METHOTREXATE, VIALS 9 Drug Interactions

methotrexate, vials

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9.1 Serious Drug Interactions 

Serious Drug Interactions 

The use of nitrous oxide anesthesia with methotrexate is contraindicated (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS: Renal and 9.4 Drug-Drug Interactions)

9.2 Drug Interactions Overview 

Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that undergo tubular secretion, can markedly increase methotrexate serum levels. Laboratory studies demonstrate that methotrexate may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol and phenytoin. 

9.3 Drug-Behaviour Interactions

 

Use of alcohol with Methotrexate Injection USP is contraindicated (see 2 CONTRAINDICATIONS). The effects of smoking on the pharmacokinetics of methotrexate have not been specifically studied. 

9.4 Drug-Drug Interactions

Table 13 Established or Potential Drug-Drug Interactions
Proper/ Common name  Source of Evidence  Effect  Clinical comment 
Amiodarone  Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions  Use with caution. 
L-asparaginase  The administration of L-asparaginase has been reported to antagonize the effects of methotrexate.  Use with caution. 
Ciprofloxacin  Renal tubular transport is diminished by ciprofloxacin.  Serum methotrexate levels and renal function should be carefully monitored when using this drug with Methotrexate Injection USP. 
Cytarabine and other cytotoxic agents 

Cases of severe neurological adverse reactions have been reported in patients given methotrexate in combination with intravenous cytarabine. 

See 7 WARNINGS AND PRECAUTIONS, Neurologic. 

Combined use of methotrexate with other cytotoxic agents has not been studied and may increases the incidence of adverse effects. 

Caution should be used when cytotoxic agents are administered concomitantly with Methotrexate Injection USP
Disease Modifying Antirheumatic drugs (DMARDs)  Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, or sulfasalazine has not been studied and may increase the incidence of adverse effects.  Use with caution. 
Diuretics  Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.  Use with caution. 
Drugs Highly Bound to Plasma Proteins, such as sulfonylureas, aminobenzoic acid, salicylates, phenylbutazone, phenytoin, sulfonamides, some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid, and chloramphenicol  Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by other highly bound drugs.  Use with caution. 
Hepatotoxins such as leflunomide, azathioprine, sulfasalazine, retinoids  The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases.  Patients receiving concomitant therapy with Methotrexate Injection USP and other potential hepatotoxic agents should be closely monitored for possible increased risk of hepatotoxicity. 
Leflunomide  Methotrexate in combination with leflunomide may increase the risk of pancytopenia.  Use with caution. 
Mercaptopurine  Methotrexate increases the plasma levels of mercaptopurine.  Combination of Methotrexate Injection USP and mercaptopurine may require dose adjustment. 
Nephrotoxic Drugs, such as cisplatin, aminoglycoside, Amphotericin B and Cyclosporin 

Methotrexate clearance is decreased by cisplatinum. 

 

 

 

 

 

Although not documented, other nephrotoxic drugs could theoretically increase methotrexate toxicity by decreasing its elimination. 

In the treatment of patients with osteosarcoma, use caution if high-dose Methotrexate Injection USP is administered in combination with a potentially nephrotoxic chemotherapy agent.  

Use with caution. 

Nitrous oxide  The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis, neurotoxicity (with intrathecal administration of methotrexate) and nephritis (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Renal).  In case of accidental co- administration, this effect can be reduced by the use of leucovorin rescue. 
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  C, CT 

Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic (including bone marrow suppression and aplastic anemia) and gastrointestinal toxicity. These drugs have been reported to reduce the tubular secretion of methotrexate, in an animal model, and may enhance its toxicity by increasing methotrexate levels. 

The possibility of increased methotrexate toxicity with concomitant use of NSAIDs, including salicylates, in rheumatoid arthritis has not been fully explored. Despite the potential interactions, studies have usually included concurrent use of constant dosage regimens of NSAIDs without apparent problems. However, the doses used in rheumatoid arthritis (7.5 mg to 15 mg/week) are somewhat lower than those used in psoriasis. Larger doses could lead to toxicity. 

NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate. 

 

 

 

 

 

 

Caution should be used when NSAIDs, including salicylates, are administered concomitantly with lower doses of Methotrexate Injection USP. 

Oral Antibiotics, such as such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics  C, T 

Oral 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. 

Neomycin, polymyxin B, nystatin and vancomycin decrease methotrexate absorption, whereas kanamycin increases methotrexate absorption. 

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 

Use with caution. 
Packed Red Blood Cells  C, CT  Patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum- methotrexate concentrations  Care should be exercised whenever packed red blood cells and Methotrexate Injection USP are given concurrently. 
Penicillins and Sulfonamides  C, CT, T  Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity have been observed in combination with methotrexate.  Use with caution. 
Probenecid  Renal tubular transport is diminished by probenecid.  Serum methotrexate levels and renal function should be carefully monitored when using this drug with Methotrexate Injection USP. 
Proton Pump Inhibitors (PPI) such as omeprazole, esomeprazole, and pantoprazole  C, CT  Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite 7-hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. 

Use caution when administering high- dose methotrexate to patients receiving PPI therapy. 

