Azathioprine

Azathioprine also known as Imuran or Azasan is an immunosuppressant or a drug that weakens your body’s immune system in order to help keep it from “rejecting” a transplanted organ such as a kidney ¹⁾. Organ rejection happens when your immune system treats the new organ as an invader and attacks it. Azathioprine is used with other medications to prevent transplant rejection (attack of the transplanted organ by your immune system) in people who received kidney transplants. Azathioprine is also used as a disease-modifying antirheumatic drug (DMARD) or immunomodulator to treat autoimmune conditions such as severe rheumatoid arthritis (a condition in which the body attacks its own joints, causing pain, swelling, and loss of function), Crohn’s disease, ulcerative colitis and autoimmune hepatitis when other medications and treatments have not helped ²⁾, ³⁾.

Azathioprine was introduced into use in the early 1960s and represented a major breakthrough in the development of organ rejection therapy, allowing for more widespread and successful use of kidney, heart and liver transplantation. Azathioprine was approved for use in the United States in 1968 and is still widely used in organ transplantation and in treatment of  autoimmune conditions.

Azathioprine comes as a tablet 50, 75 and 100 mg to be taken by mouth; a parenteral formulation is also available. Azathioprine is usually taken once or twice a day after meals. The usual Azathioprine dose is 1 to 3 mg/kg of body weight or 50 to 150 mg daily and it is typically given long term. Take azathioprine at around the same time(s) every day. Follow the directions on your prescription label carefully, and ask your doctor or pharmacist to explain any part you do not understand. Take azathioprine exactly as directed. Do not take more or less of it or take it more often than prescribed by your doctor.

If you are taking azathioprine to treat rheumatoid arthritis, your doctor may start you on a low dose and gradually increase your dose after 6-8 weeks and then not more than once every 4 weeks. Your doctor may gradually decrease your dose when your condition is controlled. If you are taking azathioprine to prevent kidney transplant rejection, your doctor may start you on a high dose and decrease your dose gradually as your body adjusts to the transplant.

Azathioprine controls rheumatoid arthritis but does not cure it. It may take up to 12 weeks before you feel the full benefit of azathioprine. Azathioprine prevents transplant rejection only as long as you are taking the medication. Continue to take azathioprine even if you feel well. Do not stop taking azathioprine without talking to your doctor.

Azathioprine usually requires 6 to 8 weeks to work. The recommendation is to consider stopping Azathioprine if there is no improvement in 3 months ⁴⁾. Checking thiopurine S-methyltransferase (TPMT) activity is suggested before starting azathioprine. Thiopurine S-methyltransferase (TPMT) deficiency is a condition characterized by significantly reduced activity of thiopurine S-methyltransferase (TPMT) enzyme that helps the body process drugs called thiopurines, which include 6-thioguanine, 6-mercaptopurine, and azathioprine ⁵⁾. A potential complication of treatment with thiopurine drugs is damage to the bone marrow (hematopoietic toxicity). Although this complication can occur in anyone who takes these drugs, people with thiopurine S-methyltransferase (TPMT) deficiency are at highest risk. Bone marrow normally makes several types of blood cells, including red blood cells, which carry oxygen; white blood cells, which help protect the body from infection; and platelets, which are involved in blood clotting. Damage to the bone marrow results in myelosuppression, a condition in which the bone marrow is unable to make enough of these cells. A shortage of red blood cells (anemia) can cause pale skin (pallor), weakness, shortness of breath, and extreme tiredness (fatigue). Low numbers of white blood cells (neutropenia) can lead to frequent and potentially life-threatening infections. A shortage of platelets (thrombocytopenia) can cause easy bruising and bleeding.

Many doctors recommend that patients’ TPMT activity levels be tested before Azathioprine is prescribed. In people who are found to have reduced TPMT enzyme activity, thiopurine drugs may be given at a significantly lower dose or different medications can be used to reduce the risk of hematopoietic toxicity. Misclassification of TMPT phenotype can occur by prior blood transfusion ⁶⁾.

TPMT deficiency does not appear to cause any health problems other than those associated with thiopurine drug treatment ⁷⁾.

Azathioprine common side effects include nausea, abdominal upset, rash, aphthous ulcers and dose related bone marrow suppression. Long term use of azathioprine is associated with an increased risk of certain types of cancer, especially skin cancer and lymphoma and possibly liver carcinoma.

