Azathioprine

Name: Azathioprine

What Is Azathioprine (Imuran)?

Azathioprine is the generic form of the brand-name drug Imuran, which is used along with other medicines to prevent organ rejection after a kidney transplant.

The drug is also used to treat severe rheumatoid arthritis, psoriasis, ulcerative colitis, and Crohn's disease.

Azathioprine is in class of drugs known as immunosuppressants. It works by altering the activity of the body's immune system so it won't attack a transplanted organ or joint.

The Food and Drug Administration (FDA) approved this medicine in 1968.

Azathioprine has different name brands and is produced by several manufacturers. In the United States, Imuran is manufactured by GlaxoSmithKline.

Azathioprine Warnings

Azathioprine carries a black-box warning because it may increase your risk of developing certain cancers such as lymphoma, leukemia, and skin cancer.

However, if you have a kidney transplant, you may be at a higher risk for developing cancer even if you don't take azathioprine.

Tell your doctor if you've ever had cancer or if you've ever taken any of the following drugs:

  • Chlorambucil (Leukeran)
  • Cyclophosphamide (Cytoxan)
  • Melphalan (Alkeran)

Avoid unnecessary exposure to sunlight to decrease your risk of skin cancer while taking azathioprine. You should wear protective clothing, sunglasses, and sunscreen when outdoors.

Some teenagers and young males who took this drug alone or with another medicine known as a tumor necrosis factor (TNF) blocker to treat Crohn's disease or ulcerative colitis developed a serious type of cancer called hepatosplenic T-cell lymphoma (HSTCL).

Azathioprine is not approved by the FDA to treat Crohn's or ulcerative colitis, but some doctors may prescribe the medicine off-label.

You should call your doctor immediately if you are taking the drug for Crohn's or ulcerative colitis and experience the following symptoms:

  • Fever
  • Unexplained weight loss
  • Stomach pain or tenderness
  • Night sweats
  • Easy bleeding or bruising

Azathioprine may also cause a decrease in blood cells in your bone marrow, which can lead to serious or life-threatening infections.

Certain medicines may also increase this risk when taken with azathioprine. Tell your doctor if you are taking:

  • ACE inhibitors such as benazepril (Lotensin), captopril, enalapril (Vasotec), fosinopril, lisinopril (Prinivil, Zestril), moexipril (Univasc), perindopril (Aceon), quinapril (Accupril), Ramipril (Altace), or trandolapril (Mavik)
  • Trimethoprim and sulfamethoxazole (Bactrim, Septra)
  • Ribavirin (Copegus, Rebetol, Virazole)

You should also call your doctor immediately if you experience any of the following symptoms:

  • Pale skin
  • Excessive fatigue
  • Headache
  • Confusion
  • Dizziness
  • Fast heartbeat
  • Shortness of breath
  • Difficulty sleeping
  • Weakness
  • Sore throat
  • Fever
  • Chills
  • Other signs of an infection

Your health care provider will probably order tests to check your blood cells and liver enzymes during your treatment with azathioprine.

Tell your doctor if you are allergic to azathioprine or any other medications.

This medicine controls symptoms of rheumatoid arthritis, but it doesn't cure it. It might take up to 12 weeks before you feel the full benefits.

Don't stop taking azathioprine without first talking to your doctor.

You should tell your doctor you are taking this drug before having any type of surgery, including a dental procedure.

Don't have any vaccinations during or after your treatment with azathioprine without first talking to your healthcare provider.

Before taking this medicine, tell your doctor if you have or have had:

  • Any type of infection
  • Kidney disease
  • Liver disease
  • Any blood disorder
  • TPMT deficiency (an enzyme disorder)

Azathioprine for Dogs and Cats

Azathioprine may be used in dogs to treat certain conditions such as the following:

  • Hemolytic anemia
  • Arthritis and skin disease caused by an immune problem
  • Chronic liver, kidney, or stomach diseases
  • Thrombocytopenia (low blood platelet count)

The drug may also be used in very low doses to treat cats with certain skin disorders caused by an immune disorder.

Azathioprine can increase the risk of infection in a pet, so owners should monitor their animals for unusual symptoms.

Azathioprine and Pregnancy

Azathioprine might harm an unborn baby.

You shouldn't take this drug during pregnancy, or if there's a chance you may become pregnant.

