indication

For the treatment of gestational choriocarcinoma, chorioadenoma destruens and hydatidiform mole. Also for the treatment of severe psoriasis and severe, active, classical or definite rheumatoid arthritis.

pharmacology

Methotrexate is an antineoplastic anti-metabolite. Anti-metabolites masquerade as purine or pyrimidine - which become the building blocks of DNA. They prevent these substances becoming incorporated in to DNA during the "S" phase (of the cell cycle), stopping normal development and division. Methotrexate inhibits folic acid reductase which is responsible for the conversion of folic acid to tetrahydrofolic acid. At two stages in the biosynthesis of purines and at one stage in the synthesis of pyrimidines, one-carbon transfer reactions occur which require specific coenzymes synthesized in the cell from tetrahydrofolic acid. Tetrahydrofolic acid itself is synthesized in the cell from folic acid with the help of an enzyme, folic acid reductase. Methotrexate looks a lot like folic acid to the enzyme, so it binds to it quite strongly and inhibits the enzyme. Thus, DNA synthesis cannot proceed because the coenzymes needed for one-carbon transfer reactions are not produced from tetrahydrofolic acid because there is no tetrahydrofolic acid. Methotrexate selectively affects the most rapidly dividing cells (neoplastic and psoriatic cells). Methotrexate is also indicated in the management of severe, active, classical, or definite rheumatoid arthritis.

mechanism of action

Methotrexate anti-tumor activity is a result of the inhibition of folic acid reductase, leading to inhibition of DNA synthesis and inhibition of cellular replication. The mechanism involved in its activity against rheumatoid arthritis is not known.

toxicity

Symptoms of overdose include bone marrow suppression and gastrointestinal toxicity. LD₅₀=43mg/kg(orally in rat).

biotransformation

Hepatic.

absorption

Generally well absorbed with a mean bioavailability of about 60%.

half life

Low doses: 3 to 10 hours; High doses: 8 to 15 hours.

route of elimination

With IV administration, 80% to 90% of the administered dose is excreted unchanged in the urine within 24 hours. There is limited biliary excretion amounting to 10% or less of the administered dose.

drug interactions

Acetylsalicylic acid: Acetylsalicylic acid increases the effect and toxicity of methotrexate.

Acitretin: Acitretin/etretinate increases the effect and toxicity of methotrexate

Amoxicillin: The penicillin increases the effect and toxicity of methotrexate

Ampicillin: The penicillin increases the effect and toxicity of methotrexate

Bacampicillin: The penicillin increases the effect and toxicity of methotrexate

Bismuth Subsalicylate: The salicylate, bismuth subsalicylate, increases the effect and toxicity of methotrexate.

Carbenicillin: The penicillin increases the effect and toxicity of methotrexate

Cholestyramine: Decreased levels of methotrexate

Ciprofloxacin: Ciprofloxacine may decrease the metabolism of methotrexate. Monitor for changes adverse effects of methotrexate if ciprofloxacin is initiated.

Cisplatin: Cisplatin increases methotrexate toxicity

Clavulanate: The penicillin increases the effect and toxicity of methotrexate

Cloxacillin: The penicillin increases the effect and toxicity of methotrexate

Cyclosporine: Cyclosporine may increase the effect and toxicity of methotrexate.

Diclofenac: The NSAID, diclofenac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Dicloxacillin: The penicillin increases the effect and toxicity of methotrexate

Diflunisal: The NSAID, diflunisal, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Digoxin: The antineoplasic agent decreases the effect of digoxin

Doxycycline: The tetracycline, doxycycline, may increase methotrexate toxicity.

Ethotoin: The antineoplasic agent decreases the effect of hydantoin

Etodolac: The NSAID, etodolac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Etretinate: Acitretin/etretinate increases the effect and toxicity of methotrexate

Fenoprofen: The NSAID, fenoprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Flucloxacillin: The penicillin increases the effect and toxicity of methotrexate

Flurbiprofen: The NSAID, flurbiprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Fosphenytoin: The antineoplasic agent decreases the effect of hydantoin

Hydroxychloroquine: Hydroxychloroquine increases the effect and toxicity of methotrexate

Ibuprofen: The NSAID, ibuprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Indomethacin: The NSAID, indomethacin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Ketoprofen: The NSAID, ketoprofen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Ketorolac: The NSAID, ketorolac, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Magnesium salicylate: The salicylate, magnesium salicylate, increases the effect and toxicity of methotrexate.

