Cancer Drug Interactions from Radboud UMC and University of Liverpool

No Interaction Expected

Methotrexate

Acarbose

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Acenocoumarol

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Methotrexate

Acetylsalicylic acid (Aspirin)

Quality of Evidence: Very Low

Summary:

Coadministration should be avoided if acetylsalicylic acid is used at a dose > 100 mg daily. If acetylsalicylic acid is used at a dose < 100 mg daily, 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). Methotrexate does not inhibit or induce UGTs. However, methotrexate is partially bound to serum albumin as is acetylsalicylic acid. Acetylsalicylic acid may displace or be displaced by methotrexate. Therefore, the toxicity of both acetylsalicylic acid and methotrexate may be increased. Acetylsalicylic acid in high doses for analgesic or anti-rheumatic use may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration of high dose acetylsalicylic acid (> 100 mg) should be avoided.

Description:

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No Interaction Expected

Methotrexate

Agomelatine

Quality of Evidence: Very Low

Summary:

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%). Methotrexate does not inhibit or induce CYPs.

Description:

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Do Not Coadminister

Methotrexate

Alendronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Alendronate is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Coadministration of methotrexate with alendronate may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided. Furthermore, 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.

Description:

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No Interaction Expected

Methotrexate

Alfentanil

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Alfuzosin

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Aliskiren

Quality of Evidence: Very Low

Summary:

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. Aliskiren is also a substrate of P-gp. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Methotrexate

Allopurinol

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Alosetron

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Alprazolam

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Aluminium hydroxide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aluminium hydroxide is not metabolised. Methotrexate is unlikely to interfere with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Ambrisentan

Quality of Evidence: Very Low

Summary:

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

Description:

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Do Not Coadminister

Methotrexate

Amikacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amikacin is eliminated by glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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No Interaction Expected

Methotrexate

Amiloride

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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Potential Weak Interaction

Methotrexate

Amiodarone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Amiodarone is metabolised by CYP3A4 and CYP2C8. The major metabolite of amiodarone, desethylamiodarone, is an inhibitor of CYPs 3A4 (weak), 2C9 (moderate), 2D6 (moderate), 2C19 (weak), 1A1 (strong), 2B6 (moderate) and P-gp (strong). Concentrations of methotrexate may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

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No Interaction Expected

Methotrexate

Amisulpride

Quality of Evidence: Very Low

Summary:

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). Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Methotrexate

Amitriptyline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Amitriptyline is metabolised predominantly by CYP2D6 and CYP2C19, with a small proportion metabolised by CYPs 3A4, 1A2 and 2C9. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Amlodipine

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Interaction

Methotrexate

Amoxicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Amoxicillin is mainly excreted in the urine by glomerular filtration and tubular secretion. In vitro data indicate that amoxicillin is a substrate of OAT3. Methotrexate does not interact with this elimination pathway. However, penicillins can reduce the renal clearance of methotrexate. Haematological and gastrointestinal toxicities have been observed in combination with high and low dose methotrexate due to elevated methotrexate concentrations. In addition, orally administered amoxicillin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

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Do Not Coadminister

Methotrexate

Amphotericin B

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Amphotericin B is not appreciably metabolised and is eliminated to a large extent in the bile. Methotrexate does not interfere with this elimination pathway. However, the European SPC for amphotericin B states that concomitant use of amphotericin B and antineoplastic agents can increase the risk of renal toxicity, bronchospasm and hypotension. Furthermore, coadministration of amphotericin B with methotrexate may decrease the renal excretion of methotrexate. Decreased excretion may lead to an increased methotrexate toxicity. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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Potential Interaction

Methotrexate

Ampicillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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. Methotrexate does not interfere with this elimination pathway. However, penicillins can reduce the renal clearance of methotrexate. Haematological and gastrointestinal toxicities have been observed in combination with high and low dose methotrexate due to elevated methotrexate concentrations. In addition, orally administered ampicillin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

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No Interaction Expected

Methotrexate

Anidulafungin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Antacids

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Antacids are not metabolised by CYPs. Methotrexate is unlikely to interfere with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Apixaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Apixaban is a substrate of P-gp and BCRP, and is metabolised by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8, 2C9 and 2C19. Methotrexate does not inhibit or induce CYPs, P-gp or BCRP.

Description:

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No Interaction Expected

Methotrexate

Aprepitant

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. During treatment, aprepitant is a moderate inhibitor of CYP3A4. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Methotrexate does not interact with this pathway.

Description:

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No Interaction Expected

Methotrexate

Aripiprazole

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Asenapine

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Astemizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Astemizole is metabolised by CYPs 2D6, 2J2 and 3A4. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Atenolol

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Methotrexate

Atorvastatin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs, P-gp or OATP1B1.

Description:

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Potential Interaction

Methotrexate

Azathioprine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Azathioprine is converted to 6-mercaptopurine which is metabolised analogously to natural purines. Methotrexate increases plasma concentrations of mercaptopurine. The combination of methotrexate and mercaptopurine may require dose adjustment. In addition, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

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Potential Interaction

Methotrexate

Azithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Azithromycin is mainly eliminated via biliary excretion; animal data suggest this may occur via P-gp and MRP2. Methotrexate is unlikely to interfere with this elimination pathway. Azithromycin is also an inhibitor of P-gp and may increase methotrexate concentrations. However, the clinical relevance of P-gp inhibition by azithromycin is unknown. In addition, orally administered azithromycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

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No Interaction Expected

Methotrexate

Beclometasone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

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Potential Interaction

Methotrexate

Bedaquiline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bedaquiline is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs. However, orally administered bedaquiline may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

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Potential Interaction

Methotrexate

Bendroflumethiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Bendroflumethiazide is mainly eliminated by hepatic metabolism (70%) and excreted unchanged in the urine (30%) via OAT1 and OAT3. In vitro data indicate that bendroflumethiazide inhibits these renal transporters but a clinically significant interaction is unlikely in the range of observed clinical concentrations. Although methotrexate is a substrate of OAT1/3, no clinically relevant effect on methotrexate exposure is expected. However, thiazide diuretics may decrease methotrexate renal excretion and methotrexate toxicity may increase. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations.

Description:

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No Interaction Expected

Methotrexate

Bepridil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bepridil is metabolised by CYP2D6 (major) and CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Betamethasone

Quality of Evidence: Very Low

Summary:

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

Description:

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Potential Weak Interaction

Methotrexate

Bezafibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Half of a bezafibrate dose is eliminated unchanged in the urine. Methotrexate is unlikely to interfere with this elimination pathway. However, in vitro data suggest that bezafibrate inhibits the renal transporter OAT1 and may increase methotrexate concentrations. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

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No Interaction Expected

Methotrexate

Bisacodyl

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Bisoprolol

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this metabolic or elimination pathway.

Description:

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No Interaction Expected

Methotrexate

Bosentan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Bosentan is a substrate and weak inducer of CYP3A4 and CYP2C9. Methotrexate does not interact with this pathway.

Description:

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No Interaction Expected

Methotrexate

Bromazepam

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Budesonide

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Buprenorphine

Quality of Evidence: Very Low

Summary:

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). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

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No Interaction Expected

Methotrexate

Bupropion

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Buspirone

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Calcium

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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No Interaction Expected

Methotrexate

Candesartan

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

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Do Not Coadminister

Methotrexate

Capreomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Capreomycin is predominantly excreted via the kidneys as unchanged drug. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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No Interaction Expected

Methotrexate

Captopril

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce OATs.