Tell your doctor immediately if you become pregnant or plan to become pregnant while taking this medicine. You should use birth control if you're able to become pregnant while taking azathioprine.

Most evidence finds that breastfeeding is safe while taking azathioprine, but talk to your doctor about breastfeeding while taking the drug.

Azathioprine Dosage

Azathioprine comes as a tablet to take by mouth. It's typically taken once or twice a day after meals.

Dosage is based on your weight, medical condition, and response to treatment.

You should follow the directions on your prescription label when taking this drug. Don't take more or less of the medicine than is prescribed.

Try to take azathioprine around the same time each day. You can take this drug with or without food.

If you're taking azathioprine to treat rheumatoid arthritis, your physician may start you on a low dose and then gradually increase it.

Once your condition is controlled, your doctor may decrease your dose again.

If you're taking this drug to prevent organ rejection, your doctor may start you on a high dose and then decrease it as your body adjusts to the transplant.

Azathioprine Overdose

If you suspect an overdose, you should contact a poison control center or emergency room immediately.

You can get in touch with a poison control center at (800) 222-1222.

Missed Dose of Azathioprine

If you miss a dose of azathioprine, take it as soon as you remember.

However, if it's almost time for your next dose, skip the missed dose and continue on your regular medication schedule.

Don't double up on doses to make up for a missed one.

How supplied

50 mg overlapping circle-shaped, yellow to off-white, scored tablets imprinted with “IMURAN” and “50” on each tablet; bottle of 100 (NDC 65483-590-10).

Store at 15° to 25°C (59° to 77°F) in a dry place and protect from light.

REFERENCES

25. Recommendations for the safe handling of parenteral antineoplastic drugs. Washington, DC: Division of Safety; Clinical Center Pharmacy Department and Cancer Nursing Services, National Institute of Health; 1992. US Dept of Health and Human Services. Public Health Service Publication NIH 92-2621.

26. AMA Council on Scientific Affairs. Guidelines for handling parenteral antineoplastics. JAMA. 1985; 253:15901592.

27. National Study Commission on Cytotoxic Exposure. Recommendations for handling cytotoxic agents. 1987. Available from Louis P. Jeffrey, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences, 179 Longwood Avenue, Boston, MA 02115.

28. Clinical Oncological Society of Australia. Guidelines and recommendations for safe handling of antineoplastic agents. Med J Aust. 1983; 1:426-428.

29. Jones RB, Frank R, Mass T. Safe handling of chemotherapeutic agents: a report from The Mount Sinai Medical Center. CA Cancer J for Clinicians. 1983; 33:258-263.

30. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on handling cytotoxic and hazardous drugs. Am J Hosp Pharm. 1990; 47:1033-1049.

31. Yodaiken RE, Bennett D. OSHA Work-Practice guidelines for personnel dealing with cytotoxic (antineoplastic) drugs. Am J Hosp Pharm, 1996; 43:1193-1204.

Manufactured by Pharmaceutics International, Inc. Hunt Valley, MD 21031 for Prometheus Laboratories Inc. San Diego, CA 92121. Revised: Feb 2014

Azathioprine Overview

Azathioprine is a prescription medication used to treat rheumatoid arthritis. It is also used in kidney transplant patients to prevent rejection of the new kidney. Azathioprine belongs to a group of drugs called immunosuppressive antimetabolites, which work by decreasing the activity of the body's immune system so it will not attack the transplanted organ or the joints.

This medication comes in tablet form and is taken once or twice a day, with or without food.

This medication is also available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

Common side effects of azathioprine include nausea, vomiting, hair loss, and rash.

Azathioprine Drug Class

Azathioprine is part of the drug class:

  • Other immunosuppressants

Side Effects of Azathioprine

Oral/Injectable:

Serious side effects have been reported with azathioprine. See the “Azathioprine Precautions” section.

Common side effects of azathioprine include the following:

  • nausea
  • vomiting
  • hair loss
  • rash
  • diarrhea
  • fever
  • muscle aches
  • hair loss

This is not a complete list of azathioprine side effects. Ask your doctor or pharmacist for more information.

Call your doctor for medical advice about side effects. You may report side effects to the FDA at 1-800-FDA-1088.

Azathioprine and Lactation

Tell your doctor if you are breastfeeding or plan to breastfeed.

