Idiopathic Pulmonary Fibrosis (IPF)


Imuran®, the brand name for azathioprine, is an immunosuppressant drug used to treat idiopathic pulmonary fibrosis (IPF). It is used in conjunction with other drugs to prevent transplant rejection and can also be used to treat inflammatory, autoimmune, and connective tissue diseases. Patients diagnosed with pulmonary fibrosis were recently advised not to start treatment with azathioprine as part of triple-drug therapy as per the PANTHER IPF clinical trial (NCT00650091). The results of the clinical trial showed that triple therapy (prednisone, N-acetylcysteine [NAC], and azathioprine) can be potentially harmful to patients diagnosed with pulmonary fibrosis. PANTHER IPF was designed to assess the safety and benefits of the treatments associated with pulmonary fibrosis. The trial compared triple-drug therapy and NAC with a placebo. The trial assessed the effect on lung function and other outcomes in newly diagnosed patients with pulmonary fibrosis. The clinical trial outcome showed that patients who undertook triple-drug therapy had higher mortality rates, discontinuation, and more serious adverse events, which led to the stopping of the triple-drug combination therapy. Most of the mortality cases were related to respiratory illness. The recommended dose for Imuran is 50 mg once daily for 2 weeks. It can be increased by 25 mg every 7 to 14 days. A maintenance dose of 2 to 3 mg per kg per day is required with a maximum of 150 mg per day. The dose can be maintained at a level where a therapeutic response is noted; however, an attempt should be made to decrease it to the possible lowest level that can maintain the therapeutic response.¹

Characteristics of Imuran

Imuran is administered orally, as each tablet contains 50 mg of azathioprine along with inactive ingredients such as stearic acid, magnesium stearate, potato starch, povidone, and lactose. The chemical formula of Imuran is 6-[(1-methyl-4-nitro-1H-imidazole-5-yl)thio]-1H-purine. Imuran is an imidazolyl derivative of 6 mercaptopurine, and its biological effects are similar to the parent compound. Imuran is insoluble in water and gets dissolved with the addition of 1 molar equivalent to alkali. Hydrolysis to mercaptopurine takes place in the presence of excess sodium hydroxide (0.1N), especially during warming. Imuran is a stable solution at acid or neutral pH. Imuran converts to mercaptopurine in the presence of sulfhydryl compounds such as glutathione, hydrogen sulfide, and cysteine.²

Azathioprine
Azathioprine, molecular model. Immunosuppressive drug used to prevent organ rejection after organ transplantation. Atoms are represented as spheres and are colour-coded: carbon (grey), hydrogen (white), nitrogen (blue), oxygen (red) and sulfur (yellow).
Credit: Getty Images

Mechanism of Action

Imuran converts to its active metabolites, thioguanine and mercaptopurine, by the action of the enzymes thiopurine methyltransferase and hypoxanthine-guanine phosphoribosyl transferase. It is a purine analog, and its metabolites replicate DNA and stop division. It inhibits purine synthesis and mediates immunosuppressive and toxic effects. It is rapidly absorbed in the gastrointestinal system and undergoes metabolism in the liver. It is excreted via the kidneys; thereby, its toxicity increases in renal failure. It does not penetrate the blood-brain barrier.3

Imuran and Triple Combination Therapy for IPF

Combination therapy for IPF includes NAC, azathioprine, and prednisone. The safety and efficacy of the triple combination therapy are unknown. A double-blind, randomized, and placebo-controlled trial was conducted with patients suffering from IPF. Patients had mild to moderate lung function impairment and were administered NAC, azathioprine, and prednisone in a 1:1:1 ratio combination. The 60-week treatment outcome involved longitudinal measurement of forced vital capacity. The trial showed that the treatment preserved lung function better than 2-drug regimens. The efficacy of the triple combination therapy was inconclusive as the trial did not include any placebos for prednisone and azathioprine. The international guidelines differ in terms of their recommendation for triple combination therapy. The PANTHER-IPF study evaluated the response of triple-drug therapy in patients with IPF. It compared the matched placebos for patients with mild to moderate impairment in lung function. Drug therapy was stopped according to a prespecified interim assessment by the data and safety monitoring board. The placebo and NAC-only groups continued to recruit according to the prespecified duration of 60 weeks.⁴ 

Precautions Prior to Taking Imuran

Before being administered Imuran, the patient must disclose all allergic reactions to azathioprine, any other medications, or any active ingredients in azathioprine. Patients can consult with their physician about the list of ingredients. The patient can also discuss with their physician about any prescription or nonprescription medications they plan to take with Imuran. This can include nutritional supplements, herbal products, and vitamins. The patient must be aware of the medications mentioned in the important warning section of Imuran. The following medications should not be taken with Imuran: sulfasalazine (Azulfidine®), olsalazine (Dipentum®), mesalamine (Asacol®, Apriso®, Pentasa®), warfarin (Coumadin®), and allopurinol (Zyloprim®). If there are adverse effects, a physician may need to change the doses accordingly and carefully monitor for any others. A patient may need to reveal any past medical history of kidney disease or any type of infection. They should inform their doctor if they are pregnant or plan to become pregnant, as Imuran has the potential to harm the fetus.⁵

Get detailed prescribing information on the Imuran monograph page at MPR.

Drug-Drug Interactions with Imuran

Imuran metabolism can decrease with acetaminophen and acetylsalicylic acid. Acetazolamide can increase the excretion rate of Imuran, which can lead to potentially reduced efficacy and lower serum levels. Acemetacin can decrease the excretion rate of Imuran and increase its serum level. The therapeutic efficacy of acenocoumarol can decrease with Imuran when used as a combination dose. The serum concentration of Imuran increases with abiraterone and abametapir. Abatacept can increase the metabolism of Imuran.⁶

References

  1. Azathioprine (Imuran) for pulmonary fibrosis. Pulmonary Fibrosis News. Accessed August 3, 2021.
  2. Imuran (azathioprine). The United States Food and Drug Administration. May 2011. Accessed August 3, 2021.
  3. Mohammadi O, Kassim TA. Azathioprine. StatPearls. January 2021. Accessed August 10, 2021.
  4. Idiopathic Pulmonary Fibrosis Clinical Research Network, Raghu G, Anstrom KJ, King TE Jr, Lasky JA, Martinez FJ. Prednisone, azathioprine, and N-acetylcysteine for pulmonary fibrosis. N Engl J Med. 2012;366(21):1968-1977. doi:10.1056/NEJMoa1113354
  5. Azathioprine: MedlinePlus drug information. MedlinePlus.gov. Updated July 27, 2021. Accessed August 4, 2021.
  6. Azathioprine: uses, interactions, mechanism of action. DrugBank. June 13, 2005. Updated August 10, 2021. Accessed August 11, 2021. 

Reviewed by Harshi Dhingra, MD, on 8/12/2021.

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