Azathioprine

Pronunciation: (AY-za-THYE-oh-preen)
Class: Immunosuppressive

Trade Names

Azasan
- Tablets, oral 75 mg
- Tablets, oral 100 mg

Azathioprine
- Injection, lyophilized powder for solution 100 mg (as sodium)

Imuran
- Tablets, oral 50 mg

Apo-Azathioprine (Canada)
Gen-Azathioprine (Canada)

Pharmacology

Suppresses cell-mediated hypersensitivities; alters antibody production and may reduce inflammation.

Pharmacokinetics

Absorption

Well absorbed after oral administration. T _max is 1 to 2 h.

Distribution

Azathioprine and mercaptopurine are approximately 30% bound to serum proteins.

Metabolism

Extensively metabolized. Azathioprine is cleaved to mercaptopurine (active). Both compounds are oxidized or methylated in erythrocytes or liver. Converted to inactive 6-thiouric acid by xanthine oxidase.

Elimination

Azathioprine and mercaptopurine are rapidly eliminated from blood. Half-life (including metabolites) is 5 h. No azathioprine or mercaptopurine is detectable in urine after 8 h. Partially dialyzable.

Special Populations

Renal Function Impairment

Renal Cl is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.

Indications and Usage

Adjunct for prevention of rejection in renal homotransplantation; treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms.

Unlabeled Uses

Idiopathic thrombocytopenic purpura; juvenile idiopathic arthritis; multiple sclerosis; psoriasis.

Contraindications

Hypersensitivity to any component of the product; treatment of RA in pregnant women.

Patients with RA previously treated with alkylating agents (eg, chlorambucil, cyclophosphamide, melphalan) may have a prohibitive risk of neoplasia if treated with azathioprine.

Dosage and Administration

Renal Transplantation
Adults

IV/PO Initiate with 3 to 5 mg/kg/day as single daily dose on the day of, and in a minority of cases, 1 to 3 days before transplantation. Maintenance dosage is 1 to 3 mg/kg/day.

Rheumatoid Arthritis
Adults

IV/PO Initial dose is 1 mg/kg (50 to 100 mg) given as single dose or in divided doses given twice daily. Dose is increased by 0.5 mg/kg/day at 6 to 8 wk, then every 4 wk if there are no serious toxicities and if initial response is unsatisfactory. Max dosage is 2.5 mg/kg/day. Maintenance therapy should be at the lowest effective dose; the dose can be lowered in decrements of 0.5 mg/kg (approximately 25 mg) daily every 4 wk.

General Advice

• Discontinuation of azathioprine in renal transplantation patients may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.
• An adequate trial of azathioprine for treatment of RA is 12 wk. Patients who have not improved after 12 wk can be considered refractory.

• IV
• Reserve IV formulation for patients unable to tolerate oral medications.
• Reconstitute with 10 mL of sterile water for injection and swirl until a clear solution results. Further dilution with saline or dextrose is usually made for infusion; final volume depends on time for infusion. Administer over 30 to 60 min; however, infusion has been as short as 5 min and as long as 8 h.
• For IV use only.

• PO
• Administer with food to decrease GI discomfort.

Storage/Stability

Store between 59° and 77°F in a dry place. Protect from light. Diluted IV solution should be used within 24 h.

Drug Interactions

ACE inhibitors (eg, captopril)

Concurrent use may induce severe leukopenia and increase the risk of anemia. Closely monitor for possible leukopenia and anemia.

Allopurinol

Decreases metabolism of azathioprine. Dose of azathioprine should be reduced to approximately one-third to one-fourth usual dose when used concomitantly.

Aminosalicylates (eg, mesalamine, olsalazine, sulfasalazine)

Aminosalicylate derivatives inhibit the enzyme that is responsible for metabolizing azathioprine to an inactive metabolite. Bone marrow toxicity may occur. Use with caution and close clinical monitoring.

Anticoagulants (eg, warfarin)

Azathioprine may decrease the action of anticoagulants. Monitor anticoagulant activity and adjust the dose as needed.

Cyclosporine

Cyclosporine blood concentrations may be decreased. Monitor cyclosporine blood concentrations and observe the patient for signs of organ rejection.

Febuxostat

Azathioprine plasma concentrations may be elevated, increasing the risk of toxicity. Coadministration of febuxostat and azathioprine is contraindicated.