Meclofenamic acid: The NSAID, meclofenamic acid, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Mefenamic acid: The NSAID, mefenamic acid, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Mephenytoin: The antineoplasic agent decreases the effect of hydantoin

Methicillin Acyl-Serine: The penicillin increases the effect and toxicity of methotrexate

Mezlocillin: The penicillin increases the effect and toxicity of methotrexate

Nabumetone: The NSAID, nabumetone, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Nafcillin: The penicillin increases the effect and toxicity of methotrexate

Naproxen: The NSAID, naproxen, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Omeprazole: Omeprazole increases the levels of methotrexate

Oxaprozin: The NSAID, oxaprozin, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Penicillin G: The penicillin increases the effect and toxicity of methotrexate

Penicillin V: The penicillin increases the effect and toxicity of methotrexate

Phenylbutazone: The NSAID, phenylbutazone, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Phenytoin: The antineoplasic agent decreases the effect of hydantoin

Piperacillin: The penicillin increases the effect and toxicity of methotrexate

Piroxicam: The NSAID, piroxicam, may decrease the renal excretion of methotrexate. Increased risk of methotrexate toxicity.

Pivampicillin: The penicillin increases the effect and toxicity of methotrexate

Probenecid: Probenecid increases the effect and toxicity of methotrexate

Procarbazine: Increased nephrotoxicity with this combination

Rofecoxib: Rofecoxib increases the levels of methotrexate

Salicylate-sodium: The salicylate, salicylate-sodium, increases the effect and toxicity of methotrexate.

Salsalate: The salicylate, salsalate, increases the effect and toxicity of methotrexate.

Sulfacytine: The sulfamide increases the toxicity of methotrexate

Sulfadiazine: The sulfamide increases the toxicity of methotrexate

Sulfadimethoxine: The sulfamide increases the toxicity of methotrexate

Sulfadoxine: The sulfamide increases the toxicity of methotrexate

Sulfamerazine: The sulfamide increases the toxicity of methotrexate

Sulfamethazine: The sulfamide increases the toxicity of methotrexate

Sulfamethizole: The sulfamide increases the toxicity of methotrexate

Sulfamethoxazole: The sulfamide increases the toxicity of methotrexate

Sulfapyridine: The sulfamide increases the toxicity of methotrexate

Sulfathiazole: The sulfamide increases the toxicity of methotrexate

Sulfisoxazole: The sulfamide increases the toxicity of methotrexate

Sulindac: The NSAID, sulindac, may decrease the clearance methotrexate. Consider alternate therapy, especially in patients receiving high antineoplastic doses of methotrexate. Otherwise, monitor for hematologic and renal toxicities.

Tenoxicam: Tenoxicam may increase the serum concentration of Methotrexate by reducing renal tubular secretion of Methotrexate. Monitor for changes in Methotrexate therapeutic and adverse effects if Tenoxicam is initiated, discontinued or dose changed.

Tetracycline: Tetracycline may increase methotrexate toxicity.

Tiaprofenic acid: Tiaprofenic acid may decrease renal excretion of methotrexate. Consider alternate therapy or monitor for methotrexate toxicity.

Ticarcillin: The penicillin increases the effect and toxicity of methotrexate

Tolmetin: Tolmetin may decrease the renal excretion of Methotrexate. Alternate therapy should be considered. Otherwise, monitor for hemotologic and renal toxicities.

Trastuzumab: Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.

Trimethoprim: Trimethoprim may increase the adverse/toxic effects of Methotrexate (e.g. bone marrow suppression). Concomitant use should be avoided or closely monitored for Methotrexate toxicity.

Trisalicylate-choline: The salicylate, trisalicylate-choline, increases the effect and toxicity of methotrexate.