Description:

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No Interaction Expected

Methotrexate

Carbamazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Carbamazepine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2C8. Carbamazepine is also an inducer of CYPs 2C8 (strong), 2C9 (strong), 3A4 (strong), 1A2 (weak), 2B6 and UGT1A1. Methotrexate does not interact with this pathway.

Description:

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Potential Weak Interaction

Methotrexate

Carvedilol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Carvedilol undergoes glucuronidation via UGTs 1A1, 2B4 and 2B7, and additional metabolism via CYP2D6 and to a lesser extent by CYP2C9 and CYP1A2. Carvedilol is also an inhibitor of P-gp. However, the clinical relevance of P-gp inhibition by carvedilol is unknown. Concentrations of methotrexate may increase due to P-gp inhibition. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

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No Interaction Expected

Methotrexate

Caspofungin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

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Do Not Coadminister

Methotrexate

Cefalexin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cefalexin is predominantly renally eliminated unchanged by glomerular filtration and tubular secretion via OAT1 and MATE1. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. In addition, orally administered cefalexin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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Do Not Coadminister

Methotrexate

Cefazolin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cefazolin is predominantly excreted unchanged in the urine, mainly by glomerular filtration with some renal tubular secretion via OAT3. Coadministration of methotrexate and cefazolin may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided

Description:

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Do Not Coadminister

Methotrexate

Cefixime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Cefixime is renally excreted predominantly by glomerular filtration. Coadministration of methotrexate and cefixime may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Moreover, orally administered cefixime may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

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Do Not Coadminister

Methotrexate

Cefotaxime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. 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. Coadministration of methotrexate and cefotaxime may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ceftazidime

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ceftazidime is excreted predominantly by renal glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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Do Not Coadminister

Methotrexate

Ceftriaxone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. 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. Coadministration of methotrexate with ceftriaxone may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

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Do Not Coadminister

Methotrexate

Celecoxib

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Celecoxib is primarily metabolised by CYP2C9. Methotrexate does not inhibit or induce CYPs. However, celecoxib may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Methotrexate

Cetirizine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cetirizine is only metabolised to a limited extent and is eliminated unchanged in the urine through both glomerular filtration and tubular secretion. In vitro data indicate that cetirizine is also an inhibitor of OCT2. Methotrexate does not interact with this pathway.

Description:

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Potential Interaction

Methotrexate

Chloramphenicol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chloramphenicol is predominantly glucuronidated. In vitro studies have shown that chloramphenicol can inhibit metabolism mediated by CYPs 3A4 (strong), 2C19 (strong) and 2D6 (weak). Methotrexate does not interact with this pathway. However, chloramphenicol may decrease the renal excretion of methotrexate and thereby increase methotrexate toxicity. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations. Ocular use: Although chloramphenicol is systemically absorbed when used topically in the eye, the absorbed concentrations are unlikely to cause a clinically significant interaction.

Description:

See Summary

No Interaction Expected

Methotrexate

Chlordiazepoxide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Chlorphenamine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Chlorpromazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Chlorpromazine is metabolised mainly by CYP2D6, but also by CYP1A2. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Chlortalidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Chlortalidone is mainly excreted unchanged in the urine and faeces. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate is unlikely to interfere with this elimination pathway. However, thiazide diuretics may decrease methotrexate renal excretion. Methotrexate is also partially bound to serum albumin as is chlortalidone. Chlortalidone may displace or be displaced by methotrexate and both chlortalidone and methotrexate toxicity may be increased. If coadministration is necessary, monitor closely for chlortalidone and methotrexate toxicity and monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ciclosporin (Cyclosporine)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ciclosporin is a substrate of CYP3A4 and P-gp. Methotrexate does not inhibit or induce CYPs or P-gp. However, ciclosporin is also an inhibitor of CYP3A4 and OATP1B1. Methotrexate concentrations may increase due to OATP1B1 inhibition. Furthermore, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Methotrexate

Cilazapril

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Cimetidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Cimetidine is metabolised by CYP450 enzymes. Cimetidine is also a weak inhibitor of CYPs 3A4, 1A2, 2D6 and 2C19. Methotrexate does not interact with this pathway. However, in vitro data indicate that cimetidine inhibits OAT1 and OCT2 but at concentrations much higher than the observed clinical concentrations. Although methotrexate is a substrate of OAT1, no clinically relevant effect on methotrexate exposure is expected.

Description:

See Summary

Potential Interaction

Methotrexate

Ciprofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ciprofloxacin is primarily eliminated unchanged in the kidneys by glomerular filtration and tubular secretion via OAT3. It is metabolised and partially cleared through the bile and intestine. Ciprofloxacin is also a weak to moderate inhibitor of CYP3A4 and a strong inhibitor of CYP1A2. Methotrexate does not interact with this pathway. However, orally administered ciprofloxacin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Bacterial metabolism of methotrexate may decrease. In addition, renal elimination of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Cisapride

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Citalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Citalopram is metabolised by CYPs 2C19 (38%), 2D6 (31%) and 3A4 (31%). Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Clarithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clarithromycin is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs. Clarithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. Methotrexate concentrations may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. In addition, orally administered clarithromycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Clavulanic acid

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Clemastine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Clindamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clindamycin is metabolised by CYP3A4 and in vitro data suggest that it is a CYP3A4 inhibitor. Methotrexate does not interact with this pathway. However, orally administered clindamycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Clobetasol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Clofazimine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Clofazimine is largely excreted unchanged in the faeces. In vitro data suggest that clofazimine is a CYP3A4 inhibitor. Methotrexate does not interact with this pathway. However, orally administered clofazimine may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Therefore, coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Clofibrate

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Clomipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Clomipramine is metabolised by CYPs 3A4, 1A2 and 2C19 to desmethylclomipramine, an active metabolite which has a higher activity than the parent drug. Clomipramine and desmethylclomipramine are both metabolised by CYP2D6. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Clonidine

Quality of Evidence: Very Low

Summary:

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 also a weak inhibitor of OCT2. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Clopidogrel

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Clorazepate

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Cloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. 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. Methotrexate is unlikely to interfere with this elimination pathway. However, penicillins can reduce the renal clearance of methotrexate. Haematological and gastrointestinal toxicities have been observed in combination with high and low dose methotrexate due to elevated methotrexate concentrations. In addition, orally administered cloxacillin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Clozapine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Codeine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Colchicine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Cycloserine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Cycloserine is predominantly renally excreted via glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered cycloserine may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Dabigatran

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dabigatran is transported via P-gp and is renally excreted. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Dalteparin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dalteparin is excreted largely unchanged via the kidneys. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Dapsone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metabolism of dapsone is mainly by N-acetylation with a component of N-hydroxylation, and is via multiple CYP450 enzymes. Methotrexate does not inhibit or induce CYPs. However, orally administered dapsone may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Desipramine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Desogestrel

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Desogestrel is a prodrug which is activated to etonogestrel by CYP2C9 (and possibly CYP2C19); the metabolism of etonogestrel is mediated by CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Dexamethasone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dexamethasone is a substrate of CYP3A4. Dexamethasone has also been described as a weak inducer of CYP3A4, but the induction of CYP3A4 by dexamethasone has yet to be established. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Dextropropoxyphene

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Diamorphine (diacetylmorphine)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Diazepam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Diclofenac

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Diclofenac is partly glucuronidated by UGT2B7 and partly oxidised by CYP2C9. Methotrexate does not inhibit or induce CYPs or UGTs. However, diclofenac may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Digoxin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Dihydrocodeine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Diltiazem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Diltiazem is metabolised by CYP3A4 and CYP2D6. Diltiazem is also a moderate inhibitor of CYP3A4 and P-gp. The clinical relevance of P-gp inhibition by diltiazem is unknown. Concentrations of methotrexate may increase due to P-gp inhibition. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required. Furthermore, after coadministration diltiazem did not prevent the nephrotoxic effects of methotrexate.

