Azathioprine

Generic Name

Azathioprine

Brand Names

Imuran

Azapress

Azathioprine Sodium (injectable form)

Imurel (France)

Various generics available worldwide in oral and injectable forms

Drug Class

Immunosuppressant

Antimetabolite

Purine analog

Prodrug of 6-mercaptopurine (6-MP)

Classified under Disease-Modifying Anti-Rheumatic Drugs (DMARDs) in rheumatology

Used as a steroid-sparing agent

Mechanism of Action

Azathioprine is a prodrug that is converted into 6-mercaptopurine (6-MP) in the body

6-MP is metabolized into active thioguanine nucleotides, which are incorporated into DNA and RNA of proliferating cells, leading to suppression of cell replication

It inhibits the proliferation of T and B lymphocytes, which are essential for the immune response

This results in immunosuppression, reduced antibody synthesis, and decreased inflammation

It also reduces delayed hypersensitivity reactions and cell-mediated immunity

Pharmacogenetics

Azathioprine metabolism is influenced by the enzyme thiopurine S-methyltransferase (TPMT)

TPMT polymorphisms affect drug toxicity—patients with low or absent TPMT activity are at higher risk of severe myelosuppression

Testing for TPMT activity or genotype is recommended before starting therapy

Indications

Approved and Common Uses

Prevention of organ transplant rejection (especially kidney transplants)

Rheumatoid arthritis (moderate to severe disease)

Systemic lupus erythematosus (SLE)

Inflammatory bowel disease (Crohn’s disease and ulcerative colitis)

Autoimmune hepatitis

Dermatomyositis and polymyositis

Myasthenia gravis

Vasculitis (e.g., ANCA-associated vasculitis)

Pemphigus vulgaris and other autoimmune blistering diseases

Behçet’s disease

Relapsing multiple sclerosis (off-label)

Off-Label or Investigational Uses

Chronic inflammatory demyelinating polyneuropathy (CIDP)

Eczema and atopic dermatitis (refractory cases)

Refractory autoimmune hemolytic anemia

Autoimmune uveitis

Immune thrombocytopenic purpura (ITP)

Nephrotic syndrome (steroid-sparing)

Sjögren’s syndrome

Autoimmune myocarditis

Dosage and Administration

Adults (Oral)

Initial dose: 1–3 mg/kg/day, usually once daily

Maintenance dose: adjusted based on clinical response and tolerance

In organ transplant: 1–5 mg/kg/day (higher end of the range)

In autoimmune diseases: typically 1–2.5 mg/kg/day

Dose should be adjusted in renal or hepatic impairment

Children (Oral)

Pediatric transplant and autoimmune conditions: 1–3 mg/kg/day

Requires close monitoring of blood counts and liver function

Injectable (IV use)

Used when oral administration is not feasible

IV dose is equivalent to oral dose, diluted in compatible solution and administered slowly

IV route is rarely used long-term

Dosing Considerations

Start at lower end of dose range in patients with impaired TPMT activity

Dose should be reduced when used concomitantly with allopurinol (xanthine oxidase inhibitor), typically to one-quarter of the usual dose

Takes weeks to months to observe full therapeutic effect

Pharmacokinetics

Bioavailability: ~30–70% (oral)

Peak plasma level: 1–2 hours after oral administration

Metabolism: extensively hepatic via non-enzymatic and enzymatic conversion to 6-MP, and further via TPMT, xanthine oxidase, and hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

Half-life: ~4.5 hours for azathioprine; 6-MP active metabolites may persist longer

Excretion: renal (mainly as inactive metabolites)

Contraindications

Known hypersensitivity to azathioprine or 6-mercaptopurine

Pregnancy (relative contraindication depending on indication and clinical context)

Breastfeeding

Severe infections

Severe bone marrow suppression

Hepatic impairment (relative)

Concomitant live vaccine administration

Concomitant use with allopurinol without dose adjustment

Warnings and Precautions

Risk of myelosuppression (especially in TPMT-deficient individuals)

Increased risk of infection, including opportunistic infections

Increased risk of lymphomas, especially with long-term use or when combined with other immunosuppressants