Azathioprine special precautions

Before taking azathioprine:

• tell your doctor and pharmacist if you are allergic to azathioprine, any other medications, or any of the ingredients in azathioprine tablets. Ask your doctor or pharmacist for a list of the ingredients.
• tell your doctor and pharmacist what prescription and nonprescription medications, vitamins, nutritional supplements, and herbal products you are taking or plan to take. Be sure to mention the medications mentioned in the IMPORTANT WARNING section and any of the following: allopurinol (Zyloprim); aminosalicylates such as mesalamine (Apriso, Asacol, Pentasa, others), olsalazine (Dipentum), and sulfasalazine (Azulfidine); and anticoagulants (‘blood thinners’) such as warfarin (Coumadin). Your doctor may need to change the doses of your medications or monitor you carefully for side effects.
• tell your doctor if you have any type of infection, or if you have or have ever had kidney disease.
• tell your doctor if you are pregnant, plan to become pregnant, or are breast-feeding. You should use birth control to be sure you or your partner will not become pregnant while you are taking azathioprine. Call your doctor if you or your partner become pregnant while you are taking azathioprine. Azathioprine may harm the fetus.
• if you are having surgery, including dental surgery, tell the doctor or dentist that you are taking azathioprine.
• do not have any vaccinations during or after your treatment without talking to your doctor.

Test patient for hepatitis B and C and Tuberculin Skin Test (Mantoux Test) for diagnosis of silent (latent) tuberculosis (TB) infection. A pregnancy test before azathioprine treatment initiation is also a recommendation ⁸⁾.

Azathioprine contraindications

Azathioprine contraindications include ⁹⁾, ¹⁰⁾, ¹¹⁾, ¹²⁾, ¹³⁾:

• Hypersensitivity
• Pregnancy or plan for pregnancy: Contraception recommended. azathioprine can increase the risk of spontaneous miscarriage, low birth weight, and preterm delivery. Although data in systemic lupus erythematosus (SLE) and renal transplant patients showed safety in pregnancy. In some specific conditions like SLE and antiphospholipid antibody syndrome, the benefits of taking immunosuppressive medications are more than harms in keeping the mother safe.
• Breastfeeding as mercaptopurine (6-MP) was present in breast-milk of women who take azathioprine
• Unknown thiopurine S-methyltransferase (TPMT) status or deficient thiopurine S-methyltransferase (TPMT) activity due to the high risk of myelosuppression ¹⁴⁾
• Known malignancy
• Clinically active infection

Azathioprine relative contraindications ¹⁵⁾:

• Allopurinol intake concomitantly with azathioprine due to severe myelosuppression
• Cyclophosphamide or chlorambucil treatment in the past.

Azathioprine drug interactions

Tell your doctor about all your current medicines. Many drugs can affect azathioprine, especially:

• Allopurinol
• Febuxostat
• Ribavirin.

This list is not complete and many other drugs may affect azathioprine. This includes prescription and over-the-counter medicines, vitamins, and herbal products.

How does azathioprine work?

Azathioprine is a purine analog and prodrug (a pharmacologically inactive medication that metabolizes inside the body and converts into a pharmacologically active drug compound) that converts to its active metabolites, mercaptopurine (6-MP) and thioguanine (6-TGN), by the action of hypoxanthine-guanine phosphoribosyltransferase (HPRT) and thiopurine methyltransferase (TPMT) enzymes ¹⁶⁾. Azathioprine then blocks purine synthesis thus inhibiting DNA, RNA and subsequent protein synthesis ¹⁷⁾. Azathioprine metabolites are incorporated into the replicating DNA and halt cell division. Azathioprine metabolites inhibit the maturation of T cells (T  lymphocytes) and blocks delayed hypersensitivity reactions; it also has antiinflammatory activity.

Azathioprine works by decreasing the activity of the body’s immune system so it will not attack the transplanted organ or the joints.

Azathioprine is absorbed rapidly through the gastrointestinal system and does not penetrate the blood-brain barrier. Azathioprine undergoes metabolism in the liver, and excretion is via the kidneys, which increases its toxicity in kidney failure ¹⁸⁾.

Azathioprine uses

Azathioprine (Imuran or Azasan) is approved by the U.S. Food and Drug Administration (FDA) for the symptomatic treatment of active rheumatoid arthritis as a corticosteroid sparing agent. Azathioprine also has approval as add-on therapy for the prevention of kidney transplant rejection ¹⁹⁾, ²⁰⁾.

