Imuran

Imuran is an immunosuppressant drug with the active ingredient azathioprine.

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Indications Imurana

It is used in combination with corticosteroids or other drugs with immunosuppressive action - as a means of preventing the development of rejection in the body after transplantation of individual organs (heart, kidneys or liver), and in addition - to reduce the need for the presence of corticosteroids in the body after kidney transplantation.

As a monotherapeutic drug or in combination with GCS or other medications, it is often used to treat the following diseases:

• rheumatoid arthritis in a severe form;
• SKV;
• polymyositis with dermatomyositis;
• active autoimmune hepatitis in the chronic stage of development;
• vulgar pemphigus;
• polyarteritis nodosa;
• hemolytic form of anemia of autoimmune origin;
• refractory chronic ITP;
• multiple sclerosis in relapsing form.

Release form

Release in tablets, in the amount of 25 pieces inside a blister pack. Inside the box there are 4 blister plates.

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Pharmacodynamics

Azathioprine is a derivative of 6-MP, which has no activity but acts as a purine antagonist, and for the process of immunosuppression it requires absorption through cells and subsequent intracellular anabolism with the formation of NTG elements in the process. These components, together with other decay products (for example, ribonucleotides of 6-MP), inhibit de novo binding of purine, as well as the mutual transformation of purine nucleotides. In addition, NTG are incorporated into nucleic acids, which helps to enhance the immunosuppressive properties of tablets.

Other possible mechanisms of action include suppression of most biosynthetic pathways within nucleic acids, resulting in a delay in cell proliferation (of those cells that participate in amplification and determination of immune responses).

Taking into account this mechanism of action, the medicinal effect from taking pills develops after several weeks or even months.

It has not been possible to determine definitively how methylnitroimidazole (a breakdown product of azathioprine, not 6-MP) works. But in some systems it has a stronger effect on the activity of the substance azathioprine than the element 6-MP.

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Pharmacokinetics

Plasma 6-MP and azathioprine levels do not clearly correlate with drug efficacy or drug toxicity.

Absorption.

Azathioprine is absorbed variably and incompletely. The average bioavailability of the 6-MP element when taking 50 mg of the drug is 47% (range 27-80%). The absorption volume is uniform throughout the entire gastrointestinal tract (this includes the stomach with the cecum and small intestine). However, the absorption volume of 6-MP after taking azathioprine is variable, so it may differ at different absorption sites. In this case, absorption will be highest in the small intestine, moderate in the stomach, and lowest in the cecum.

Although no food interaction tests have been performed during the use of azathioprine, studies have been performed on the pharmacokinetic parameters of 6-MP, which are related to azathioprine. The mean relative bioavailability of the 6-MP element is reduced by approximately 26% after ingestion of milk or food compared to no food at night. The instability of the 6-MP element in milk is due to xanthine oxidase (30% breakdown occurs within half an hour). Tablets should be taken at least 60 minutes before or 3 hours after ingestion of milk/food.

Distribution.

The equilibrium value of the drug distribution volume is unknown. Its average equilibrium value (± the probability of standard deviation) for the 6-MP element is 0.9±0.8 l/kg, although this value may be underestimated because the 6-MP component is distributed not exclusively within the liver, but throughout the body.

When taking the drug orally or by intravenous injection, the concentrations of the 6-MP component in the cerebrospinal fluid are quite low or even insignificant.

Metabolic processes.

Azathioprine is rapidly broken down by the GST substance in vivo, converting into 6-MP and methylnitroimidazole. The 6-MP element rapidly penetrates the cell membrane and, passing further along multi-level pathways, undergoes extensive metabolism with conversion into active and inactive decay products (it should be noted that no single enzyme is considered predominant). Due to the complex metabolism, inhibition of a single enzyme cannot explain all existing cases of weak effects or strong myelosuppression.

Most often, the enzymes responsible for the metabolism of the substance 6-MP or its subsequent decay products are: TPMT with xanthine oxidase, as well as GPRT and IMPDH. Other enzymes that participate in the processes of formation of active and inactive decay products are GMPS, which promotes the formation of NTG, as well as ITPase.