Live vaccines

Effectiveness of live vaccines may be reduced. In addition, immunocompromised patients may be at increased risk for vaccine-induced infection. Live vaccines should generally be deferred until immune function has improved.

Mercaptopurine

Azathioprine and mercaptopurine may exert additive suppression on the bone marrow, increasing the risk of myelosuppression, including pancytopenia. Depletion of leukocytes, erythrocytes, and platelets may occur. Avoid concomitant use.

Methotrexate

Plasma concentrations of the 6-mercaptopurine metabolite may be increased. If an interaction is suspected (eg, unexpected hematologic toxicity), a lower dose of azathioprine may be needed.

Nondepolarizing muscle relaxants (eg, pancuronium, tubocurarine)

Azathioprine may decrease or reverse neuromuscular blockade. Closely monitor respiratory function. The dosage requirements for nondepolarizing muscle relaxants may be increased.

Ribavirin

The risk of severe pancytopenia and azathioprine-related myelotoxicity may be increased. Patients should have CBC, including platelet counts, monitored weekly for the first month of treatment, twice monthly for the second and third months, then monthly or more frequently if dosage or other therapy changes are needed.

Adverse Reactions

GI

Nausea, vomiting (12%).

Hematologic

Leukopenia (more than 50%); bleeding, bone marrow suppression, macrocytic anemia, pancytopenia, thrombocytopenia.

Hepatic

Hepatic veno-occlusive disease, hepatotoxicity.

Miscellaneous

Infections (20%); neoplasias (3%); hepatosplenic T-cell lymphoma, Sweet syndrome.

Precautions

Warnings Chronic immunosuppression with azathioprine may increase risk of malignancy. Reports of malignancy include posttransplant lymphoma and hepatosplenic T-cell lymphoma in patients with inflammatory bowel disease. Health care providers using this drug should be very familiar with this risk as well as with the mutagenic potential to men and women, and with possible hematologic toxicities. Health care providers should inform patients of the risk of malignancy with azathioprine.

Monitor Monitor CBC weekly during the first month, twice monthly for the second and third months, then monthly, or more frequently if dosage alterations or other therapy changes are necessary. Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity.

Pregnancy

Category D . Should not be used to treat RA in pregnant women.

Lactation

Excreted in breast milk.

Children

Safety and efficacy not established.

Superinfection

Serious fungal, viral, bacterial, and protozoal infections may develop in patients on long-term immunosuppression. Consider reduction of the azathioprine dose or use of other therapy if these occur.

GI toxicity

Hypersensitivity reaction with severe nausea and vomiting may occur. Symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Frequency of gastric disturbances can be reduced by giving in divided doses or after meals.

Hematologic effects

Severe leukopenia, thrombocytopenia, anemias, including macrocytic anemia, pancytopenia, and/or bone marrow suppression may occur.

Malignancy

Increased risk of developing lymphoma and other malignancies, particularly of the skin. Limit exposure to sunlight and UV light.

TPMT testing

Patients with reduced thiopurine S-methyl transferase (TPMT) activity are at increased risk of developing azathioprine toxicity. Consider TPMT genotyping or phenotyping and decreased dosages in patients with reduced TPMT activity.

Overdosage

Symptoms

Abnormalities in liver function, bleeding, bone marrow hypoplasia, death, diarrhea, infection, nausea, vomiting.

Patient Information

• Advise patients to take tablets with meals.
• Explain importance of precautions regarding contact with persons who have active infections or who have recently received oral polio vaccine.
• Identify signs of transplant rejection (eg, localized redness, tenderness and swelling in the area of the transplant, decreased transplant organ function), and remind patient that this or similar medication will be required indefinitely to prevent transplant rejection.
• Explain that frequent follow-up appointments with a health care provider are important to adjust medication dosage.
• Inform patients of the necessity of periodic blood cell counts while they are receiving azathioprine and encourage patients to report any unusual bleeding or bruising to their health care provider.
• Inform patients of the risk of infection and advise patient to report signs and symptoms of infection to their health care provider.
• Inform patient of the risk of neoplasia following therapy with azathioprine.
• Advise patient to limit exposure to sunlight and UV light by wearing protective clothing and using sunscreen with a high SPF.
• Advise patient of the potential risks of the use of azathioprine during pregnancy and while breast-feeding.

Copyright © 2009 Wolters Kluwer Health.