AZATHIOPRINE

By | 2010-06-25

AZATHIOPRINE SODIUM

Chemistry

Related structurally to adenine, guanine and hypoxanthine, azathioprine is a purine antagonist antimetabolite that is used primarily for its immunosuppressive properties. Azathioprine occurs as an odorless, pale yellow powder that is insoluble in water and slightly soluble in alcohol. Azathioprine sodium powder for injection occurs as a bright yellow, amorphous mass. After reconstituting with sterile water for injection to a concentration of 10 mg/ml it has an approximate pH of 9.6.

Storage – Stability – Compatibility

Azathioprine tablets should be stored at room temperature in well-closed containers and protected from light.

The sodium powder for injection should be stored at room temperature and protected from light. It is reportedly stable at neutral or acidic pH, but will hydrolyze to mercaptopurine in alkaline solutions. This conversion is enhanced upon warming or in the presence of sulfhydryl-containing compounds (e.g., cysteine). After reconstituting, the injection should be used within 24 hours as no preservative is present.

Azathioprine sodium is reportedly compatible with the following intravenous solutions: dextrose 5% in water, and sodium chloride 0.45% or 0.9%. Compatibility is dependent upon factors such as pH, concentration, temperature and diluents used. It is suggested to consult specialized references for more specific information (e.g., Handbook on Injectable Drugs by Trissel).

Pharmacology

While the exact mechanism how azathioprine exerts its immunosuppressive action has not been determined, it is probably dependent on several factors. Azathioprine antagonizes purine metabolism thereby inhibiting RNA, DNA synthesis and mitosis. It also may cause chromosome breaks secondary to incorporation into nucleic acids and cellular metabolism may become disrupted by the drug’s ability to inhibit coenzyme formation. Azathioprine has greater activity on delayed hypersensitivity and cellular immunity than on humoral antibody responses. Clinical response to azathioprine may require up to 6 weeks.

Uses – Indications

In veterinary medicine, azathioprine is used primarily as a second or third line immunosuppressive agent in the treatment of immune-mediated diseases in dogs. See Doses below for more information.

Pharmacokinetics

Azathioprine is absorbed from the GI tract and is rapidly metabolized to mercaptopurine which is then further metabolized to several other compounds. These metabolites are excreted by the kidneys. Only minimal amounts of either azathioprine or mercaptopurine are excreted unchanged.

Contraindications – Precautions – Reproductive Safety

Azathioprine is contraindicated in patients hypersensitive to it. The drug should be used cautiously in patients with hepatic dysfunction.

Azathioprine is mutagentic and teratogenic (in lab animals).

Adverse Effects – Warnings

The principal adverse effect associated with azathioprine is bone marrow suppression. Cats are more prone to develop these effects and the drug is generally not recommended to be used in that species. Leukopenia is the prevalent consequence, but anemias and thrombocytopenia may also be seen. Acute pancreatitis and hepatotoxicity have also been associated with azathioprine therapy in dogs.

Because azathioprine depresses the immune system, animals may be susceptible to infections or neoplastic illnesses (long-term use).

In recovering dogs with immune-mediated hemolytic anemia, taper the withdrawal of the drug slowly over several months and monitor for early signs of relapse. Rapid withdrawal can lead to a rebound hyperimmune response.

Overdosage

Acute Toxicity

No specific information was located regarding acute overdose of azathioprine. It is suggested to use standard protocols to empty the GI tract if ingestion was recent and to treat supportively.

Drug Interactions

The hepatic metabolism of azathioprine may be decreased by concomitant administration of allopurinol. In humans, it is recommended to reduce the azathioprine dose to 1/4-1/3 usual if both drugs are to used together.

The neuromuscular blocking activity of non-depolarizing muscle relaxants (e.g., pancuronium, tubocurarine) may be inhibited or reversed by azathioprine.