Description:

See Summary

No Interaction Expected

Methotrexate

Diphenhydramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Diphenhydramine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 1A2, 2C9 and 2C19. Diphenhydramine is also a weak inhibitor of CYP2D6. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Dipyridamole

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and based on metabolism and clearance a clinically significant interaction is unlikely. Dipyridamole is glucuronidated by many UGTs, specifically those of the UGT1A subfamily. Methotrexate does not inhibit or induce UGTs. Coadministration of oral dipyridamole and IV or IM methotrexate was well tolerated and did not appear to result in any more myelotoxicity or mucositis than that expected for methotrexate alone.

Description:

See Summary

No Interaction Expected

Methotrexate

Disopyramide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Disopyramide is metabolised by CYP3A4 (25%) and 50% of the drug is eliminated unchanged in the urine. Methotrexate does not interact with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Dolasetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant 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%). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Domperidone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Dopamine

Quality of Evidence: Very Low

Summary:

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 methotrexate, or to be affected if coadministered with methotrexate.

Description:

See Summary

No Interaction Expected

Methotrexate

Doxazosin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Doxepin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Doxycycline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Doxycycline is excreted in the urine and faeces as unchanged active substance. Between 40-60% of an administered dose can be accounted for in the urine. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered doxycycline may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Dronabinol

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Drospirenone

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Drospirenone is metabolised to a minor extent via CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Dulaglutide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dulaglutide is degraded by endogenous endopeptidases. Methotrexate does not interact with this metabolic pathway. 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.

Description:

See Summary

No Interaction Expected

Methotrexate

Duloxetine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Dutasteride

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Dydrogesterone

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Dydrogesterone is metabolised to dihydrodydrogesterone (possibly via CYP3A4). Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Edoxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Edoxaban is partially metabolised by CYP3A4 (<10%) and is transported via P-gp. Methotrexate does not inhibit or induce CYPs or P-gp.

Description:

See Summary

No Interaction Expected

Methotrexate

Eltrombopag

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Eltrombopag is metabolised by cleavage conjugation (via UGT1A1 and UGT1A3) and oxidation (via CYP1A2 and CYP2C8). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Enalapril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Enoxaparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Eprosartan

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Ertapenem

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Erythromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Erythromycin is a substrate of CYP3A4 and P-gp. Methotrexate does not inhibit or induce CYPs or P-gp. Erythromycin is also an inhibitor of CYP3A4 (moderate) and P-gp. Methotrexate concentrations may increase due to P-gp inhibition. The clinical relevance of P-gp inhibition on methotrexate exposure is unknown. In addition, orally administered erythromycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Escitalopram

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Escitalopram is metabolised by CYPs 2C19 (37%), 2D6 (28%) and 3A4 (35%) to form N-desmethylescitalopram. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Esomeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Esomeprazole is metabolised by CYP2C19 and CYP3A4. Esomeprazole is also an inhibitor of CYP2C19. Methotrexate does not interact with this pathway. However, studies have observed that coadministration of proton pump inhibitors and methotrexate may result in elevated and prolonged methotrexate plasma concentrations due to delayed elimination. This may lead to increased methotrexate toxicity, especially if methotrexate is administered at a high dose. Coadministration should be approached with caution. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Estazolam

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Estradiol

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Estradiol is metabolised by CYP3A4, CYP1A2 and is glucuronidated. Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

Potential Interaction

Methotrexate

Ethambutol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ethambutol is partly metabolised by alcohol dehydrogenase (20%) and partly eliminated unchanged in the faeces (20%) and urine (50%). Methotrexate does not interact with this metabolic or elimination pathway. However, orally administered ethambutol may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ethinylestradiol

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ethinylestradiol undergoes oxidation (CYP3A4>CYP2C9), sulfation and glucuronidation (UGT1A1). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

Potential Interaction

Methotrexate

Ethionamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ethionamide is extensively metabolised in the liver; animal studies suggest involvement of flavin-containing monooxygenases. Methotrexate does not interact with this metabolic pathway. However, orally administered ethionamide may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Methotrexate

Etonogestrel

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Etonogestrel is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Everolimus (Immunosuppressant)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Everolimus is mainly metabolised by CYP3A4 and is a substrate of P-gp. Methotrexate does not inhibit or induce CYPs or P-gp. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Exenatide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Ezetimibe

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Famotidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Famotidine is excreted via OAT1/OAT3. Methotrexate does not inhibit or induce OATs.

Description:

See Summary

No Interaction Expected

Methotrexate

Felodipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Methotrexate

Fenofibrate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Fenofibrate is hydrolysed to an active metabolite, fenofibric acid. In vitro data suggest that fenofibric acid inhibits OAT3 and may increase methotrexate concentrations. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Fentanyl

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fexofenadine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Finasteride

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fish oils

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Flecainide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Flecainide is metabolised mainly via CYP2D6, with a proportion (approximately 30%) of the parent drug also renally eliminated unchanged. Methotrexate does not interact with this metabolic or elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Flucloxacillin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Flucloxacillin is mainly renally eliminated partly by glomerular filtration and partly by active secretion via OAT1. Flucloxacillin has been described as a CYP3A4 inducer. Methotrexate does not interact with this pathway. However, penicillins can reduce the renal clearance of methotrexate. Haematological and gastrointestinal toxicities have been observed in combination with high and low dose methotrexate due to elevated methotrexate concentrations. In addition, orally administered flucloxacillin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Fluconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluconazole is cleared primarily by renal excretion and is also an inhibitor of CYPs 3A4 (moderate), 2C9 (moderate) and 2C19 (strong). Methotrexate does not interact with this pathway.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Flucytosine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fludrocortisone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Flunitrazepam

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Fluoxetine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fluphenazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Flurazepam

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Fluticasone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fluvastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fluvastatin is mainly metabolised by CYP2C9 (75%) and to a lesser extent by CYP3A4 (20%) and CYP2C8 (5%). Fluvastatin also potentially inhibits CYP2C9, but the clinical relevance of CYP2C9 inhibition is unknown. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Fluvoxamine

Quality of Evidence: Very Low

Summary:

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. Fluvoxamine is also an inhibitor of CYPs 1A2 (strong), 2C19 (strong), 3A4 (moderate), 2C9 (weak-moderate) and 2D6 (weak). Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Fondaparinux

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Fondaparinux does not undergo cytochrome metabolism but is predominantly renally eliminated. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Formoterol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Fosaprepitant

Quality of Evidence: Very Low

Summary:

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. Aprepitant is mainly metabolized by CYP3A4 and to a lesser extent by CYP1A2 and CYP2C19. During treatment, aprepitant is a moderate inhibitor of CYP3A4. After treatment, aprepitant is a weak inducer of CYP3A4, CYP2C9 and UGT. Methotrexate does not interact with this pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Fosphenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Fosphenytoin is rapidly converted to the active metabolite phenytoin. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Methotrexate does not inhibit or induce CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of methotrexate may decrease due to P-gp induction. Furthermore, methotrexate is partially bound to serum albumin as is phenytoin. Phenytoin may displace or be displaced by methotrexate. Therefore, the toxicity of phenytoin and methotrexate may increase. Phenytoin may decrease the renal elimination of methotrexate and thereby further increasing methotrexate toxicity. If coadministration is necessary, monitor closely for phenytoin and methotrexate toxicity. Monitor phenytoin and methotrexate plasma concentrations, if available.