Concomitant use of PPIs and high-dose methotrexate should be avoided especially in patients with renal impairment. 

Psoralen Plus Ultraviolet Light (PUVA) Therapy  Skin cancer has been reported in few patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy.  Use with caution. 
Radiotherapy  Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.  Use with caution. 
Theophylline  Methotrexate may decrease the clearance of theophylline.  Theophylline levels should be monitored when used concurrently with Methotrexate Injection USP 
Vitamins, such as folic acid or folinic acid 

Vitamin preparations containing folic acid or its derivatives may decrease responses to methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the cerebrospinal fluid primarily as 5-methyl tetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. 

However, high does of leucovorin may reduce the efficacy of intrathecally administered methotrexate. 

In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes. 

Folate deficiency states may increase methotrexate toxicity. 

Before taking a folate supplement, it is advisable to check B12 levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B12 deficiency. 

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical  

9.5 Drug-Food Interactions 

Interactions with food have not been established. 

9.6 Drug-Herb Interactions 

Interactions with herbal products have not been established. 

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

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9 Drug Interactions

9.1 Serious Drug Interactions 

Serious Drug Interactions 

The use of nitrous oxide anesthesia with methotrexate is contraindicated (see 2 CONTRAINDICATIONS, 7 WARNINGS AND PRECAUTIONS: Renal and 9.4 Drug-Drug Interactions)

9.2 Drug Interactions Overview 

Methotrexate competes with reduced folates for active transport across cell membranes by means of a single carrier-mediated active transport process. Impaired renal function, as well as concurrent use of drugs such as weak organic acids that undergo tubular secretion, can markedly increase methotrexate serum levels. Laboratory studies demonstrate that methotrexate may be displaced from plasma albumin by various compounds including sulfonamides, salicylates, tetracyclines, chloramphenicol and phenytoin. 

9.3 Drug-Behaviour Interactions

 

Use of alcohol with Methotrexate Injection USP is contraindicated (see 2 CONTRAINDICATIONS). The effects of smoking on the pharmacokinetics of methotrexate have not been specifically studied. 

9.4 Drug-Drug Interactions

Table 13 Established or Potential Drug-Drug Interactions
Proper/ Common name  Source of Evidence  Effect  Clinical comment 
Amiodarone  Amiodarone administration to patients receiving methotrexate treatment for psoriasis has induced ulcerated skin lesions  Use with caution. 
L-asparaginase  The administration of L-asparaginase has been reported to antagonize the effects of methotrexate.  Use with caution. 
Ciprofloxacin  Renal tubular transport is diminished by ciprofloxacin.  Serum methotrexate levels and renal function should be carefully monitored when using this drug with Methotrexate Injection USP. 
Cytarabine and other cytotoxic agents 

Cases of severe neurological adverse reactions have been reported in patients given methotrexate in combination with intravenous cytarabine. 

See 7 WARNINGS AND PRECAUTIONS, Neurologic. 

Combined use of methotrexate with other cytotoxic agents has not been studied and may increases the incidence of adverse effects. 

Caution should be used when cytotoxic agents are administered concomitantly with Methotrexate Injection USP
Disease Modifying Antirheumatic drugs (DMARDs)  Combined use of methotrexate with gold, penicillamine, hydroxychloroquine, or sulfasalazine has not been studied and may increase the incidence of adverse effects.  Use with caution. 
Diuretics  Bone marrow suppression and decreased folate levels have been described in the concomitant administration of triamterene and methotrexate.  Use with caution. 
Drugs Highly Bound to Plasma Proteins, such as sulfonylureas, aminobenzoic acid, salicylates, phenylbutazone, phenytoin, sulfonamides, some antibiotics such as penicillins, tetracycline, pristinamycin, probenecid, and chloramphenicol  Methotrexate is partially bound to serum albumin, and toxicity may be increased because of displacement by other highly bound drugs.  Use with caution. 
Hepatotoxins such as leflunomide, azathioprine, sulfasalazine, retinoids  The potential for increased hepatotoxicity when methotrexate is administered with other hepatotoxic agents has not been evaluated. However, hepatotoxicity has been reported in such cases.  Patients receiving concomitant therapy with Methotrexate Injection USP and other potential hepatotoxic agents should be closely monitored for possible increased risk of hepatotoxicity. 
Leflunomide  Methotrexate in combination with leflunomide may increase the risk of pancytopenia.  Use with caution. 
Mercaptopurine  Methotrexate increases the plasma levels of mercaptopurine.  Combination of Methotrexate Injection USP and mercaptopurine may require dose adjustment. 
Nephrotoxic Drugs, such as cisplatin, aminoglycoside, Amphotericin B and Cyclosporin 

Methotrexate clearance is decreased by cisplatinum. 

 

 

 

 

 

Although not documented, other nephrotoxic drugs could theoretically increase methotrexate toxicity by decreasing its elimination. 

In the treatment of patients with osteosarcoma, use caution if high-dose Methotrexate Injection USP is administered in combination with a potentially nephrotoxic chemotherapy agent.  

Use with caution. 