Azathioprine (Imuran or Azasan) is also used off-label for the treatment of inflammatory bowel disease (Crohn’s disease & ulcerative colitis) ²¹⁾, Churg-Strauss syndrome, autoimmune hepatitis (for maintenance treatment along with steroids) ²²⁾, ²³⁾, chronic immune thrombocytopenic purpura (rare autoimmune disorder that causes you to have low platelet levels) as second-line agent) ²⁴⁾, lupus glomerulonephritis ²⁵⁾, fibrotic connective tissue disease-associated interstitial lung disease ²⁶⁾, multiple sclerosis, severe myasthenia gravis, recurrent pericarditis ²⁷⁾, psoriasis, non-infectious uveitis ²⁸⁾, relapsing polychondritis (a very rare autoimmune disease characterized by a relapsing inflammation of the cartilaginous tissues such as joints, ears, nose, intervertebral discs, larynx, trachea and cartilaginous bronchi) ²⁹⁾, dermatomyositis/polymyositis, erythema multiforme, severe and refractory atopic dermatitis, chronic actinic dermatitis, pyoderma gangrenosum, Behcet disease, cutaneous vasculitis, pityriasis rubra pilaris, lichen planus, bullous pemphigoid, and pemphigus vulgaris ³⁰⁾, ³¹⁾. Azathioprine or mercaptopurine (6-MP) are treatment options in children with Crohn’s disease as a maintenance treatment ³²⁾. Azathioprine is also used to treat ulcerative colitis (a condition which causes swelling and sores in the lining of the colon [large intestine] and rectum) and Crohn’s disease.

Azathioprine dosage

The starting dose for azathioprine is 2 to 2.5 mg/kg of body weight per day, except for patients with TPMT or NUDT15 gene mutation, in which the starting dose is lower than normal ³³⁾. Azathioprine dose adjustments are necessary for liver and kidney disease ³⁴⁾.

Azathioprine tablets may be administered after meals to decrease gastrointestinal adverse effects. Administration can be by intravenous (IV) push over 5 minutes, at a concentration not exceeding 5 mg/ml. Azathioprine can be further diluted with normal saline or dextrose 5% in water and administered by intermittent infusion over 30 to 60 minutes. However, it may also be infused over 5 minutes up to over 8 hours.

Adult dose for kidney transplant

Use: Adjunctive therapy for prevention of rejection in renal homotransplantation.

• Initial dose: Azathioprine 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
• Maintenance dose: Azathioprine 1 to 3 mg/kg orally or IV once a day

Comments:

• In a minority of cases, Azathioprine therapy has been started 1 to 3 days before transplantation
• Azathioprine dose should not be increased to toxic levels because of threatened rejection

Adult dose for rheumatoid arthritis

• Initial dose: 1 mg/kg (50 to 100 mg) orally or IV per day given in 1 to 2 divided doses
• Maintenance dose: Lowest effective dose
• Maximum dose: 2.5 mg/kg orally or IV per day
• Duration: At least 12 weeks

Comments:

• Azathioprine dose may be increased by 0.5 mg/kg/day (or approximately 25 mg/day), after 6 to 8 weeks of starting treatment and thereafter at 4 week intervals if necessary.
• Gradual dose reduction is recommended to reduce the risk of toxicities.
• Therapeutic response occurs after several weeks of therapy, usually 6 to 8 weeks. Patients not improved after 12 weeks can be considered refractory.
• Azathioprine may be continued long-term in patients with clinical response.

Adult dose for Acute Crohn’s disease

• Azathioprine dose 1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Adult dose for Maintenance Crohn’s disease

• Azathioprine dose 1.5 to 4 mg/kg per day for 10 days up to 52 weeks

Adult dose for Ulcerative Colitis

Study (n=9)

• IV: Azathioprine dose 20 to 40 mg/kg via IV infusion over 36 hours or 40 mg/kg as three 8-hour infusions over 3 days followed by oral azathioprine
• Oral: Azathioprine dose 2 mg/kg orally per day beginning the day after completion of the IV loading dose

Study (n=12)

• Azathioprine dose 50 mg per day for 2 weeks, then 2 to 2.5 mg/kg per day plus mesalamine 500 mg orally 3 times a day; these drugs were started immediately after signs of remission was achieved (mean: 14.5 days) with cyclosporine IV (4 mg/kg/day)