The component azathioprine is also metabolized by aldehyde oxidase to form the unit 8-hydroxyazathioprine, which may have medicinal activity. However, there are many inactive breakdown products that are formed by other pathways.

There is evidence that gene polymorphism (genes that encode different enzyme systems involved in the metabolism of the active substance of the drug) can predict side effects from the use of tablets.

Excretion.

When 100 mg ^{of 35} S-azathioprine was administered, approximately 50% of the radioactivity was excreted in the urine and another 12% in the faeces after 24 hours. In the urine, the major constituent is often the inactive oxidized breakdown product of thiouric acid. Less than 2% of the substance is excreted in the urine as either 6-MP or azathioprine. Azathioprine has a high excretion rate, with a total clearance exceeding 3 L/min in volunteers. There are no data on the renal clearance or half-life of the component. The renal clearance and half-life of 6-MP are 191 mL/min/m2 ^and 0.9 hours, respectively.

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Dosing and administration

The tablets are taken at least 20 minutes before eating or after 3 hours have passed (this also includes drinking milk).

Adult dosages in case of organ transplantation.

Taking into account the immunosuppression regimen, on the first day of therapy it is allowed to take up to 5 mg/kg per day in 2-3 doses. The maintenance dosage is 1-4 mg/kg/day and is prescribed taking into account the hematological tolerance of the body, as well as the clinical picture of the patient's condition.

Test results show that treatment with Imuran should be long-term, without any specific time frame, even when taking the drug in small doses, because there is a risk of rejection of the transplanted organ.

Dosage sizes for the treatment of multiple sclerosis.

For intermittent multiple sclerosis (relapsing type), it is recommended to take 2-3 mg/kg/day in 2-3 doses. For the treatment to be effective, it may be necessary to take the medicine for more than 12 months. It is possible to begin monitoring the progression of the pathology after 2 years of the therapeutic course.

Dosage sizes for other pathologies.

The standard initial dosage is 1-3 mg/kg/day, but it should be adjusted based on the clinical response (which occurs after several weeks or months of therapy) and hematological tolerance.

After the development of the medicinal effect, it is necessary to reduce the maintenance dosage to the minimum maintenance amounts. If after 3 months of the course there is no improvement, it is necessary to decide on the advisability of using the drug.

The maintenance dose of the drug is within 1-3 mg/kg/day. A more precise dose depends on the individual response of the patient, as well as his condition and hematological tolerance.

Children.

The dosages for children to prevent rejection after organ transplantation are no different from those for adults.

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Use Imurana during pregnancy

In kidney transplants in people with kidney failure, in combination with Imuran, an increase in fertility is observed in both women and men.

It is prohibited to prescribe the tablets to pregnant women without first assessing the benefit/risk ratio of their use.

There is no unambiguous information regarding the teratogenicity of the drug in humans. Animal tests show that the use of the drug during organogenesis causes the development of congenital anomalies of varying severity. As in the case of taking other cytotoxic drugs, during the period of use of the drug by one of the sexual partners, both must use high-quality contraceptives.

There are reports of premature births and low birth weight babies when a woman took the drug during pregnancy, especially when combined with GCS. In addition, there are reports of miscarriages after the use of Imuran by either the mother or father.

A significant transfer of the active component with its breakdown products from mother to child through the placenta was also discovered.

Some infants whose mothers used the drug during pregnancy developed thrombocytopenia and leukopenia. Therefore, it is necessary to carefully monitor the blood counts of pregnant women.

If possible, it is necessary to avoid taking the pills during pregnancy, since the drug may have a negative effect on the fetus. It is also prohibited to prescribe it to pregnant women suffering from rheumatoid arthritis. When deciding to take the drug during pregnancy or in case of conception already during the therapy, it is necessary to immediately warn the patient about the high probability of risk to the child.

Nursing mothers should be aware that after taking the medicine, the element 6-MP penetrates into the mother's milk. Therefore, it is recommended to stop breastfeeding while taking the medicine.

