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Methotrexate

By: Dr. Nicholas Dodman

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  • Methotrexate is an anti-metabolite used in the treatment of certain neoplastic diseases and rheumatoid arthritis.
  • It competitively inhibits dihydrofolic acid reductase. Dihydrofolates must be reduced to tetrahydrofolates by this enzyme before they can be effective in the process of purine nucleotide and thymidine synthesis. Thus, methotrexate interferes with DNA synthesis, repair, and cellular replication. Rapidly dividing cells are more sensitive to methotrexate's action.
  • Methotrexate is a prescription drug and can only be obtained from a veterinarian or by prescription from a veterinarian.
  • This drug is not approved for use in animals by the Food and Drug Administration but it is prescribed legally by veterinarians as an extra-label drug.

    Brand Names and Other Names

  • This drug is registered for use in humans only.
  • Human formulations: Rheumatrex® (STADA), Methotrexate LPF Sodium® (Xanodyne), and Methotrexate sodium (various generic manufacturers)
  • Veterinary formulations: None

    Uses of Methotrexate

    Methotrexate may be used as follows:

  • Treatment of neoplasia: Lymphoma and susceptible solid tumors (esp. osteosarcoma)
  • Treatment of rheumatoid arthritis

    Precautions and Side Effects

  • While generally safe and effective when prescribed by a veterinarian, methotrexate can cause side effects in some animals.
  • Methotrexate should not be used in animals with known hypersensitivity or allergy to the drug, or in those with pre-existing bone marrow suppression, severe hepatic or renal insufficiency.
  • Methotrexate should not be used in pregnant animals. Methotrexate is a known teratogen and can affect sperm and egg development.
  • Adverse reactions to methotrexate include anorexia, oral ulcers, gingivitis, pharyngitis, leukopenia, vomiting, diarrhea, gastrointestinal ulceration and bleeding, enteritis, pancreatitis, and general abdominal distress.
  • Other adverse effects include lethargy, fever, and decreased resistance to infection.
  • Potential cardiovascular side effects include pericarditis, pericardial effusion, hypotension, and thromboembolic events.
  • Central nervous system (CNS) side effects may include hemiparesis, paresis, and convulsions.
  • Side effects involving the skin may include erythematous rashes, pruritus, urticaria, and photosensitivity have been reported in humans treated with methotrexate.
  • Severe nephropathy, azotemia, renal failure, cystitis, and hematuria have also occurred and hepatotoxicity has been reported in a dog.
  • Monitoring should include: efficacy, toxicity, complete blood count (CBC) and chemistry profile. Ideally, blood work should be performed weekly at first, then every 4 to 6 weeks. Treatment may be discontinued if the white blood cell (WBC) count falls below 4000/mm3 or platelets fall below 100,000/mm3.

    Drug Interactions

    Methotrexate may interact with other medications. Consult with your veterinarian to determine if other drugs your pet is receiving could interact with methotrexate. Such interactions may include:

  • NSAIDs should not be used prior to or during treatment with methotrexate for reasons of enhanced methotrexate toxicity.
  • Salicylates, phenylbutazone, phenytoin, and sulphonamides displace methotrexate from albumin binding sites and may enhance its toxicity.
  • Probenecid decreases renal tubular transport of methotrexate.
  • Other potentially nephrotoxic chemotherapeutic drugs, e.g. cisplatin, may can an additive effect when combined with high dose methotrexate therapy, necessitating careful monitoring.
  • Oral antibiotics such as tetracycline, chloramphenicol, and non-absorbable broad spectrum antibiotics, may decrease the intestinal absorption of methotrexate.
  • Penicillins may decrease the renal clearance of methotrexate thus increasing its blood levels and toxicity. Careful monitoring is needed when penicillins and methotrexate are coadministered.
  • The risk of hepatoxicity is increased when methotrexate and retinoids are coadministered.
  • Methotrexate decreases the clearance of theophylline, increasing its blood levels (monitor carefully).
  • Folic acid or its derivatives decrease the response to systemically administered methotrexate: Avoid coadministration of folic acid. Folic acid deficiency increases methotrexate toxicity.
  • Trimethoprim/sulphamethoxazole has been reported to increase bone marrow suppression in human patients treated with methotrexate, probably by an additive antifolate effect.

    How Methotrexate is Supplied

  • Methotrexate sodium tablets for oral administration are available in bottles of 100 and as a dose pack for therapy. Methotrexate sodium tablets contain 2.5 mg of methotrexate.
  • The injectable forms include a 2.5 mg/mL (as base) or 20 mg (as base) powder for injection. Methotrexate sodium injection can be given by intramuscular or intravenous injection.

    Dosing Information

  • Medication should never be administered without first consulting your veterinarian.
  • The dosage prescribed may vary depending on the reason for prescribing.
  • The duration of administration depends on the condition being treated, response to the medication and the development of any adverse effects. Be certain to complete the prescription unless specifically directed by your veterinarian. Even if your pet feels better, the entire treatment plan should be completed to prevent relapse.
  • Methotrexate is frequently used as part of a multi-drug chemotherapeutic regimen. Doses and routes of administration vary.
  • In dogs, the usual dose and schedule varies. Possible strategies may include:
    - 2.5 mg/m2 orally once daily
    - 5.0 mg/m2 orally on days 1 and 5 of a biweekly maintenance schedule
  • In cats, the usual dose is 2.5-5.0 mg/ m2 PO two to three times weekly.




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