Risk of hepatotoxicity—monitor LFTs regularly

Pancreatitis (especially in IBD patients)

Hypersensitivity reactions can occur with fever, rash, and malaise

Photosensitivity and increased risk of skin cancers—advise sun protection

May reduce response to vaccines—live vaccines contraindicated

Monitor complete blood count and liver enzymes frequently during therapy

Patients with low or absent TPMT activity should not receive standard dosing

Adverse Effects

Very Common

Nausea

Vomiting

Loss of appetite

Diarrhea

Fatigue

Increased liver enzymes

Common

Leukopenia, anemia, thrombocytopenia

Infections (bacterial, viral, fungal)

Rash, hypersensitivity

Fever

Arthralgia or myalgia

Pancreatitis

Mouth ulcers

Hair thinning

Rare but Serious

Severe bone marrow suppression

Hepatitis or hepatic veno-occlusive disease

Lymphoproliferative disorders (especially in transplant patients)

Stevens–Johnson syndrome

Interstitial pneumonitis

Aplastic anemia

Severe infections: tuberculosis, CMV, PJP

Progressive multifocal leukoencephalopathy (PML)

Pregnancy and Lactation

Pregnancy

Category D (US FDA – outdated system)

Should generally be avoided in pregnancy unless benefits outweigh risks

Some data suggest it may be relatively safe in selected autoimmune diseases or transplant patients when no alternatives are available

Crosses the placenta

Associated with low birth weight and preterm delivery but not major malformations in many reports

Women of childbearing age should use effective contraception

Lactation

Excreted in breast milk in small amounts

Not recommended during breastfeeding due to potential immunosuppressive effects on infant

Drug Interactions

Allopurinol or febuxostat (xanthine oxidase inhibitors)

Inhibit 6-MP metabolism, leading to increased toxicity

Azathioprine dose must be reduced to 25% when co-administered

Co-use with febuxostat generally contraindicated

ACE inhibitors

May increase risk of leukopenia—monitor CBC closely

Warfarin

Azathioprine may reduce anticoagulant effect—monitor INR

Aminosalicylates (e.g., mesalazine, sulfasalazine)

May inhibit TPMT—monitor for myelosuppression

Live vaccines (e.g., MMR, varicella, yellow fever)

Risk of infection—contraindicated during treatment

Other immunosuppressants (e.g., cyclosporine, biologics)

Additive risk of infection, bone marrow suppression, malignancy

Monitoring Parameters

Baseline and regular full blood count (weekly to monthly initially)

Liver function tests

Renal function

TPMT activity before starting

Pancreatic enzymes if symptomatic

Monitor for signs of infection, rash, fatigue, or bruising

Yearly skin check for skin cancer (long-term users)

Counseling Points

Take at the same time each day with food to reduce GI upset

Report signs of infection, unusual bruising, or jaundice immediately

Avoid live vaccines during treatment

Use effective contraception during and for several months after therapy

Avoid excessive sunlight and use sunscreen to reduce skin cancer risk

Do not stop or change the dose without medical advice

Routine blood tests are essential for safe use

Keep out of reach of children—may be fatal if ingested in overdose

Handle tablets with care—wash hands after handling

Inform all healthcare providers you are on immunosuppressive therapy

Comparative Notes

Azathioprine vs Methotrexate

Methotrexate used weekly; azathioprine is daily

Both are DMARDs but methotrexate is more established in rheumatoid arthritis

Azathioprine preferred in lupus and IBD

Methotrexate contraindicated in pregnancy; azathioprine may be considered

Azathioprine vs Mycophenolate Mofetil

Both are antimetabolites used for immunosuppression

Mycophenolate may have higher efficacy in lupus nephritis but greater teratogenicity

Azathioprine better tolerated in pregnancy

Azathioprine vs Biologics (e.g., infliximab, rituximab)

Azathioprine is oral and less expensive

Biologics are more targeted and faster acting but require injection and monitoring for infections

Regulatory Status

Prescription-only

Approved by FDA, EMA, MHRA for transplant and autoimmune use

Included in WHO Model List of Essential Medicines

Controlled substance: No

Available in oral tablets (25 mg, 50 mg), injectable vials (for IV use)