Description:

See Summary

Potential Interaction

Methotrexate

Furosemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Furosemide is glucuronidated mainly in the kidney (UGT1A9) and to a lesser extent in the liver (UGT1A1). A large proportion of furosemide is also renally eliminated unchanged (via OATs). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. In vitro data indicate that furosemide is an inhibitor of the renal transporters OAT1/3 and may increase concentrations of methotrexate. Furosemide may also decrease methotrexate renal excretion due to competitive inhibition of tubular secretion. Therefore, methotrexate toxicity may be increased. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Gabapentin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Methotrexate

Gemfibrozil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Gemfibrozil is metabolised by UGT2B7. Methotrexate does not inhibit or induce UGTs. However, gemfibrozil is an inhibitor of CYP2C8 (strong), OATP1B1 and OAT3. In vitro data indicate gemfibrozil to be a strong inhibitor of CYP2C9 but in vivo data showed no clinically relevant effect on CYP2C9. Methotrexate concentrations may increase due to inhibition of OATP1B1 and OAT3. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

Do Not Coadminister

Methotrexate

Gentamicin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Gentamicin is eliminated unchanged predominantly via glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Methotrexate

Gestodene

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Gestodene is metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2C19. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Glibenclamide (Glyburide)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Gliclazide

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Glimepiride

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Glipizide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Granisetron

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Grapefruit juice

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Grapefruit juice is known to inhibit CYP3A4 enzymes. Methotrexate is not metabolised by CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Green tea

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Griseofulvin

Quality of Evidence: Very Low

Summary:

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. Griseofulvin is also a liver microsomal enzyme inducer and may lower plasma levels. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Haloperidol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Haloperidol has a complex metabolism as it undergoes glucuronidation (UGTs 2B7>1A4, 1A9), carbonyl reduction as well as oxidative metabolism (CYP3A4 and CYP2D6). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Heparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Hydralazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydralazine is metabolised via primary oxidative metabolism and acetylation. In vitro studies have suggested that hydralazine is a mixed enzyme inhibitor, which may weakly inhibit CYP3A4 and CYP2D6. Methotrexate does not interact with this pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Hydrochlorothiazide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Hydrochlorothiazide is not metabolised but is cleared by the kidneys via OAT1. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate is unlikely to interfere with this elimination pathway. However, thiazide diuretics may decrease methotrexate renal excretion and methotrexate toxicity may be increased. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Hydrocodone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Hydrocortisone (oral)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Hydrocortisone (topical)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Hydromorphone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce UGTs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Hydroxyurea (Hydroxycarbamide)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Hydroxyzine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Hydroxyzine is partly metabolised by alcohol dehydrogenase and partly by CYP3A4. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ibandronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ibandronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Coadministration of methotrexate with ibandronic acid may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided. Furthermore, 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.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ibuprofen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Ibuprofen is metabolised mainly by CYP2C9 and to a lesser extent by CYP2C8 and direct glucuronidation. Methotrexate does not inhibit or induce CYPs or UGTs. However, ibuprofen is nephrotoxic and may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Iloperidone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Imipenem/Cilastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipenem/cilastatin are eliminated by glomerular filtration and to a lesser extent by active tubular secretion. Methotrexate is unlikely to interfere with these elimination pathways.

Description:

See Summary

No Interaction Expected

Methotrexate

Imipramine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Imipramine is metabolised by CYPs 3A4, 2C19 and 1A2 to desipramine. Imipramine and desipramine are both metabolised by CYP2D6. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Indapamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Indapamide is extensively metabolised by CYP450s. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate does not inhibit or induce CYPs or OATs.

Description:

See Summary

No Interaction Expected

Methotrexate

Insulin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Methotrexate

Interferon alpha

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Interleukin 2 (Aldesleukin)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a pharmacokinetic interaction is unlikely. Interleukin-2 is mainly eliminated by glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Ipratropium bromide

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Irbesartan

Quality of Evidence: Very Low

Summary:

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). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Iron supplements

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Isoniazid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Isoniazid is acetylated in the liver to form acetylisoniazid which is then hydrolysed to isonicotinic acid and acetylhydrazine. Methotrexate does not interact with this metabolic pathway. However, orally administered isoniazid may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Isosorbide dinitrate

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Itraconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Itraconazole is primarily metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs. Itraconazole is also an inhibitor of CYP3A4 (strong), CYP2C9 (weak), P-gp and BCRP. Concentrations of methotrexate may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Ivabradine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Kanamycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Kanamycin is eliminated unchanged predominantly via glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Ketoconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ketoconazole is a substrate of CYP3A4. Methotrexate does not inhibit or induce CYPs. Ketoconazole is also an inhibitor of CYP3A4 (strong) and P-gp. Concentrations of methotrexate may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Labetalol

Quality of Evidence: Very Low

Summary:

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). Methotrexate does not inhibit or induce UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Lacidipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Lactulose

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Lansoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Lansoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Methotrexate does not inhibit or induce CYPs. However, studies have observed that coadministration of proton pump inhibitors and methotrexate may result in elevated and prolonged methotrexate plasma concentrations due to delayed elimination. This may lead to increased methotrexate toxicity, especially if methotrexate is administered at a high dose. Coadministration should be approached with caution. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Lercanidipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Levocetirizine

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Levofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Levofloxacin is renally eliminated mainly by glomerular filtration and active secretion (possibly OCT2). Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered levofloxacin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Levomepromazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Levonorgestrel

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Levonorgestrel is mainly metabolised by CYP3A4 and is glucuronidated to a minor extent. Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

Potential Interaction

Methotrexate

Levonorgestrel (Emergency Contraception)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Levothyroxine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Lidocaine (Lignocaine)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Linagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Linagliptin is mainly eliminated as parent compound in faeces with metabolism by CYP3A4 representing a minor elimination pathway. Linagliptin is also a substrate of P-gp and is a weak inhibitor of CYP3A4. Methotrexate does not interact with this pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Linezolid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Linezolid undergoes non-CYP mediated metabolism. Methotrexate is unlikely to interfere with this metabolic pathway. However, orally administered linezolid may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Liraglutide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Lisinopril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Lithium

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Lithium is mainly eliminated unchanged through the kidneys. Lithium is freely filtered at a rate that is dependent upon the glomerular filtration rate. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to an increased methotrexate toxicity. Therefore, coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Methotrexate

Live vaccines

Quality of Evidence: Very Low

Summary:

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 generalised infections can occur.

Description:

See Summary

No Interaction Expected

Methotrexate

Loperamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Loperamide is mainly metabolised by CYP3A4 and CYP2C8, and is a substrate of P-gp. Methotrexate does not inhibit or induce CYPs or P-gp.

