azathioprine (Rx)

>10%

Leukopenia (28-50%)

Infection (20%)

<1%

Lymphoma

Frequency Not Defined

Abdominal pain

Alopecia

Arthralgia

Bacterial, fungal, protozoal, viral infections

Bone marrow suppression

Diarrhea

Fever

Hepatotoxicity

Macrocytic anemia

Myalgia

Nausea or vomiting

Rash

Skin cancer

Steatorrhea

Sweet syndrome (acute febrile neutrophilic dermatosis)

Thrombocytopenia

Contraindications

Documented hypersensitivity

Pregnancy, lactation

Rheumatoid arthritis: Patients previously treated with alkylating agents

Cautions

Long-term use increases risk of neoplasia

Increased risk of infection and hepatotoxicity; monitor liver function periodically; hepatic sinudoidal obstruction syndrome reported; discontinue therapy if suspected

Cases of JC virus-associated infection resulting in progressive multifocal leukoencephalopathy (PML), sometimes fatal, reported in patients treated with immunosuppressants, including azathioprine

Severe leukopenia, thrombocytopenia, anemias including macrocytic anemia, and/or pancytopenia may occur; severe bone marrow suppression may also occur; patients with or nucleotide diphosphatase (NUDT15) deficiency may be at an increased risk of myelotoxicity if patient receiving conventional doses of drug; delayed hematologic suppression may occur; prompt reduction in dosage or temporary withdrawal of drug may be necessary if there is rapid fall in or persistently low leukocyte count, or other evidence of bone marrow depression; leukopenia does not correlate with therapeutic effect; therefore dose should not be increased intentionally to lower white blood cell count

In patients with severe myelosuppression, consider evaluation for TPMT and NUDT15 deficiency; consider alternative therapy in patients with homozygous TPMT or NUDT15 deficiency and reduced dosages in patients with heterozygous deficiency

Patients receiving immunosuppressants, are at increased risk for bacterial, viral, fungal,protozoal, and opportunistic infections, including reactivation of latent infections; these infections may lead to serious, including fatal outcomes

Frequency of gastrointestinal adverse effects (nausea and vomiting) may decrease with dividing dose or administering after meals

Hepatosplenic T-cell lymphoma

• Rare postmarketing cases of HSTCL reported primarily in adolescent and young adult patients with Crohn disease and ulcerative colitis treated with tumor necrosis factor (TNF) blockers
• Reports have also included 1 patient being treated for psoriasis and 2 patients being treated for rheumatoid arthritis
• HSTCL is an aggressive, rare type of T-cell lymphoma that is usually fatal
• Most reported cases with TNF blockers have occurred in context of concomitant treatment with azathioprine or 6-mercaptopurine (6-MP), though cases have been reported with azathioprine or 6-MP alone
• In the FDA Adverse Event Reporting System (AERS) database, the literature, and the HSTCL Cancer Survivors' Network, HSTCL cases have been identified in association with the following drugs: infliximab (20), etanercept (1), adalimumab (2), infliximab/adalimumab (5), certolizumab (0), golimumab (0), azathioprine (12), 6-MP (3)

Pregnancy category: D

Lactation: Drug excreted at low levels in breast milk; use not recommended

Pregnancy Categories

A: Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

B: May be acceptable. Either animal studies show no risk but human studies not available or animal studies showed minor risks and human studies done and showed no risk.

C: Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

D: Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

X: Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

NA: Information not available.

Mechanism of Action

Purine antimetabolite, converted to 6-MP; may inhibit synthesis of DNA, RNA, and proteins; interferes with cellular metabolism; may inhibit mitosis

Absorption

Well absorbed orally

Duration: Variable (crosses placenta)

Peak plasma time: PO, 1-2 hr

Peak plasma concentration: <1 mcg/mL

Distribution

Protein bound: 30%

Metabolism

Metabolized in liver

Metabolites: 6-MP, 6-thiouric acid

Elimination

Half-life: Parent drug, 12 min; 6-MP, 0.7-3 hr; slightly prolonged in end-stage renal disease

Dialyzable: Partially

Excretion: Urine (primarily as metabolites)

Oral suspension of 50 mg/mL requires extemporaneous compounding by pharmacist

IV Incompatibilities

Stable in neutral or acid solutions; in alkaline solutions, hydrolyzed to 6-MP

IV Administration

Can be administered by IV push over 5 minutes at concentration not exceeding 10 mg/mL

Can be further diluted with NS or D5W and administered by intermittent infusion over 30-60 minutes (usual approach); however, infusions over periods ranging from 5 minutes to 8 hours have been done

Storage

Store powder at room temperature (25°C); reconstituted solution is stable for 2 weeks at room temperature but may be less stable under refrigeration

Protect from light

Because there are no preservatives, drug must be used within 24 hours