Adult dose for Chronic Inflammatory Demyelinating Polyradiculoneuropathy

• Study (n=14): Azathioprine dose 2 to 3 mg/kg orally once a day for 9 months

Adult dose for Atopic Dermatitis

• Study (n=37): Azathioprine dose 2.5 mg/kg orally once a day, in the morning, for 3 months

Adult dose for Sarcoidosis

Study (n=11)

• Initial dose: Azathioprine dose 2 mg/kg per day in combination with prednisolone 0.6 to 0.8 mg/kg per day, with prednisolone reduced to 0.1 mg/kg within 2 to 3 months
• Maintenance dose: Azathioprine dose 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months

Adult dose for Uveitis

Study (n=14)

• Treatment of choroidal neovascularization: Azathioprine dose 1 to 1.5 mg/kg orally per day, in combination with prednisolone and cyclosporine

Adult dose for Multiple Sclerosis

Study (n=6)

Patients refractory to interferon beta-1b:

• Initial dose: Azathioprine should be titrated up to 1.5 mg/kg per day over 1 month, followed by 50 mg increments in 6-month intervals, concomitantly with 8 million international units subcutaneous interferon beta-1b on alternate days
• Maintenance dose: Azathioprine dose 2 mg/kg per day

Adult dose for Systemic Lupus Erythematosus (SLE)

Studies: Azathioprine dose 1 to 3 mg/kg actual body weight/day orally or IV once a day

Study (n=55)

• Diffuse proliferative lupus glomerulonephritis: Sequential therapy starting with prednisone (1 mg/kg/day) for 8 to 10 weeks, gradually tapering to maintenance dosage of 5 to 10 mg/day, together with oral cyclophosphamide (1 to 2 mg/kg/day) for 6 to 9 months followed by azathioprine 50 to 100 mg/day

Adult dose for Chronic Active Hepatitis

Study (n=72)

• Autoimmune hepatitis: Azathioprine dose 1 to 2 mg/kg per day, concomitantly with prednisolone (5 to 15 mg/day) for a minimum of 1 year (average 5 years)

Adult dose for Takayasu’s Arteritis

Study (n=15): Azathioprine dose2 mg/kg actual body weight/day for 1 year in combination with prednisolone taper

Children dose for Atopic Dermatitis

Study (n=37)

• Greater than 17 years: Azathioprine dose 2.5 mg/kg orally once a day, in the morning, for 3 months

Children dose for Organ Transplant (Rejection Prevention)

• Initial dose: Azathioprine dose 3 to 5 mg/kg orally or IV once a day, beginning at the time of transplant
• Maintenance dose: Azathioprine dose 1 to 3 mg/kg orally or IV once a day

Children dose for Eczema

Study (n=91)

• Greater than 6 years: Azathioprine dose 2.5 to 3.5 mg/kg per day in patients with normal levels of thiopurine methyltransferase

Children dose for Systemic Lupus Erythematosus (SLE)

Case Study (n=67)

Lupus Nephritis:

• Greater than 5 years: Azathioprine dose 2 to 3 mg/kg per day (maximum dose: 150 mg/day)
• Dose should be titrated to maintain a total white blood cell count between 3 and 4 x 10(3) cells/mL.

What should I do if I forget a dose?

Take the missed dose as soon as you remember it. However, if it is almost time for the next dose, skip the missed dose and continue your regular dosing schedule. Do not take a double dose to make up for a missed one.

Azathioprine side effects

Azathioprine may cause side effects. Tell your doctor if any of these symptoms are severe or do not go away.

Azathioprine common side effects include the following ³⁵⁾, ³⁶⁾, ³⁷⁾, ³⁸⁾, ³⁹⁾, ⁴⁰⁾, ⁴¹⁾, ⁴²⁾, ⁴³⁾, ⁴⁴⁾, ⁴⁵⁾, ⁴⁶⁾:

• Nausea; is the most frequent side effect
  • Dose-dependent.
  • Early-onset nausea usually resolves without dose alteration
• Fever
• Fatigue
• Joint aches and pain (arthralgias) and muscle aches & pain (myalgia)
• Bone marrow suppression causing pancytopenia, thrombocytopenia, leukopenia – there are reports of dose-dependent, life-threatening cases.
  • This complication correlates with the thioguanine (6-TGN) level
  • There is a higher risk of myelosuppression in patients who take allopurinol or angiotensin-converting enzyme inhibitors (ACEIs) and in kidney disease
  • An increase in the mean corpuscular volume of the red blood cells is also an expected side effect
• Rash
• Liver injury: Liver injury correlates with a 6-mercaptopurine (6-MP) level of more than 5700 pmol/8 x 10⁸ red blood cell.
  • Liver injury categorizes into two groups.
    • Acute idiosyncratic liver injury happens in the early course and resolves with stopping the medication.
    • Nodular regenerative hyperplasia occurs in inflammatory bowel disease and organ transplant patients several years after therapy.
• Infections (7.4%): Concomitant use of azathioprine and steroids will increase the risk of Pneumocystis pneumonia (PCP, a serious infection caused by the fungus Pneumocystis jirovecii) in leukopenic patients.
• Hypersensitivity: symptoms including fever, chills, arthralgia/myalgia, liver abnormalities, erythema nodosum
• Kidney damage

Some side effects can be serious. If you experience any of the following symptoms or those listed in the IMPORTANT WARNING section, see your doctor immediately.

• • rash
  • fever
  • weakness
  • muscle pain

Complete blood count (CBC) and liver function test (LFT) monitoring weekly are recommended initially for the first 4 to 8 weeks. Complete blood count (CBC) and liver function test (LFT) should get checked every three months for the rest of the treatment once the maintenance dose is achieved. However, it is advisable to check CBC and LFT more frequently in patients with kidney or liver diseases or elderly patients on high dosages of azathioprine or low TPMT activity. If labs show leukopenia (WBC less than 3 x 10⁹/L), thrombocytopenia (platelet less than 120 x 10⁹/L), or transaminitis (liver biochemistry more than half of the normal upper limit), the medication should be stopped ⁴⁷⁾.

If patients have abdominal pain or severe nausea/vomiting, serum amylase is required to rule out pancreatitis. Lymph node and skin examination should be performed biannually ⁴⁸⁾. If a generalized wart occurs, the azathioprine dose should be reduced or switched to another agent.

Some studies suggested monitoring the level of azathioprine metabolites (e.g., 6-TGN and 6-MP) to avoid specific complications ⁴⁹⁾.

Azathioprine rare side effects include ⁵⁰⁾, ⁵¹⁾, ⁵²⁾, ⁵³⁾, ⁵⁴⁾, ⁵⁵⁾, ⁵⁶⁾, ⁵⁷⁾:

• Diarrhea
• Carcer: cutaneous hyperkeratosis and nonmelanoma skin cancer (squamous cell carcinoma [SCC]) in myasthenia gravis (most likely due to increased risk of photosensitivity), solid-organ transplant and IBD patients/ lymphoma in transplant and inflammatory bowel disease (IBD) patients
• Pancreatitis (3.3%): more in females with Crohn disease
  • Dose-dependent
  • Usually happens in the first six weeks
  • In the case of pancreatitis, discontinue azathioprine
• Alopecia including telogen effluvium, anagen effluvium, and plica neuropathica
• Macrocytic anemia
• Sweet syndrome (acute febrile neutrophilic dermatosis)
• Pneumonitis: in inflammatory bowel disease (IBD) and kidney transplant patients
• Upper airway edema
• Tremor: in organ transplant and Crohn patient: dose-dependent

In cases of hepatic sinusoidal obstruction syndrome, azathioprine must be discontinued permanently. If severely leukopenic, thrombocytopenic, or infected, azathioprine treatment should stop.

Azathioprine may cause other side effects. Call your doctor if you have any unusual problems while you are taking azathioprine.

Azathioprine overdose

Azathioprine overdose symptoms may include the following:

• nausea
• vomiting
• diarrhea
• sore throat, fever, chills, and other signs of infection

Azathioprine overdose symptoms include gastrointestinal symptoms, bradycardia, hepatotoxicity and bone marrow suppression (myelosuppression) ⁵⁸⁾. Azathioprine overdose usually happens when more than 1.5 times of daily dose is taken by the patient.

In the acute azathioprine overdose setting, activated charcoal may help with decreasing the symptoms within two hours of ingestion ⁵⁹⁾. No specific antidote is known for azathioprine. In severe cases of azathioprine overdose, dialysis is permissible as azathioprine is dialysable.