Description:

See Summary

No Interaction Expected

Methotrexate

Loratadine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Lorazepam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Lorazepam undergoes non-CYP mediated elimination. Methotrexate is unlikely to interfere with this unspecified metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Lormetazepam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Losartan

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Lovastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Macitentan

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Magnesium

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Maprotiline

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Medroxyprogesterone (depot)

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Medroxyprogesterone (non-depot)

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Medroxyprogesterone is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Mefenamic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Mefenamic acid is metabolised by CYP2C9 and glucuronidated by UGT2B7 and UGT1A9. Methotrexate does not inhibit or induce CYPs or UGTs. However, mefenamic acid may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Megestrol acetate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Megestrol acetate is mainly eliminated in the urine. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Meropenem

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Mesalazine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Metamizole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Metamizole is metabolised by hydrolysis to the active metabolite MAA in the gastrointestinal tract. Metamizole is metabolised in serum and excreted via urine (90%) and faeces (10%). Metamizole is an inducer of CYP3A4. Methotrexate does not interact with this pathway. However, metamizole may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Metformin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Metformin is mainly eliminated unchanged in the urine and is a substrate of OCT1/2/3, MATE1 and MATE2K. Methotrexate does not inhibit or induce OCTs or MATEs.

Description:

See Summary

No Interaction Expected

Methotrexate

Methadone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Methyldopa

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Methylphenidate

Quality of Evidence: Very Low

Summary:

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. Therefore, there is little potential for methylphenidate to affect disposition of methotrexate, or to be affected if coadministered with methotrexate.

Description:

See Summary

No Interaction Expected

Methotrexate

Methylprednisolone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Metoclopramide

Quality of Evidence: Very Low

Summary:

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). Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Metolazone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metolazone is largely excreted unchanged in the urine. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate is unlikely to interfere with this elimination pathway. However, thiazide diuretics may decrease methotrexate renal excretion and methotrexate toxicity may be increased. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Metoprolol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Metronidazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Metronidazole is eliminated via glomerular filtration. Elevated plasma concentrations have been reported for some CYP3A substrates (e.g. tacrolimus, ciclosporin) with metronidazole. Metronidazole did not increase concentrations of several CYP3A probe drugs (e.g. midazolam, alprazolam). Methotrexate is unlikely to interfere with this pathway. However, orally administered metronidazole may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Mexiletine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Mianserin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Miconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Miconazole is extensively metabolized by the liver. Methotrexate is unlikely to interact with this unspecified metabolic pathway. Miconazole is also an inhibitor of CYP2C9 (moderate) and CYP3A4 (strong). Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Midazolam (oral)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Midazolam (parenteral)

Quality of Evidence: Very Low

Summary:

Description:

See Summary

No Interaction Expected

Methotrexate

Milnacipran

Quality of Evidence: Very Low

Summary:

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%). Methotrexate does not interact with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Mirtazapine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Mometasone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Montelukast

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Morphine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Moxifloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Moxifloxacin is predominantly glucuronidated by UGT1A1. Methotrexate does not inhibit or induce UGTs. However, orally administered moxifloxacin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Mycophenolate

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Mycophenolate is mainly glucuronidated by UGT1A9 and UGT2B7. Methotrexate does not inhibit or induce UGTs. The active metabolite of mycophenolate, mycophenolic acid, is an inhibitor of OAT1/OAT3 and may increase methotrexate concentrations. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required. Furthermore, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Nadroparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Nandrolone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Naproxen

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Naproxen is mainly glucuronidated by UGT2B7 (major) and demethylated to desmethylnaproxen by CYP2C9 (major) and CYP1A2. Methotrexate does not inhibit or induce CYPs or UGTs. However, naproxen may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Nateglinide

Quality of Evidence: Very Low

Summary:

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%). Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Nebivolol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Nefazodone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Nefazodone is metabolised mainly by CYP3A4 and is also a strong inhibitor of CYP3A4. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Nicardipine

Quality of Evidence: Very Low

Summary:

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. Nicardipine is also a weak inhibitor of CYP3A4. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Nicotinamide (Niacinamide)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Nifedipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Nimesulide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Nimesulide is extensively metabolised in the liver following multiple pathways including CYP2C9. Methotrexate does not inhibit or induce CYPs. However, nimesulide may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Nisoldipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Nitrendipine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Nitrofurantoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Nitrofurantoin is partly metabolised in the liver via glucuronidation and N-acetylation and partly eliminated in the urine as unchanged drug (30-40%). Methotrexate does not interact with this metabolic or elimination pathway. However, orally administered nitrofurantoin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Do Not Coadminister

Methotrexate

Norelgestromin

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norelgestromin is metabolised to norgestrel (possibly by CYP3A4). Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Norethisterone (Norethindrone)

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norethisterone is extensively biotransformed, first by reduction and then by sulfate and glucuronide conjugation. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Norgestimate

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestimate is rapidly deacetylated to the active metabolite which is further metabolised via CYP450. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Norgestrel

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Norgestrel is a racemic mixture with levonorgestrel being biologically active. Levonorgestrel is mainly metabolized by CYP3A4 and is glucuronidated to a minor extent. Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Nortriptyline

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Nystatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Ofloxacin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Ofloxacin is renally eliminated unchanged by glomerular filtration and active tubular secretion via both cationic and anionic transport systems. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered ofloxacin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Olanzapine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Olanzapine is metabolised mainly by CYP1A2 (major) and CYP2D6, but also by glucuronidation (UGT1A4). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Olmesartan

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Omeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Omeprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYP3A4. Omeprazole is also an inducer of CYP1A2 and an inhibitor of CYP2C19. Methotrexate does not interact with this pathway. However, studies have observed that coadministration of proton pump inhibitors and methotrexate may result in elevated and prolonged methotrexate plasma concentrations due to delayed elimination. This may lead to increased methotrexate toxicity, especially if methotrexate is administered at a high dose. Coadministration should be approached with caution. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Ondansetron

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Oxazepam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Oxcarbazepine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Oxcarbazepine is extensively metabolized to the active metabolite monohydroxyderivate (MHD) through cystolic enzymes. Both oxcarbazepine and MHD are inducers of CYP3A4 (moderate) and CYP3A5 and are inhibitors of CYP2C19. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Oxprenolol

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Oxycodone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Paliperidone

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Palonosetron

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Pamidronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Pamidronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Coadministration of methotrexate with pamidronic acid may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided.

Description:

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Potential Interaction

Methotrexate

Pantoprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pantoprazole is mainly metabolised by CYP2C19 and to a lesser extent by CYPs 3A4, 2D6 and 2C9. Methotrexate does not inhibit or induce CYPs. However, studies have observed that coadministration of proton pump inhibitors and methotrexate may result in elevated and prolonged methotrexate plasma concentrations due to delayed elimination. This may lead to increased methotrexate toxicity, especially if methotrexate is administered at a high dose. Coadministration should be approached with caution. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Potential Interaction

Methotrexate

Para-aminosalicylic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Para-aminosalicylic acid and its acetylated metabolite are mainly excreted in the urine by glomerular filtration and tubular secretion. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered para-aminosalicylic acid may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Paracetamol (Acetaminophen)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Paroxetine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Paroxetine is mainly metabolised by CYP2D6. Paroxetine is also an inhibitor of CYP2D6 (strong) and CYP2C9. Methotrexate does not interact with this pathway.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Peginterferon alfa-2a

Quality of Evidence: Very Low

Summary:

Description:

See Summary

Potential Interaction

Methotrexate

Penicillins

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Penicillins are mainly eliminated in the urine (20% by glomerular filtration and 80% by tubular secretion via OAT). Methotrexate is unlikely to interfere with this elimination pathway. However, penicillins can reduce the renal clearance of methotrexate. Haematological and gastrointestinal toxicities have been observed in combination with high and low dose methotrexate due to elevated methotrexate concentrations. In addition, penicillins may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Perazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Perazine is mainly metabolised by CYPs 1A2, 3A4 and 2C19, and to a lesser extent by CYPs 2C9, 2D6 and 2E1, with oxidation via FMO3. Methotrexate does not inhibit or induce CYPs or FMO3.