Nitrous oxide  The use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate metabolism, yielding increased toxicity such as severe, unpredictable myelosuppression, stomatitis, neurotoxicity (with intrathecal administration of methotrexate) and nephritis (see 2 CONTRAINDICATIONS and 7 WARNINGS AND PRECAUTIONS, Renal).  In case of accidental co- administration, this effect can be reduced by the use of leucovorin rescue. 
Nonsteroidal Anti-inflammatory Drugs (NSAIDs)  C, CT 

Concomitant administration of NSAIDs with high-dose methotrexate therapy has been reported to elevate and prolong serum methotrexate levels, resulting in deaths from severe hematologic (including bone marrow suppression and aplastic anemia) and gastrointestinal toxicity. These drugs have been reported to reduce the tubular secretion of methotrexate, in an animal model, and may enhance its toxicity by increasing methotrexate levels. 

The possibility of increased methotrexate toxicity with concomitant use of NSAIDs, including salicylates, in rheumatoid arthritis has not been fully explored. Despite the potential interactions, studies have usually included concurrent use of constant dosage regimens of NSAIDs without apparent problems. However, the doses used in rheumatoid arthritis (7.5 mg to 15 mg/week) are somewhat lower than those used in psoriasis. Larger doses could lead to toxicity. 

NSAIDs should not be administered prior to or concomitantly with high doses of methotrexate. 

 

 

 

 

 

 

Caution should be used when NSAIDs, including salicylates, are administered concomitantly with lower doses of Methotrexate Injection USP. 

Oral Antibiotics, such as such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics  C, T 

Oral 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. 

Neomycin, polymyxin B, nystatin and vancomycin decrease methotrexate absorption, whereas kanamycin increases methotrexate absorption. 

Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression in patients receiving methotrexate, probably by decreased tubular secretion and/or an additive antifolate effect. 

Use with caution. 
Packed Red Blood Cells  C, CT  Patients receiving 24-hr methotrexate infusion and subsequent transfusions have showed enhanced toxicity probably resulting from prolonged high serum- methotrexate concentrations  Care should be exercised whenever packed red blood cells and Methotrexate Injection USP are given concurrently. 
Penicillins and Sulfonamides  C, CT, T  Penicillins and sulfonamides may reduce the renal clearance of methotrexate; hematologic and gastrointestinal toxicity have been observed in combination with methotrexate.  Use with caution. 
Probenecid  Renal tubular transport is diminished by probenecid.  Serum methotrexate levels and renal function should be carefully monitored when using this drug with Methotrexate Injection USP. 
Proton Pump Inhibitors (PPI) such as omeprazole, esomeprazole, and pantoprazole  C, CT  Case reports and published population pharmacokinetic studies suggest that concomitant use of some PPIs with methotrexate (primarily at high dose), may elevate and prolong serum levels of methotrexate and/or its metabolite 7-hydroxymethotrexate, possibly leading to methotrexate toxicities. In two of these cases, delayed methotrexate elimination was observed when high-dose methotrexate was co-administered with PPIs, but was not observed when methotrexate was co-administered with ranitidine. However, no formal drug interaction studies of methotrexate with ranitidine have been conducted. 

Use caution when administering high- dose methotrexate to patients receiving PPI therapy. 

Concomitant use of PPIs and high-dose methotrexate should be avoided especially in patients with renal impairment. 

Psoralen Plus Ultraviolet Light (PUVA) Therapy  Skin cancer has been reported in few patients with psoriasis or mycosis fungoides (a cutaneous T-cell lymphoma) receiving a concomitant treatment with methotrexate plus PUVA therapy.  Use with caution. 
Radiotherapy  Methotrexate given concomitantly with radiotherapy may increase the risk of soft tissue necrosis and osteonecrosis.  Use with caution. 
Theophylline  Methotrexate may decrease the clearance of theophylline.  Theophylline levels should be monitored when used concurrently with Methotrexate Injection USP 
Vitamins, such as folic acid or folinic acid 

Vitamin preparations containing folic acid or its derivatives may decrease responses to methotrexate. Preliminary animal and human studies have shown that small quantities of intravenously administered leucovorin enter the cerebrospinal fluid primarily as 5-methyl tetrahydrofolate and, in humans, remain 1 to 3 orders of magnitude lower than the usual methotrexate concentrations following intrathecal administration. 

However, high does of leucovorin may reduce the efficacy of intrathecally administered methotrexate. 

In patients with rheumatoid arthritis or psoriasis, folic acid or folinic acid may reduce methotrexate toxicities such as gastrointestinal symptoms, stomatitis, alopecia and elevated liver enzymes. 

Folate deficiency states may increase methotrexate toxicity. 

Before taking a folate supplement, it is advisable to check B12 levels, particularly in adults over the age of 50, since folate administration can mask symptoms of B12 deficiency. 

Legend: C = Case Study; CT = Clinical Trial; T = Theoretical  

9.5 Drug-Food Interactions 

Interactions with food have not been established. 

9.6 Drug-Herb Interactions 

Interactions with herbal products have not been established. 

9.7 Drug-Laboratory Test Interactions

Interactions with laboratory tests have not been established.

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