Select therapeutic use:

Arthritis/rheumatic disorders:

Indications for: IMURAN

To reduce signs/symptoms of active rheumatoid arthritis.

Adult Dosage:

Initially 1mg/kg per day in 1–2 divided doses. After 6–8 weeks, if needed, increase by 0.5mg/kg per day increments every 4 weeks; max 2.5mg/kg/day. Maintenance: use lowest effective dose; can decrease by 0.5mg/kg/day (approx. 25mg daily) every 4 weeks. May continue use of aspirin, NSAIDs, and/or low dose steroids during therapy. Concomitant allopurinol: reduce azathioprine to ⅓ or ¼ of usual dose.

Children Dosage:

Not established.

IMURAN Contraindications:

Rheumatoid arthritis: pregnancy; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others).

Boxed Warning:

Malignancy.

IMURAN Warnings/Precautions:

Increased risk of lymphoma, other malignancies (esp. skin). Risk of hepatosplenic T-cell lymphoma in inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Monitor CBCs with platelets weekly during 1st month, then twice monthly for 2nd and 3rd months, then monthly or more frequently during dose adjustments. Reduce dose or suspend if rapid fall in or persistently low leukocyte count, or other bone marrow depression develops. Consider TPMT or NUDT15 testing in patients with severe myelosuppression; use alternative therapy if homozygous TPMT or NUDT15 deficiency and reduce dose if heterozygous deficiency. Risk of serious infections (eg, bacterial, viral, fungal, protozoal, opportunistic, including reactivation of latent ones). Discontinue if hepatic veno-occlusive disease is suspected. Avoid sun, UV light. Renal impairment: give lower doses. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

IMURAN Classification:

Immunosuppressant (antimetabolite).

IMURAN Interactions:

See Contraindications. Concomitant febuxostat, DMARDs: not recommended. Anemia, leukopenia with ACEIs. Pancytopenia, myelotoxicity with ribavirin. Exaggerated leukopenia with cotrimoxazole. Caution with concomitant aminosalicylates (eg, sulfasalazine, mesalazine, olsalazine). May antagonize warfarin.

Adverse Reactions:

Leukopenia, thrombocytopenia, anemia, GI toxicity, secondary infection, malignancy, hepatotoxicity, rash, alopecia, fever, arthralgias, diarrhea, steatorrhea, others; progressive multifocal leukoencephalopathy (consider reducing dose).

Metabolism:

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Activation of 6-MP occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

6-MP undergoes two major inactivation routes. One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The nucleotide diphosphatase (NUDT15) enzyme is involved in conversion of the 6-TGNs to inactive 6-TG monophosphates. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities.

Drug Elimination:

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

Azathioprine decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine.

How Supplied:

Tabs—100

Organ rejection prophylaxis:

Indications for: IMURAN

Adjunct for the prevention of rejection in renal homotransplantation.

Adult Dosage:

Individualize. Initially 3–5mg/kg once daily starting day of, or in some cases 1–3 days before, transplant. Maintenance: may reduce to 1–3mg/kg daily. Concomitant allopurinol: reduce azathioprine to ⅓ or ¼ of usual dose.

Children Dosage:

Not established.

IMURAN Contraindications:

Rheumatoid arthritis: pregnancy; prior treatment with alkylating agents (eg, cyclophosphamide, chlorambucil, melphalan, others).

Boxed Warning:

Malignancy.

IMURAN Warnings/Precautions:

Increased risk of lymphoma, other malignancies (esp. skin). Risk of hepatosplenic T-cell lymphoma in inflammatory bowel disease (eg, Crohn's disease, ulcerative colitis). Monitor CBCs with platelets weekly during 1st month, then twice monthly for 2nd and 3rd months, then monthly or more frequently during dose adjustments. Reduce dose or suspend if rapid fall in or persistently low leukocyte count, or other bone marrow depression develops. Consider TPMT or NUDT15 testing in patients with severe myelosuppression; use alternative therapy if homozygous TPMT or NUDT15 deficiency and reduce dose if heterozygous deficiency. Risk of serious infections (eg, bacterial, viral, fungal, protozoal, opportunistic, including reactivation of latent ones). Discontinue if hepatic veno-occlusive disease is suspected. Avoid sun, UV light. Renal impairment: give lower doses. Pregnancy (Cat.D); avoid. Nursing mothers: not recommended.

IMURAN Classification:

Immunosuppressant (antimetabolite).

IMURAN Interactions:

See Contraindications. Concomitant febuxostat, DMARDs: not recommended. Anemia, leukopenia with ACEIs. Pancytopenia, myelotoxicity with ribavirin. Exaggerated leukopenia with cotrimoxazole. Caution with concomitant aminosalicylates (eg, sulfasalazine, mesalazine, olsalazine). May antagonize warfarin.

Adverse Reactions:

Leukopenia, thrombocytopenia, anemia, GI toxicity, secondary infection, malignancy, hepatotoxicity, rash, alopecia, fever, arthralgias, diarrhea, steatorrhea, others; progressive multifocal leukoencephalopathy (consider reducing dose).

Metabolism:

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Activation of 6-MP occurs via hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and a series of multi-enzymatic processes involving kinases to form 6-thioguanine nucleotides (6-TGNs) as major metabolites. The cytotoxicity of azathioprine is due, in part, to the incorporation of 6-TGN into DNA.

6-MP undergoes two major inactivation routes. One is thiol methylation, which is catalyzed by the enzyme thiopurine S-methyltransferase (TPMT), to form the inactive metabolite methyl-6-MP (6-MeMP). Another inactivation pathway is oxidation, which is catalyzed by xanthine oxidase (XO) to form 6-thiouric acid. The nucleotide diphosphatase (NUDT15) enzyme is involved in conversion of the 6-TGNs to inactive 6-TG monophosphates. TPMT activity correlates inversely with 6-TGN levels in erythrocytes and presumably other hematopoietic tissues, since these cells have negligible xanthine oxidase (involved in the other inactivation pathway) activities.

Drug Elimination:

Azathioprine is metabolized to 6-mercaptopurine (6-MP). Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours.

Azathioprine decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself, but is the decay rate for all 35S-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine.

How Supplied:

Tabs—100