Description:

See Summary

No Interaction Expected

Methotrexate

Periciazine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Perindopril

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Perphenazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Pethidine (Meperidine)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Phenelzine

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Phenobarbital (Phenobarbitone)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Phenobarbital is metabolized by CYP2C19 and CYP2C9 (major) and to a lesser extent by CYP2E1. Phenobarbital is also a strong inducer of CYPs 3A4, 2C9, 2C8 and UGTs. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Phenprocoumon

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Phenytoin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Phenytoin is mainly metabolized by CYP2C9 and to a lesser extent by CYP2C19. Methotrexate does not inhibit or induce CYPs. However, phenytoin is a potent inducer of CYP3A4, UGT and P-gp. Concentrations of methotrexate may decrease due to P-gp induction. Furthermore, methotrexate is partially bound to serum albumin as is phenytoin. Phenytoin may displace or be displaced by methotrexate. Therefore, the toxicity of phenytoin and methotrexate may increase. Phenytoin may decrease the renal elimination of methotrexate and thereby further increasing methotrexate toxicity. If coadministration is necessary, monitor closely for phenytoin and methotrexate toxicity. Monitor phenytoin and methotrexate plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Methotrexate

Phytomenadione (Vitamin K)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Pimozide

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Pindolol

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Pioglitazone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Pipotiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. The metabolism of pipotiazine has not been well described but may involve CYP2D6. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Do Not Coadminister

Methotrexate

Piroxicam

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Piroxicam is primarily metabolised by CYP2C9. Methotrexate does not inhibit or induce CYPs. However, piroxicam may interact with the renal elimination of methotrexate. Coadministration of methotrexate and NSAIDs led to severe adverse events, including acute renal failure and pancytopenia, due to elevated and prolonged methotrexate concentrations. Therefore, coadministration should be avoided.

Description:

See Summary

No Interaction Expected

Methotrexate

Pitavastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Posaconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Posaconazole is primarily metabolised by UGTs and is a substrate of P-gp. Posaconazole is also a strong inhibitor of CYP3A4. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Potassium

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Prasugrel

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Pravastatin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Pravastatin is minimally metabolised via CYP enzymes and is a substrate of OATP1B1. Methotrexate does not inhibit or induce CYPs or OATP1B1.

Description:

See Summary

No Interaction Expected

Methotrexate

Prazosin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Prednisolone

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and based on metabolism and clearance a clinically significant interaction is unlikely. Prednisolone undergoes hepatic metabolism via CYP3A4. Methotrexate does not inhibit or induce CYPs. After coadministration, no significant change in prednisolone clearance was found.

Description:

See Summary

No Interaction Expected

Methotrexate

Prednisone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs. After coadministration with prednisolone, no significant change in prednisolone clearance was found.

Description:

See Summary

No Interaction Expected

Methotrexate

Pregabalin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically relevant drug interaction is unlikely. Pregabalin is cleared mainly by glomerular filtration (90% as unchanged drug). Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Prochlorperazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prochlorperazine is metabolised by CYP2D6 and CYP2C19. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Promethazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Propafenone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Propranolol

Quality of Evidence: Very Low

Summary:

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). Methotrexate does not inhibit or induce CYPs or UGTs.

Description:

See Summary

No Interaction Expected

Methotrexate

Prucalopride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Prucalopride is minimally metabolised and mainly renally eliminated, partly by active secretion by renal transporters. Prucalopride is also a substrate of P-gp. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Pyrazinamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Pyrazinamide is mainly metabolised by xanthine oxidase. Methotrexate does not interact with this metabolic pathway. However, the potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated, but hepatotoxicity has been reported in some cases. In addition, orally administered pyrazinamide may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations. Monitoring for hepatotoxicity should be considered.

Description:

See Summary

No Interaction Expected

Methotrexate

Pyridoxine (Vitamin B6)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Quetiapine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Quinapril

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Quinidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Quinidine is mainly metabolised by CYP3A4 and to a lesser extent by CYP2C9 and CYP2E1. Quinidine is also a substrate of P-gp. Methotrexate does not inhibit or induce CYPs or P-gp. However, quinidine is an inhibitor of CYP2D6 (strong), CYP3A4 (weak) and P-gp (moderate). Concentrations of methotrexate may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

Potential Interaction

Methotrexate

Rabeprazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rabeprazole is mainly metabolised via non-enzymatic reduction and to a lesser extent by CYP2C19 and CYP3A4. Methotrexate does not interact with this pathway. However, studies have observed that coadministration of proton pump inhibitors and methotrexate may result in elevated and prolonged methotrexate plasma concentrations due to delayed elimination. This may lead to increased methotrexate toxicity, especially if methotrexate is administered at a high dose. Coadministration should be approached with caution. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Ramipril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ramipril is hydrolysed to the active metabolite ramiprilat, and is metabolised to the diketopiperazine ester, diketopiperazine acid and the glucuronides of ramipril and ramiprilat. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Ranitidine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ranitidine is excreted via OAT1/OAT3. Methotrexate does not inhibit or induce OATs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Ranolazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Ranolazine is primarily metabolized by CYP3A4 and to a lesser extent by CYP2D6. Ranolazine is also a substrate of P-gp. Methotrexate does not inhibit or induce CYPs or P-gp. However, ranolazine is a weak inhibitor of P-gp, CYP3A4 and CYP2D6. Methotrexate concentrations may increase due to P-gp inhibition. As the clinical relevance of this interaction is unknown, monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Reboxetine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Repaglinide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Repaglinide is metabolised by CYP2C8 and CYP3A4, with clinical data indicating it is a substrate of the hepatic transporter OATP1B1. Methotrexate does not inhibit or induce CYPs or OATP1B1.

Description:

See Summary

No Interaction Expected

Methotrexate

Retinol (Vitamin A)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Riboflavin (Vitamin B2)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Interaction

Methotrexate

Rifabutin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifabutin is metabolised by CYP3A4 and via deacetylation. Methotrexate does not interact with this metabolic pathway. Rifabutin is also a strong CYP3A4 and P-gp inducer. Methotrexate concentrations may decrease due to P-gp induction. The clinical relevance of P-gp inhibition on methotrexate exposure is unknown. In addition, orally administered rifabutin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Interaction

Methotrexate

Rifampicin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifampicin is metabolised via deacetylation and is also a strong CYP3A4 and P-gp inducer. Methotrexate concentrations may decrease due to P-gp induction. The clinical relevance of P-gp induction on methotrexate exposure is unknown. In addition, orally administered rifampicin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Interaction

Methotrexate

Rifapentine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifapentine is metabolised via deacetylation and is also a strong CYP3A4, CYP2C8 and P-gp inducer. Methotrexate concentrations may decrease due to P-gp induction. The clinical relevance of P-gp induction on methotrexate exposure is unknown. In addition, orally administered rifapentine may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and efficacy and, if available, plasma concentrations.