Tell your doctor if you are breastfeeding or plan to breastfeed.

The use of azathioprine in nursing mothers is not recommended. azathioprine or its products are transferred at low levels in breast milk. Because of the possibility for serious adverse reactions in nursing infants with use of this medication, a choice should be made whether to stop nursing or stop the use of this medication. Your doctor and you will decide if the benefits outweigh the risk of using azathioprine.

Azathioprine Usage

Take azathioprine exactly as prescribed.

Oral:

  • This medication comes in tablet form and is taken once or twice a day, with or without food.
  • If you miss a dose, take the missed dose as soon as you remember. If it is almost time for the next dose, skip the missed dose and take your next dose at the regular time. Do not take two doses of azathioprine at the same time.

Injectable:

  • This medication is available in an injectable form to be given directly into a vein (IV) by a healthcare professional.

 

Other Requirements

  • Store azathioprine at room temperature.
  • Protect from light.
  • Keep this and all medicines out of the reach of children.

What is the most important information I should know about azathioprine?

Some people using azathioprine have developed a rare fast-growing type of lymphoma (cancer). This condition affects the liver, spleen, and bone marrow, and it can be fatal. This has occurred mainly in teenagers and young adults using azathioprine or similar medicines to treat Crohn's disease or ulcerative colitis.

Uses for Azathioprine

Renal Allotransplantation

Prevention of rejection of renal allografts.100 134 136

Rheumatoid Arthritis

Management of the signs and symptoms of rheumatoid arthritis.100 134 136

Crohn’s Disease

Has been used to induce and maintain remission in adults with moderate to severely or chronically active Crohn’s disease†.110 111 112 113 114 117 118 119 120 122

Has been used in the management of fistulizing Crohn’s disease†.111 115 116 131 132

Has been used in children with refractory or corticosteroid-dependent Crohn’s disease†.128 129 133

Carefully consider risks and benefits in patients with inflammatory bowel disease†, especially in adolescents and young adults.100 136 137 (See Malignancies and Lymphoproliferative Disorders under Cautions.)

Interactions for Azathioprine

Drugs Affecting Myelopoiesis

Risk of severe leukopenia, especially in renal transplant recipients.100 134 136

Specific Drugs

Drug

Interaction

Comments

ACE inhibitors

Potential for increased toxicity (anemia, severe leukopenia)100 134 136

Allopurinol

Allopurinol inhibits metabolic pathway catalyzed by xanthine oxidase; may increase risk of azathioprine toxicity100 134 136

Reduce azathioprine dosage to 25–33% of usual dosage; consider further dosage reduction or alternative therapy in patients with low or absent TPMT activity100 134 136

Aminosalicylates (mesalamine, olsalazine, sulfasalazine)

Aminosalicylates inhibit metabolic pathway catalyzed by TPMT; may increase risk of azathioprine toxicity100 134 136

Use concomitantly with caution100 134 136

Co-trimoxazole

Possible increased leukopenia, especially in renal transplant recipients100 134 136

Ribavirin

Ribavirin inhibits metabolic pathway catalyzed by inosine monophosphate dehydrogenase, resulting in accumulation of myelotoxic metabolite of azathioprine; severe pancytopenia reported100 136

Monitor CBC, including platelet counts, weekly for first month, twice monthly during second and third months, then monthly thereafter (or more frequently if dosage or other therapy changes needed)100 136

Warfarin

Possible reduced anticoagulant effect100 134 136

Azathioprine Description

Azathioprine is an immunosuppressive antimetabolite. Each uncoated Azathioprine tablet intended for oral administration contains 50 mg of Azathioprine. In addition, each tablet contains the following inactive ingredients: croscarmellose sodium, lactose monohydrate, magnesium stearate, povidone and starch.

Azathioprine is chemically 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine. The structural formula of Azathioprine is:

It is an imidazolyl derivative of 6-mercaptopurine and many of its biological effects are similar to those of the parent compound.

Azathioprine, USP is a pale yellow, odorless powder. It is insoluble in water, soluble in dilute solutions of alkali hydroxides, sparingly soluble in dilute mineral acids, very slightly soluble in alcohol and in chloroform. The sodium salt of Azathioprine is sufficiently soluble to make a 10 mg/mL water solution which is stable for 24 hours at 59° to 77°F (15° to 25°C). Azathioprine is stable in solution at neutral or acid pH but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione, and hydrogen sulfide.