Doses

Doses for dogs:

As an immunosuppressive:

a) For adjunctive therapy for immune-mediated hemolytic anemia (probably should be reserved for dogs w/fulminant intravascular hemolysis, autoagglutination or those that require repeated transfusion or have persistant reticulocytopenia): Initially at 2 mg/kg/day PO. Reduce to 1 mg/kg/day after the first 7-10 days.

b) For adjunctive therapy of immune-mediated glomerulopathy: 2 mg/kg PO once daily initially. When remission is achieved, give at same dose every other day. Prednisolone and azathioprine should be given on alternate days at this time.

c) For adjunctive therapy in myasthenia gravis in non-responsive patients: 2 mg/kg PO once a day to every other day; may decrease dose if response is seen.

d) For adjunctive therapy of chronic atrophic gastritis: 0.5 mg/kg PO once a day to every other day (with corticosteroids).

e) For adjunctive therapy in chronic active hepatitis: If no improvement seen with corticosteroids, add azathioprine at 2 – 2.5 mg/kg PO once daily; recheck in 10-14 days. If improved, continue for additional 2-3 months; if no improvement, reconsider diagnosis.

f) For adjunctive therapy in immune-mediated hemolytic anemia:

2 mg/kg PO once daily (in combination with corticosteroids ± cyclophosphamide; see reference or individual mono graphs).

g) For adjunctive therapy in immune-mediated thrombocytopenia: If corticosteroids ineffective, may add azathioprine at 2 mg/kg PO; taper to 0.5 – 1.0 mg/kg PO every other day. Alternatively, may use vincristine or cyclophosphamide.

h) For adjunctive therapy in autoimmune skin diseases: 2.2 mg/kg PO once a day to every other day. May require 2-3 weeks before benefits are seen; may allow reduction or withdrawal of prednisone.

i) For adjunctive therapy of SLE or other multisystemic immune-mediated diseases: 2.2 mg/kg PO once a day to every other day;, used alone or in combination with other immunosuppressants. Once remission is achieved, may reduce dose to 1 – 2 mg/kg every other day.

j) For immune-mediated chronic inflammatory bowel disease: 50 mg/m2 once daily for 2 weeks, then every other day. Used rarely, but is helpful in a few cases.

i) For rheumatoid arthritis: In conjunction with a glucocorticoid (predniso(lo)ne); give azathioprine 2 mg/kg PO once daily for 14-21 days; then give every other day (usually alternating with corticosteroids) until 1 month after remission of synovial inflammation.

For adjunctive treatment of ocular fibrous histiocytomas:

a) 2 mg/kg PO daily for 2 weeks, reevaluate, and reduce to 1 mg/kg every other day for 2 weeks, then 1 mg/kg once weekly for 1 month.

Cats:

Note: Several authors do not recommend azathioprine for use in cats because of the potential for development of fatal toxicity and the difficulty in accurately dosing.

As an immunosuppressive:

a) For immune-mediated dermatologic diseases: Cats are prone to develop bone marrow toxicity from azathioprine and the drug is generally recommended not to be used in that species. However, if the drug is to be used, the dose is 1.1 mg/kg PO every other day.

Monitoring Parameters

1) Hemograms (including platelets) should be monitored closely; initially every 1-2 weeks and every 1-2 months once on maintenance therapy. It is recommended by some clinicians that if the WBC count drops to between 5,000-7,000 cells/mm2 the dose be reduced by 25%. If WBC count drops below 5,000 cells/mm2 treatment should be discontinued until leukopenia resolves.

2) Liver function tests; serum amylase, if indicated

3) Efficacy

Client Information

Clients must be briefed on the possibilities of severe toxicity developing from this drug, including drug-related neoplasms or mortality. Clients should contact veterinarian should the animal exhibit symptoms of abnormal bleeding, bruising, anorexia, vomiting or infection.

Although, no special precautions are necessary with handling intact tablets, it is recommended to wash hands after administering the drug.

Dosage Forms – Preparations – FDA Approval Status – Withholding Times

Veterinary-Approved Products:

None

Human-Approved Products:

Azathioprine Tablets 50 mg; Imuran® (Glaxo Wellcome) (Rx)

Azathioprine Sodium Injection 100 mg per vial in 20 ml vials; Imuran® (Glaxo Wellcome) ; (Rx); generic, (Rx)