Description:

See Summary

Potential Interaction

Methotrexate

Rifaximin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Rifaximin is mainly excreted in faeces, almost entirely as unchanged drug. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered rifaximin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Risperidone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs or P-gp.

Description:

See Summary

No Interaction Expected

Methotrexate

Rivaroxaban

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant is unlikely. Rivaroxaban is partly metabolised in the liver (by CYP3A4, CYP2J2 and hydrolytic enzymes) and partly eliminated unchanged in urine. Rivaroxaban is also a substrate of P-gp and BCRP. Methotrexate is unlikely to interfere with this metabolic or elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Rosiglitazone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Rosuvastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Salbutamol

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Salmeterol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Salmeterol is metabolised by CYP3A4. The systemic exposure of salmeterol is low and methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Saxagliptin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs or P-gp.

Description:

See Summary

No Interaction Expected

Methotrexate

Senna

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Sertindole

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Sertraline

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Sildenafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Simvastatin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Methotrexate

Sirolimus

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs or P-gp. However, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Sitagliptin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Sodium nitroprusside

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sodium nitroprusside is rapidly metabolised, likely by interaction with sulfhydryl groups in the erythrocytes and tissues. Cyanogen (cyanide radical) is produced which is converted to thiocyanate in the liver by the enzyme thiosulfate sulfurtransferase. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Sotalol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sotalol is excreted unchanged via renal elimination. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Spectinomycin

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Spironolactone

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Stanozolol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Stanozolol undergoes hepatic metabolism. Methotrexate is unlikely to interfere with this metabolic pathway.

Description:

See Summary

Potential Weak Interaction

Methotrexate

St John's Wort

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. St John’s wort is a P-gp and CYP3A4 inducer. Methotrexate concentrations may decrease due to P-gp induction. As the clinical relevance of this interaction is unknown, monitoring of methotrexate efficacy and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Streptokinase

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Like other proteins, streptokinase is metabolised proteolytically in the liver and eliminated via the kidneys. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Streptomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Streptomycin is eliminated by glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration of streptomycin with methotrexate may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. Coadministration should be avoided. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

Do Not Coadminister

Methotrexate

Sulfadiazine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. In vitro studies suggest a role of CYP2C9 in sulfadiazine metabolism. Methotrexate does not inhibit or induce CYPs. However, methotrexate is partially bound to serum albumin as is sulfadiazine. Sulfadiazine may displace or be displaced by methotrexate. Therefore, the toxicity of both sulfadiazine and methotrexate may be increased. In addition, orally administered sulfadiazine may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Bacterial metabolism of methotrexate may decrease. Furthermore, coadministration of methotrexate and sulfadiazine may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Coadministration should be avoided. If coadministration is necessary, monitor closely for sulfadiazine and methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Methotrexate

Sulpiride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Sulpiride is mainly excreted in the urine and faeces as unchanged drug. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Tacrolimus

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Tacrolimus is metabolised mainly by CYP3A4. Methotrexate does not inhibit or induce CYPs. Tacrolimus is also an inhibitor of CYP3A4 and OATP1B1 in vitro but produced modest inhibition of CYP3A4 and OATP1B1 in the range of clinical concentrations. Methotrexate concentrations may increase due to OATP1B1 inhibition. If coadministration is necessary, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available. In addition, due to the risk of additive haematological toxicity, haematological parameters should be monitored if coadministered.

Description:

See Summary

No Interaction Expected

Methotrexate

Tadalafil (Pulmonary Arterial Hypertension)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Tamsulosin

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Tazobactam

Quality of Evidence: Very Low

Summary:

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. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Potential Interaction

Methotrexate

Telithromycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Telithromycin is metabolised by CYP3A4 (50%) with the remaining 50% metabolised via non-CYP mediated pathways. Methotrexate does not interact with this pathway. Telithromycin is also an inhibitor of CYP3A4 (strong) and P-gp. Methotrexate concentrations may increase due to P-gp inhibition. The clinical relevance of P-gp inhibition is unknown. In addition, orally administered telithromycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Telmisartan

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Temazepam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Potential Weak Interaction

Methotrexate

Terbinafine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Terbinafine is metabolised by CYPs 1A2, 2C9, 3A4 and to a lesser extent by CYP2C8 and CYP2C19. Terbinafine is also a moderate-strong inhibitor of CYP2D6. Methotrexate does not interact with this pathway. However, the potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated, but hepatotoxicity has been reported in some cases. Therefore, care should be taken. Monitoring for hepatotoxicity should be considered.

Description:

See Summary

Do Not Coadminister

Methotrexate

Testosterone

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Testosterone is metabolised by CYP3A4. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Tetracycline

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Tetracycline is eliminated unchanged primarily by glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, orally administered tetracycline may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. In addition, tetracycline may decrease the renal elimination of methotrexate and thereby further increase methotrexate toxicity. Coadministration should be approached with caution if methotrexate is administered orally. Monitor closely for methotrexate toxicity and, if available, plasma concentrations.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Theophylline

Quality of Evidence: Very Low

Summary:

Coadministration has been studied and care should be taken. Theophylline is mainly metabolised by CYP1A2. Methotrexate does not inhibit or induce CYPs. However, after coadministration theophylline clearance was significantly decreased by an average of 19%. A considerable variability was observed. As the clinical relevance of this interaction is unknown, monitoring for theophylline toxicity and, if available, plasma concentrations may be required.

Description:

See Summary

No Interaction Expected

Methotrexate

Thiamine (Vitamin B1)

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Thioridazine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Tiapride

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tiapride is excreted largely unchanged in urine. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Ticagrelor

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ticagrelor is a substrate and mild inhibitor of CYP3A4. Ticagrelor is also a substrate of P-gp. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Timolol

Quality of Evidence: Very Low

Summary:

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. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Tinzaparin

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Tolbutamide

Quality of Evidence: Very Low

Summary:

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 CYP2C8 and CYP2C19. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Tolterodine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tolterodine is primarily metabolised by CYP2D6 with CYP3A4 playing a minor role. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Interaction

Methotrexate

Torasemide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Torasemide is metabolised mainly by CYP2C9. OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate does not inhibit or induce CYPs or OATs. However, torasemide may decrease methotrexate renal excretion due to competitive inhibition of tubular secretion and a similar effect may occur with torasemide. Therefore, methotrexate toxicity may be increased. If coadministration is unavoidable, monitor closely for methotrexate toxicity and, if available, methotrexate plasma concentrations.