Indications and Usage for Azathioprine

Azathioprine tablets, USP are indicated as an adjunct for the prevention of rejection in renal homotransplantation. It is also indicated for the management of active rheumatoid arthritis to reduce signs and symptoms.

Renal Homotransplantation

Azathioprine tablets, USP are indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16,000 transplants shows a 5-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti-B-cell alloantigen antibody, and other variables. The effect of Azathioprine tablets on these variables has not been tested in controlled trials.

Rheumatoid Arthritis

Azathioprine tablets, USP are indicated for the treatment of active rheumatoid arthritis (RA) to reduce signs and symptoms. Aspirin, non-steroidal anti-inflammatory drugs and/or low dose glucocorticoids may be continued during treatment with Azathioprine tablets. The combined use of Azathioprine tablets with disease modifying anti-rheumatic drugs (DMARDs) has not been studied for either added benefit or unexpected adverse effects. The use of Azathioprine tablets with these agents cannot be recommended.

How is Azathioprine Supplied

Azathioprine Tablets USP, 50 mg are yellow, round, flat, beveled edge tablets with bisect on one side; one side of the bisect is debossed with logo of "ZC" and other side is debossed with "59" and other side is plain and are supplied as follows:

NDC 68382-003-01 in bottles of 100 tablets

NDC 68382-003-05 in bottles of 500 tablets

STORAGE

Store at 20° to 25° C (68° to 77° F) [See USP Controlled Room Temperature] in a dry place and protect from light.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

Pronunciation

(ay za THYE oh preen)

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Solution Reconstituted, Injection:

Generic: 100 mg (1 ea)

Tablet, Oral:

Azasan: 75 mg, 100 mg [scored]

Imuran: 50 mg [scored]

Generic: 50 mg

Brand Names U.S.

  • Azasan
  • Imuran

Dosing Hepatic Impairment

There are no dosage adjustments provided in the manufacturer’s labeling.

Administration

Oral: Most commonly administered once daily. Administering tablets after meals or in divided doses may decrease adverse GI events.

IV: Infusion is usually administered over 30 to 60 minutes. Infusion time is dependent upon the final volume after dilution. While normally given over 30 to 60 minutes, it may be infused over 5 minutes up to over 8 hours.

ALERT U.S. Boxed Warning

Malignancy:

Chronic immunosuppression with azathioprine, a purine antimetabolite, increases risk of malignancy in humans. Reports of malignancy include post-transplant 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 both men and women, and with possible hematologic toxicities. Inform patients of the risk of malignancy with azathioprine.

What is azathioprine (azasan, imuran)?

Azathioprine lowers your body's immune system. The immune system helps your body fight infections. The immune system can also fight or "reject" a transplanted organ such as a liver or kidney. This is because the immune system treats the new organ as an invader.

Azathioprine is used to prevent your body from rejecting a transplanted kidney. It is also used to treat symptoms of rheumatoid arthritis.

Azathioprine may also be used for purposes not listed in this medication guide.

Usual Adult Dose for Sarcoidosis

Study (n=11)
Initial 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: 2 mg/kg per day with prednisolone 0.1 mg/kg per day for 21 to 22 months

Renal Dose Adjustments

Lower doses may be required; however, no specific guidelines have been suggested.

Other Comments

Administration advice:
-IV: Doses should generally be infused over 30 to 60 minutes; it may be administered over 5 minutes and, for the daily dose, over 8 hours

Reconstitution/preparation techniques: The manufacturer product information should be consulted

Storage requirements:
-IV: Once reconstituted, the solution for injection should be used within 24 hours

General:
-TPMT testing may be required in patients with abnormal CBC results that do not respond to dose reduction
-Treatment cessation may be required for severe hematologic or other toxicity
-Appropriate handling procedures for immunosuppressive agents according to local guidelines should be considered

Monitoring:
-Hematologic: CBC, including platelet count, weekly for the first month, twice a month for the second and third months, then once a month or more often if necessary
-Hepatic: Liver function
-Immunologic: Signs and symptoms of infection

Patient advice:
-Minimize exposure to sunlight and UV light by wearing protective clothing and using a sunscreen with a high protection factor
-Report any unusual bleeding or bruising, or signs and symptoms of infection

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