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Indications

Inflammatory Bowel Disease Rheumatoid Arthritis Anemia

Imruza is used as an immunosuppressant antimetabolite, either on its own or, more commonly, together with other agents (usually corticosteroids) and procedures that influence the immune response. Its therapeutic effect may become evident only after weeks or months of treatment and can include a steroid-sparing effect, which in turn reduces the toxicity associated with high doses and prolonged use of corticosteroids. In combination with corticosteroids and/or other immunosuppressive agents and procedures, Imruza is indicated to improve the survival of organ transplants, including renal, cardiac and hepatic transplants. It also reduces the corticosteroid requirements of renal transplant recipients. Imruza is indicated for the treatment of moderate to severe inflammatory bowel disease (IBD), namely Crohn's disease or ulcerative colitis, in patients who require corticosteroid therapy, in patients who cannot tolerate corticosteroid therapy, or in patients whose disease does not respond to other standard first-line therapy. Used either alone or, more usually, in combination with corticosteroids and/or other medicinal products and procedures, Imruza has been shown to provide clinical benefit (which may include a reduction in the dose, or discontinuation, of corticosteroids) in a proportion of patients with the following conditions: severe active rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis and polymyositis, autoimmune chronic active hepatitis, pemphigus vulgaris, polyarteritis nodosa, autoimmune haemolytic anaemia, and chronic refractory idiopathic thrombocytopenic purpura.

⚠️ Always consult a registered physician before taking any medicine.

Pharmacology

Azathioprine is an immunosuppressive antimetabolite. Its chemical name is 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine, and it is an imidazolyl derivative of 6-mercaptopurine. Many of its biological effects are similar to those of the parent compound.

Azathioprine is an imidazole derivative of 6-mercaptopurine (6-MP). In the body it is quickly broken down into 6-MP and a methylnitroimidazole moiety. The 6-MP crosses cell membranes easily and is converted inside cells into several purine thioanalogues, including the main active nucleotide, thioinosinic acid. The rate of this conversion differs from one person to another. Nucleotides cannot cross cell membranes, so they do not circulate in body fluids.

Whether 6-MP is given directly or comes from azathioprine in the body, it is mostly eliminated as thiouric acid, an inactive oxidised metabolite. Xanthine oxidase, the enzyme that brings about this oxidation, is blocked by allopurinol. The activity of the methylnitroimidazole moiety has not been clearly defined. In several systems, though, it seems to change how azathioprine acts compared with 6-MP. Measuring plasma levels of azathioprine or 6-MP tells us nothing useful about how well these drugs will work or how likely they are to cause toxicity.

Because of these mechanisms, the therapeutic effect of azathioprine may only appear after several weeks or months of treatment. Azathioprine seems to be well absorbed from the upper gastro-intestinal tract. As with the plasma levels, the levels of azathioprine and 6-mercaptopurine do not correlate well with how effective or toxic the drug is.

Absorption: Azathioprine is well absorbed after it is taken by mouth. No food effect studies have been done on azathioprine itself, but pharmacokinetic studies on 6-mercaptopurine are relevant. The mean relative bioavailability of 6-mercaptopurine was about 27% lower when it was taken with food and milk than after an overnight fast. 6-mercaptopurine is also unstable in milk because of xanthine oxidase present there, with 30% degradation within 30 minutes. Azathioprine can be taken with food or on an empty stomach, but patients should keep to one method and not change it. The dose should not be taken with milk or dairy products.

After an oral dose of [35S]-azathioprine, the maximum plasma radioactivity occurs at 1-2 hours and falls with a half-life of 4-6 hours. This is not the half-life of azathioprine itself. It reflects how quickly azathioprine and the [35S]-containing metabolites leave the plasma. Azathioprine is mainly excreted in urine as 6-thiouric uric acid. A minor urinary product, 1-methyl-4-nitro-5-thioimidazole, has also been found. A small part of the drug may be cleaved between the S atom and the purine ring. Only a small amount of an azathioprine dose leaves the body in urine unchanged.

Biotransformation: Thiopurine S-Methyl Transferase (TPMT): TPMT activity is inversely related to the concentration of 6-mercaptopurine derived thioguanine nucleotides in red blood cells. Higher thioguanine nucleotide concentrations cause bigger drops in white blood cell and neutrophil counts. People with TPMT deficiency build up very high concentrations of cytotoxic thioguanine nucleotides.

Pregnancy & Breastfeeding

Teratogenicity: Evidence for the teratogenicity of azathioprine in humans is inconclusive. As with any cytotoxic chemotherapy, both partners should be advised to use adequate contraceptive precautions while either one is receiving azathioprine.

Mutagenicity: Chromosomal abnormalities that disappear over time have been found in the lymphocytes of children born to patients treated with azathioprine. Except in extremely rare cases, no visible physical abnormalities have been observed in these offspring. Azathioprine combined with long wave ultraviolet light has shown a synergistic clastogenic effect in patients treated with azathioprine for various disorders.

Fertility: The specific effect of azathioprine therapy on human fertility is not known.

Pregnancy: Azathioprine and its metabolites are known to cross the placenta and amniotic membrane in substantial amounts, passing from mother to fetus. Azathioprine falls under Pregnancy Category D. It should not be given to patients who are pregnant or likely to become pregnant soon without a careful assessment of the risks against the benefits. As noted above, evidence for its teratogenicity in humans is inconclusive, and adequate contraceptive precautions should be used by either partner during treatment.

Women of childbearing potential and contraception for men and women: Because of azathioprine's genotoxic potential, women of childbearing potential should use effective contraception during treatment and for one month after finishing it. Men are advised to use effective contraception and avoid fathering a child while receiving azathioprine and for three months after completing treatment.

Lactation: Mothers receiving azathioprine are advised not to breastfeed, since 6 mercaptopurine has been detected in the colostrum and breast milk of women treated with the drug.

⚠️ Talk to your doctor before taking any medicine during pregnancy or while breastfeeding.

Dosage Reference

⚠️ Reference ranges from official sources only. Consult your doctor for personalized dosing.

Adults: Transplants: Depending on the immunosuppressive regimen used, a dose of up to 5 mg/kg body weight per day may be given by mouth or intravenously on the first day of treatment. The maintenance dose should range from 1 to 4 mg/kg body weight per day and must be adjusted according to clinical need and how well the blood counts tolerate the drug. Evidence indicates that azathioprine treatment should be continued indefinitely, even if only low doses are needed, because of the risk of graft rejection. Other indications: In general, the starting dose is 1 to 3 mg/kg body weight per day, adjusted within these limits according to the clinical response (which may not be evident for weeks or months) and blood count tolerance. Once a therapeutic response is evident, reducing the maintenance dose to the lowest level that keeps that response should be considered. If the patient's condition has not improved within three months, withdrawing azathioprine should be considered. However, for patients with inflammatory bowel disease (IBD), a treatment duration of at least twelve months should be considered, and a response to treatment may not become clinically apparent until after three to four months. The maintenance dose needed may range from less than 1 mg/kg body weight per day to 3 mg/kg body weight per day, depending on the condition being treated and the individual patient's response, including blood count tolerance. Overweight children: Children considered overweight may need doses at the higher end of the range, so close monitoring of the response to treatment is recommended. Elderly: There is limited experience with giving azathioprine to elderly patients. Although the available data do not show that side effects are more common in elderly patients than in other patients treated with azathioprine, doses at the lower end of the range are recommended. Renal impairment: In patients with reduced kidney function, a dose reduction should be considered. Hepatic impairment: In patients with reduced liver function, a dose reduction should be considered.

Side Effects & Interactions

Side Effects

No side-effect data recorded yet.