Description:

See Summary

No Interaction Expected

Methotrexate

Tramadol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tramadol is metabolised by CYPs 3A4, 2B6, and 2D6. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Trandolapril

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Trandolapril is hydrolysed to trandolaprilat. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Tranexamic acid

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Tranylcypromine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tranylcypromine is hydroxylated and acetylated. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Trazodone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Triamcinolone

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Triazolam

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

Do Not Coadminister

Methotrexate

Trimethoprim/Sulfamethoxazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Trimethoprim is primarily eliminated by the kidneys through glomerular filtration and tubular secretion. To a lesser extent (approximately 30%) trimethoprim is metabolised by CYP enzymes (in vitro data suggest CYPs 3A4, 1A2 and 2C9). Sulfamethoxazole is metabolised by CYP2C9. Trimethoprim is a weak CYP2C8 inhibitor and in vitro data also suggest that trimethoprim is an inhibitor of OCT2 and MATE1. Sulfamethoxazole is a weak inhibitor of CYP2C9. Coadministration of methotrexate with trimethoprim/sulfamethoxazole may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. An increased methotrexate toxicity, such as severe and unpredictable myelosuppression, stomatitis and neurotoxicity, has been observed after coadministration. Some adverse events were fatal in some cases. Furthermore, methotrexate is partially bound to serum albumin as is sulfamethoxazole. Trimethoprim/sulfamethoxazole may displace or be displaced by methotrexate. Changes in protein binding and tubular clearance of methotrexate, caused by competition with co-trimoxazole, resulted in a mean 66% increase in systemic exposure to methotrexate, and may explain the myelotoxicity often observed with the coadministration of the two drugs. In addition, orally administered trimethoprim/sulfamethoxazole may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is necessary, the British Colombia Cancer Agency protocol for lymphoma treated with high dose MTX with rituximab, advises to discontinue trimethoprim/sulfamethoxazole treatment 48 hours before the start of methotrexate. Treatment with trimethoprim/sulfamethoxazole may be resumed if the methotrexate level is <0.2 uM. Monitor very closely for trimethoprim/sulfamethoxazole and methotrexate toxicity. Furthermore, monitor methotrexate plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Methotrexate

Trimipramine

Quality of Evidence: Very Low

Summary:

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

Description:

See Summary

No Interaction Expected

Methotrexate

Tropisetron

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Tropisetron is metabolised mainly by CYP2D6 and is a substrate of P-gp. Methotrexate does not inhibit or induce CYPs or P-gp.

Description:

See Summary

Do Not Coadminister

Methotrexate

Ulipristal

Quality of Evidence: Very Low

Summary:

Coadministration is contraindicated if methotrexate is used for treatment of hormone-sensitive cancer. If used for hormone-insensitive tumours the following information is applicable: Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Ulipristal is mainly metabolised by CYP3A4 and to a lesser extent by CYP1A2 and CYP2D6. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

No Interaction Expected

Methotrexate

Valproic acid (Valproate)

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valproic acid is primarily metabolized by glucuronidation (50%) and mitochondrial beta-oxidation (30-40%). To a lesser extent (10%) valproic acid is metabolized by CYP2C9 and CYP2C19. Valproic acid is also an inhibitor of CYP2C9. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Valsartan

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Valsartan is eliminated unchanged mostly through biliary excretion. Methotrexate is unlikely to interfere with this elimination pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Vancomycin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Vancomycin is excreted unchanged via glomerular filtration. Methotrexate is unlikely to interfere with this elimination pathway. However, coadministration may decrease the renal excretion of methotrexate. Decreased excretion may lead to increased methotrexate toxicity. In addition, orally administered vancomycin may decrease the intestinal absorption of oral methotrexate and/or interfere with the enterohepatic circulation by inhibiting the bowel flora. Furthermore, bacterial metabolism of methotrexate may decrease. If coadministration is unavoidable, monitor closely for methotrexate toxicity. Monitor methotrexate plasma concentrations, if available.

Description:

See Summary

No Interaction Expected

Methotrexate

Venlafaxine

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Venlafaxine is mainly metabolised by CYP2D6 and to a lesser extent by CYPs 3A4, 2C19 and 2C9. Methotrexate does not inhibit or induce CYPs.

Description:

See Summary

Potential Weak Interaction

Methotrexate

Verapamil

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but care should be taken. Verapamil is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 1A2, 2C8 and 2C9. Verapamil is also an inhibitor of CYP3A4 (moderate) and P-gp (strong). Concentrations of methotrexate may increase due to P-gp inhibition. The clinical relevance of this interaction is unknown. Monitoring for methotrexate toxicity and, if available, plasma concentrations may be required.

Description:

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No Interaction Expected

Methotrexate

Vildagliptin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Vildagliptin is inactivated via non-CYP mediated hydrolysis and is a substrate of P-gp. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Vitamin E

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Voriconazole

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Voriconazole is metabolised by CYP2C19 (major) and to a lesser extent by CYP3A4 and CYP2C9. Voriconazole is also a strong inhibitor of CYP3A4 and a weak inhibitor of CYPs 2C9, 2C19 and 2B6. Methotrexate does not interact with this pathway.

Description:

See Summary

No Interaction Expected

Methotrexate

Warfarin

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Warfarin is a mixture of enantiomers which are metabolised by different cytochromes. R-warfarin is primarily metabolised by CYP1A2 and CYP3A4. S-warfarin (more potent) is metabolised by CYP2C9. Methotrexate does not inhibit or induce CYPs.

Description:

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Potential Interaction

Methotrexate

Xipamide

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be approached with caution. Approximately 90% of xipamide is excreted in the urine, mainly as unchanged drug (~50%) and glucuronides (30%). OAT1/3 are the major transporters of loop and thiazide diuretics. Secretion of these diuretics into the urinary tract by transporters in the proximal tubular cells is necessary for the diuretic effect in later tubule segments. Methotrexate is unlikely to interfere with this elimination pathway. However, thiazide diuretics may decrease methotrexate renal excretion and methotrexate toxicity may be increased. If coadministration is necessary, monitor closely for methotrexate toxicity. Furthermore, monitor methotrexate plasma concentrations, if available.

Description:

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No Interaction Expected

Methotrexate

Zaleplon

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zaleplon is mainly metabolised by aldehyde oxidase and to a lesser extent by CYP3A4. Methotrexate does not interact with this metabolic pathway.

Description:

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No Interaction Expected

Methotrexate

Ziprasidone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Approximately two thirds of ziprasidone metabolic clearance is by reduction, with less than one third by CYP enzymes (mainly CYP3A4). Methotrexate does not interact with this metabolic pathway.

Description:

See Summary

Do Not Coadminister

Methotrexate

Zoledronic acid

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but should be avoided. Zoledronic acid is not metabolised but is cleared from the plasma by uptake into bone and elimination via renal excretion. Coadministration of methotrexate with zoledronic acid may increase or exacerbate nephrotoxicity, particularly in patients with decreased renal function. Therefore, coadministration should be avoided.

Description:

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No Interaction Expected

Methotrexate

Zolpidem

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zolpidem is metabolised mainly by CYP3A4 and to a lesser extent by CYPs 2C9, 2C19, 2D6 and 1A2. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Zopiclone

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zopiclone is metabolised mainly by CYP3A4 and to a lesser extent by CYP2C8. Methotrexate does not inhibit or induce CYPs.

Description:

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No Interaction Expected

Methotrexate

Zotepine

Quality of Evidence: Very Low

Summary:

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

Description:

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No Interaction Expected

Methotrexate

Zuclopenthixol

Quality of Evidence: Very Low

Summary:

Coadministration has not been studied but based on metabolism and clearance a clinically significant interaction is unlikely. Zuclopenthixol is metabolised by sulphoxidation, N-dealkylation (via CYP2D6 and CYP3A4) and glucuronidation. Methotrexate does not interact with this metabolic pathway.

Description:

See Summary