≥501 msec and of QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with the trametinib (2% and 3%, respectively) and the dabrafenib (<1% and 3%, respectively) monotherapy populations.

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

Coadministration has not been studied. Pioglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYPs 3A4, 1A2 and 2C9. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase pioglitazone concentrations. As the clinical relevance of this interaction is unknown, monitoring for toxicity may be required.

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. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with pipotiazine 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 metabolised by CYP2C9. Trametinib 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. Trametinib is a weak inhibitor of CYP2C8 in vitro, but since CYP-mediated metabolism is only a minor pathway, a clinically relevant interaction is unlikely. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Posaconazole is primarily metabolised by UGTs. Trametinib does not inhibit or induce UGTs. Posaconazole is a strong inhibitor of CYP3A4 but no clinically significant interaction is expected on trametinib exposure as CYP3A4-mediated metabolism is only a minor pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with posaconazole is necessary, close monitoring including ECG assessment is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prasugrel is a prodrug and is converted to its active metabolite mainly by CYP3A4 and CYP2B6. Trametinib does not inhibit or induce CYP3A4 and CYP2B6. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is not metabolised to a clinically significant extent by CYPs but is a substrate of OATP1B1. Trametinib does not interfere with this elimination pathway.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prednisone is converted to the active metabolite prednisolone by 11-B-hydroxydehydrogenase. Prednisolone is then metabolised by CYP3A4. Trametinib 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. Trametinib does not interfere with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Trametinib does not inhibit or induce CYP2D6 or CYP2C19. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with prochlorperazine 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. Promethazine is metabolised by CYP2D6. Trametinib does not inhibit or induce CYP2D6. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with promethazine 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 metabolised mainly by CYP2D6 and to a lesser extent CYP1A2 and CYP3A4. Trametinib does not inhibit or induce CYPs 2D6, 1A2 and 3A4.

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

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

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Quetiapine is primarily metabolised by CYP3A4. Trametinib 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. Trametinib does not interact with this renal transporter. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Quinidine is a substrate of CYP3A4 and an inhibitor of CYP2D6. Trametinib is not metabolised by CYP2D6 and does not interfere with the metabolism of quinidine. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with quinidine 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 CYP2C19 and CYP3A4. Trametinib does not inhibit or induce CYP2C19 or CYP3A4. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

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 probably via CYP3A4, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Trametinib does not interfere with these pathways.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Trametinib does not inhibit or induce OAT1/OAT3. Furthermore, since the solubility of trametinib appears independent of pH, no clinically significant effect of gastric pH increasing drugs on trametinib exposure is expected.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic significant interaction is unlikely. Ranolazine is primarily metabolised by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Furthermore, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Although ranolazine is an inhibitor of CYP3A4, no clinically significant effect on trametinib exposure is expected as CYP3A4 mediated metabolism is a minor pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with ranolazine 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 metabolised by CYP3A4. Trametinib does not inhibit or induce CYP3A4.

Coadministration has not been studied. Repaglinide is metabolised by CYP2C8 and CYP3A4 with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase repaglinide concentrations. As the clinical relevance of this interaction is unknown, monitoring of blood glucose concentrations may be required.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifabutin is metabolised by CYP3A and via deacetylation. Rifabutin is also a potent CYP3A4 and P-gp inducer. Trametinib does not interfere with this metabolic pathway and no clinically significant effect is expected on trametinib concentrations since CYP3A4-mediated metabolism is a minor pathway and P-gp is not clinically relevant in trametinib metabolism or clearance.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rifampicin is metabolised via deacetylation. Trametinib is unlikely to interfere with this pathway. Rifampicin is also a potent CYP3A4 and P-gp inducer. However, no clinically significant effect is expected on trametinib exposure since CYP3A4 is a minor pathway and P-gp is not clinically relevant in trametinib metabolism or clearance.

Coadministration has not been but based on metabolism and clearance a clinically significant interaction is unlikely. Rifapentine is metabolised via deacetylation. Trametinib is unlikely to interfere with this metabolic pathway. Rifapentine is also a potent CYP3A4, CYP2C8 and P-gp inducer. However, no clinically significant effect is expected on trametinib exposure since CYP3A4-mediated metabolism is a minor pathway and P-gp is not clinically relevant in trametinib metabolism or clearance.

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. Trametinib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Risperidone is metabolised by CYP2D6 and to a lesser extent by CYP3A4. Risperidone is also a substrate of P-gp. Trametinib does not inhibit or induce CYP2D6, CYP3A4 or P-gp.

Coadministration has not been studied. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine (by P-gp and BCRP). Trametinib is an inhibitor of BCRP in vitro and may increase rivaroxaban concentrations. The local effect of trametinib on BCRP inhibition in the gastro-intestinal tract is unknown. Therefore, monitoring for rivaroxaban toxicity may be required. Coadministration may also increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

Coadministration has not been studied. Rosiglitazone is metabolised mainly by CYP2C8 and to a lesser extent by CYP2C9. Trametinib is a weak inhibitor of CYP2C8 in vitro and may increase rosiglitazone concentrations. As the clinical relevance of this interaction is unknown, monitoring for toxicity may be required.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Rosuvastatin is largely excreted unchanged in faeces by OATP1B1. Trametinib does not interfere with this elimination pathway. 

