What medications should not be given with methotrexate?

From the Guidelines

Methotrexate should not be given with certain medications, including NSAIDs, trimethoprim-sulfamethoxazole, penicillins, tetracyclines, proton pump inhibitors, folic acid antagonists, and alcohol, due to potentially dangerous interactions that can increase the risk of toxicity and serious side effects. When considering medications to avoid with methotrexate, it's essential to prioritize those that can significantly increase methotrexate toxicity.

• NSAIDs like ibuprofen, naproxen, and aspirin can increase methotrexate levels in the blood, raising the risk of toxicity 1.
• Certain antibiotics, particularly trimethoprim-sulfamethoxazole (Bactrim), should be avoided as they can cause bone marrow suppression and immunosuppression, especially in elderly patients with renal impairment 1.
• Other medications that may increase methotrexate toxicity include salicylates, sulfonamides, probenecid, ciclosporin, statins, azathioprine, tetracyclines, phenytoin, and retinoids 1.
• Alcohol should be strictly limited or avoided as both methotrexate and alcohol can cause liver damage, creating a dangerous combination 1.
• Folic acid antagonists such as trimethoprim should not be combined with methotrexate as they work through similar mechanisms, increasing the risk of toxicity 1. These interactions occur because many of these substances compete with methotrexate for protein binding or elimination pathways in the body, leading to higher methotrexate blood levels and increased risk of serious side effects like bone marrow suppression, liver damage, and kidney injury. Given the potential for severe interactions, it's crucial to carefully review a patient's medication list before initiating methotrexate therapy and to monitor them closely for signs of toxicity.

From the FDA Drug Label

Nonsteroidal anti-inflammatory drugs should not be administered prior to or concomitantly with the high doses of methotrexate, such as used in the treatment of osteosarcoma Concomitant administration of some NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic and gastrointestinal toxicity. Caution should be used when NSAIDs and salicylates are administered concomitantly with lower doses of methotrexate Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by certain drugs, such as salicylates, phenylbutazone, phenytoin, and sulfonamides Renal tubular transport is also diminished by probenecid; use of methotrexate with this drug should be carefully monitored. Methotrexate increases the plasma levels of mercaptopurine. Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, may decrease intestinal absorption of methotrexate or interfere with the enterohepatic circulation by inhibiting bowel flora and suppressing metabolism of the drug by bacteria Penicillins may reduce the renal clearance of methotrexate; increased serum concentrations of methotrexate with concomitant hematologic and gastrointestinal toxicity have been observed with high and low dose methotrexate. The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. Methotrexate may decrease the clearance of theophylline; theophylline levels should be monitored when used concurrently with methotrexate. Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate

The medications that should not be given with methotrexate include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs), especially with high doses of methotrexate
• Salicylates, as they can displace methotrexate from serum albumin and increase toxicity
• Phenylbutazone, as it can displace methotrexate from serum albumin and increase toxicity
• Phenytoin, as it can displace methotrexate from serum albumin and increase toxicity
• Sulfonamides, as they can displace methotrexate from serum albumin and increase toxicity
• Probenecid, as it can diminish renal tubular transport of methotrexate
• Oral antibiotics such as tetracycline, chloramphenicol, and nonabsorbable broad spectrum antibiotics, as they can decrease intestinal absorption of methotrexate
• Penicillins, as they can reduce the renal clearance of methotrexate and increase serum concentrations
• Hepatotoxic agents such as azathioprine, retinoids, and sulfasalazine, as they can increase the risk of hepatotoxicity
• Vitamin preparations containing folic acid or its derivatives, as they can decrease responses to systemically administered methotrexate 2

From the Research

Medications to Avoid with Methotrexate

• Trimethoprim-sulfamethoxazole (TS) at therapeutic doses, as the combination can lead to mucocutaneous ulceration, leukopenia, and renal insufficiency 3
• Nephrotoxic drugs, as they can decrease methotrexate renal clearance 4, 5, 6
• Nonabsorbable antibiotics, as they can decrease methotrexate absorption 5
• Salicylates and probenecid, as they may decrease the plasma protein binding and renal tubular secretion of methotrexate 5
• NSAIDs, as they can increase the risk of renal toxicity 3

Important Considerations

• The concomitant use of a prophylactic dose of trimethoprim-sulfamethoxazole with methotrexate was not significantly associated with an increased risk of cytopenia 7
• Patients with chronic liver disease may be at increased risk of cytopenia when taking methotrexate 7
• Close monitoring of serum methotrexate and creatinine concentrations is necessary to assess renal clearance and prevent toxicity 4, 6