Azathioprine Side Effects and Treatment

Introduction

Azathioprine is an immunomodulator that is linked with several adverse effects. The susceptibility to toxicity depends on several factors like dosage, genetics, age, etc. Physicians should be aware of the potential side effects even in asymptomatic patients.

What Is Azathioprine?

Azathioprine is a drug that has been FDA (food and drug administration) approved for the management of active rheumatoid arthritis. It is an immunomodulator that is also used as adjunctive therapy to prevent rejection in kidney transplant patients. Apart from these, it is also used off-label.

How Is the Medication Administered?

Azathioprine is available in tablet form, which is taken orally. The usual dose is once or twice daily following meals. The usual starting dose is 2 to 2.5 milligrams per kilogram daily. Dosage modifications are required for those with liver and kidney disease. Tablets are administered after meals to reduce the gastrointestinal adverse effects. When administered through the I.V. (intravenous) route, the concentration must not exceed 5 milligrams per milliliter.

When administered for rheumatoid arthritis, the physician usually starts with a small initial dose and increases the dose in six to eight weeks; once the condition is managed, the dose is lowered further. In the case of a kidney transplant patient, the physician mostly starts with a high dose and gradually lowers the dose once the body adjusts to the transplanted organ. Transplant rejection is prevented as long as the medication is taken.

For Which Conditions Azathioprine Is Used?

Azathioprine is an immunosuppressant, which means it suppresses the body’s immune system. Azathioprine is used to prevent transplant rejection (a condition in which one’s immune system attacks the transplanted organ) in people who have undergone kidney transplantation. Another indication is in the case of the management of active rheumatoid arthritis (an autoimmune condition in which the body attacks its joints, resulting in swelling, pain, and loss of function), especially in cases where other treatment options fail. Azathioprine in both these conditions is approved by the FDA (food and drug administration).

Azathioprine is used off-label for treatment of the following conditions:

• Autoimmune hepatitis.

• Multiple sclerosis.

• Recurrent pericarditis.

• Severe myasthenia gravis.

• Ulcerative colitis (an inflammatory bowel disorder that is chronic and characterized by ulcers and inflammation of the inner lining of the large intestine).

• Crohn's disease.

• Erythema multiforme, etc.

What Are the Precautions One Should Follow Before Taking the Drug?

Before taking azathioprine, one should:

• Inform the physician about any known allergy to azathioprine, its components, or any other medications.

• Inform the physician about any pre-existing kidney disease or any infections.

• Inform the health care provider about all the prescription and non-prescription medications one is taking or planning to take.

• Inform the physician if one is pregnant or breastfeeding, as the medication may harm the fetus. The physician usually advises one to use birth control pills during the treatment period.

• Avoid taking any vaccinations during the treatment period without prior consent from the physician.

• If any type of surgery, including dental surgery, is required, the doctor should be informed that one is taking azathioprine medication.

• No dietary restrictions are to be followed unless advised otherwise by the physician.

What Are the Side Effects?

Complications are reported in 15 to 28 percent of cases.

1. Common Side Effects:

• Nausea is the most common side effect and is dose-dependent.

• Fatigue.

• Fever.

• Rashes.

• Myalgia or muscle pain.

• Kidney damage.

• The use of Azathioprine along with steroids increases the risk of infections like PCP(pneumocystis pneumonia).

• Hypersensitivity reactions (exaggerated immune reactions to an antigen).

• Bone marrow suppression results in a decreased count of red blood cells, platelets, and white blood cells. In some cases, the condition can even be life-threatening.

• Hepatotoxicity (liver damage).

2. Uncommon Side Effects:

• Diarrhea.

• Increased risk of developing certain cancers has been linked with azathioprine. The cancers commonly linked with azathioprine are lymphoma and skin cancers. Therefore, it is important to inform the physician about any history of cancer, and the use of alkylating agents like cyclophosphamide, melphalan, etc., should be reported. Unnecessary exposure to sunlight should be avoided to reduce cancer risk.

• When taken in conjugation with a TNF (tumor necrosis factor) blocker for the treatment of ulcerative colitis or Crohn's disease, Azathioprine was associated with the development of HSTCL (hepatosplenic T-cell lymphoma). It is a very serious cancer type that can result in death. FDA has not approved azathioprine for treating ulcerative colitis or Crohn's disease.

• Alopecia or hair loss.

• Tremors.

• Macrolytic anemia (a blood disorder characterized by abnormally large dysfunctional red blood cells).

• Upper airway edema.

• Pancreatitis (pancreas inflammation) is mostly seen in females with Crohn’s disease.

What Are the Contraindications?

Azathioprine is contraindicated in the following cases:

• Pregnancy.

• Breastfeeding.

• Any clinically active infection.

• Cancer patients.

• Hypersensitivity.

• Certain genetic conditions can increase the risk of bone marrow suppression.

Relative contraindications are:

• Those under cyclophosphamide treatment.

• When taken with Azathioprine, Allopurinol results in severe bone marrow suppression.

What Are the Symptoms Associated With Toxicity?

Acute toxicity occurs when more than 1.5 times the daily recommended dose is taken.

Azathioprine toxicity symptoms are:

• Hepatotoxicity.

• Bene marrow suppression.

• Bradycardia (slow heart rate).

• Gastrointestinal symptoms.

• Bone marrow suppression.

Activated charcoal helps reduce the symptom severity if taken within two hours of ingestion. There is no specific known antidote for azathioprine. In cases of severe toxicity, dialysis is done as azathioprine is dialyzable. In cases of severe bone marrow suppression, azathioprine treatment is discontinued.

What to Take Care of the Storage of the Medication?

• Keep the medication out of reach of children.

• Keep it in the tightly sealed container it came in at room temperature.

• Keep the medication away from excess heat and excess moisture (near the kitchen sink, bathroom, etc.).

• Dispose of outdated medication.

• Unneeded medication should be disposed of carefully, and it is advisable to use a medical take-back program.

What to Do in Case of a Missed Dose?

In case of a missed dose, consume the dose as soon as one remembers that a dose has been missed and continue with the regular dosing schedule. If it was time to take the next dose, skip it and continue the regular schedule. Avoid taking double doses to compensate for the missed dose.

Conclusion

Azathioprine suppresses the immune system and is approved by the FDA for arthritis and transplant rejection. It is associated with many common side effects like loss of appetite, fatigue, nausea, muscle pain, rashes, etc. It is also associated with serious side effects like cancer, pancreatitis, bone marrow suppression, etc. The drug should only be taken under a healthcare provider's prescription in the recommended dosage.