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

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

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

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sertindole is metabolised by CYP2D6 and CYP3A4. Trametinib does not inhibit or induce CYP2D6 and CYP3A4. However, the product labels for sertindole contraindicate its use in the presence of other drugs that prolong the QT interval, such as trametinib coadministered with dabrafenib. The incidences of QTc ≥501 msec and of QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with the trametinib (2% and 3%, respectively) and the dabrafenib (<1% and 3%, respectively) monotherapy populations.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sertraline is mainly metabolised by CYP2B6 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 3A4. Trametinib 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 metabolised mainly by CYP3A4 and to a lesser extent by CYP2C9. Trametinib does not inhibit or induce CYP3A4 and CYP2C9.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Simvastatin is metabolised by CYP3A4 and the metabolite is a substrate of OATP1B1. Trametinib does not inhibit or induce CYP3A4 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. Trametinib does not inhibit or induce CYP3A4 and P-gp. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered with trametinib plus dabrafenib.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sitagliptin is primarily eliminated in urine as unchanged drug (active secretion by OAT3, OATP4C1, and P-gp) and metabolism by CYP3A4 represents only a minor metabolic pathway. Trametinib does not interfere with this pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in erythrocytes and tissue. Cyanogen (cyanide radicals) 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 trametinib, or to be affected if coadministered with trametinib. 

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Sotalol is excreted unchanged via renal elimination. Trametinib does not interfere with this elimination pathway. However, coadministration is not recommended due to the potential for life threatening arrhythmias such as torsade de pointes and sudden death. The product labels for sotalol advises extreme caution if given with other drugs that prolong the QT interval, such as trametinib coadministered with dabrafenib. The incidences of QTc ≥501 msec and of QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with the trametinib (2% and 3%, respectively) and the dabrafenib (<1% and 3%, respectively) monotherapy populations.

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. Trametinib does not interact with this elimination pathway. 

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Spironolactone is partly metabolised by the flavin containing monooxygenases. Trametinib does not interact 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. Trametinib is a weak inhibitor of CYP2C8 in vitro. However, since stanozolol has a wide therapeutic index, a clinically relevant interaction is unlikely.

Coadministration has not been but based on metabolism and clearance a clinically significant interaction is unlikely. St John’s Wort is an inducer of CYP3A4 and P-gp. However, no clinically significant effect on trametinib exposure is expected since CYP3A4 mediated metabolism is a minor pathway and P-gp is not clinically relevant in trametinib elimination.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic 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 coadministered with tyrosine kinase inhibitors. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended.

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Trametinib 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. Trametinib does not interact with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with sulpiride 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. Tacrolimus is metabolised mainly by CYP3A4. Tacrolimus is an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. No clinically significant effect on trametinib concentrations is expected as CYP3A4 mediated metabolism is a minor pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with tacrolimus 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. Tadalafil is metabolised by CYP3A4. Trametinib 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. Trametinib does not inhibit or induce CYP3A4 and CYP2D6.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tazobactam is excreted as unchanged drug (approximately 80%) and inactive metabolite (approximately 20%) in the urine. Trametinib does not interact with this elimination pathway.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Telithromycin is a strong inhibitor of CYP3A4, but no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor pathway in trametinib metabolism.

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

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Trametinib is a weak inhibitor of CYP2C8 in vitro but since CYP2C8-mediated metabolism is a minor pathway, no clinically significant effect is expected.

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolised by CYP3A4. Trametinib 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. Trametinib 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 metabolised by CYP1A2. Trametinib does not inhibit or induce CYP1A2.

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

Coadministration has not been studied but is contraindicated. Based on metabolism and clearance a pharmacokinetic interaction is unlikely. Thioridazine is metabolised by CYP2D6, and to a lesser extent by CYP3A4. Trametinib does not inhibit or induce CYP2D6 and CYP3A4. However, the product labels for thioridazine contraindicate its use in the presence of other drugs that prolong the QT interval, such as trametinib coadministered with dabrafenib. The incidences of QTc ≥501 msec and of QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with the trametinib (2% and 3%, respectively) and the dabrafenib (<1% and 3%, respectively) monotherapy populations.

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Tiapride is excreted largely unchanged in urine. Trametinib does not interfere with this elimination pathway. No clinically relevant QTc prolonging effects were observed after trametinib monotherapy. However, the incidences of QTc ≥501 msec and QTc increase of >60 msec from baseline were significantly higher with the combination dabrafenib-trametinib (4% and 13%, respectively) compared with trametinib (2% and 3%, respectively) and dabrafenib (<1% and 3%, respectively) monotherapies. Therefore, caution is needed when trametinib and dabrafenib are used concomitantly and are co-administered with a drug with a known risk of Torsade de Pointes. If coadministration with tiapride 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. Ticagrelor is transported by P-gp and undergoes extensive CYP3A4 metabolism. Trametinib does not inhibit or induce P-gp or CYP3A4. Ticagrelor is a mild inhibitor of CYP3A4 and P-gp but no clinically significant effect on trametinib exposure is expected as CYP3A4 is a minor metabolic pathway and P-gp is not clinically relevant in trametinib elimination. However, coadministration may increase the risk of haemorrhage. If coadministration is unavoidable, close monitoring for haemorrhaging is recommended. 

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. Trametinib does not inhibit or induce CYP2D6. Furthermore, the systemic absorption of timolol after ocular administration is low and so a clinically relevant interaction is unlikely. 

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

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tolbutamide is mainly metabolised by CYP2C9 and to a lesser extent by CYPs 2C8 and 2C19. Trametinib is a weak inhibitor of CYP2C8 in vitro. However, a clinically relevant interaction is unlikely since CYP2C8-mediated metabolism is only a minor pathway.