Contraindications

Contraindications include: hypersensitivity to 6-MP, as well as azathioprine and other components of the drug. The drug should also not be prescribed to children suffering from multiple sclerosis.

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Side effects Imurana

Taking pills can provoke the development of certain side effects:

• complications of an invasive or infectious type: often, people after organ transplantation, treated with Imuran in combination with other immunosuppressants, develop infections of fungal, viral or bacterial origin. Sometimes the sensitivity of patients to bacteria and viruses with fungi increases (this includes severe infections and atypical disorders caused by the chickenpox virus, herpes zoster and other infectious strains). Subcortical encephalopathy of a progressive type associated with the JC virus was noted alone;
• Malignant and benign tumors (including polyps with cysts): Rarely, tumors occur, including melanoma (and other types of skin cancer), NHL, sarcomas (including Kaposi and other types), cervical cancer, as well as acute myeloid leukemia, and myelodysplasia. The likelihood of developing NHL and other malignant tumors (mainly skin cancer), cervical cancer, or sarcoma increases in people treated with immunosuppressants, especially after organ transplantation. Therefore, treatment should be carried out in the minimum effective doses. The increased likelihood of developing NHL in people with rheumatoid arthritis who are taking immunosuppressants is most likely associated with the disease itself;
• Lymph and systemic circulation: leukopenia or suppression of bone marrow function is often observed. Thrombocytopenia develops quite often. Sometimes anemia develops. Pancytopenia, megaloblastic or aplastic anemia, as well as agranulocytosis and erythroid hypoplasia occur rarely. These disorders are especially characteristic of individuals with a tendency to develop myelotoxicity - for example, in people with a deficiency of the TPMT element, and in addition with renal / hepatic insufficiency. In addition, such disorders can develop in those who, when combined with allopurinol, did not reduce the dosage of Imuran. During treatment, a treatable increase in red blood cell volume (depending on the dose) and an increase in the hemoglobin content inside red blood cells were also detected. At the same time, megaloblastic changes in bone marrow function were noted, although severe disorders develop quite rarely;
• Immune disorders: intolerance reactions sometimes occur. TEN or Stevens-Johnson syndrome appear isolatedly. Periodically, taking the tablets causes the development of individual clinical manifestations that are symptoms of hypersensitivity. Among them are vomiting, chills, dizziness, diarrhea, a feeling of general malaise, nausea, rashes, fever, vasculitis with exanthema, as well as arthralgia with myalgia, functional renal/hepatic disorders, decreased blood pressure and cholestasis. Quite often, after repeated use of the drug, these side effects reappeared. Often, immediate discontinuation of the drug and (if necessary) supportive treatment measures helped the patient recover. With the development of other significant changes in the body, there were isolated reports of death. If the patient develops intolerance, it is necessary to carefully assess the advisability of continuing the treatment course;
• lesions in the lung area, as well as the sternum: the development of curable pneumonitis is noted sporadically;
• Gastrointestinal tract lesions: nausea often occurs (this disorder can be avoided by taking the medicine after meals). Pancreatitis sometimes develops. Diverticulitis or colitis are observed sporadically, as well as intestinal perforation after organ transplantation and severe diarrhea in people with intestinal inflammation;
• Hepatobiliary dysfunction: sometimes liver dysfunction or cholestasis may occur, probably related to hypersensitivity (if these disorders occur, the condition usually normalizes after drug withdrawal). Rarely, life-threatening liver damage develops (with chronic drug intake, especially after organ transplantation). Histological tests show liver purpura, sinusoid dilation, and also thrombosis and nodular hyperplasia of the regenerative type. There have been cases where discontinuation of Imuran caused a transient or stable improvement in histological manifestations in the liver. Hepatotoxic properties are manifested in the form of increased bilirubin, alkaline phosphatase, and serum transaminases;
• damage to the subcutaneous layer and skin: alopecia occasionally appears. Often, such a disorder disappeared on its own, even with continued treatment. It was not possible to find a 100% relationship between the use of drugs and the development of alopecia;
• other disorders and manifestations: development of arrhythmia, meningitis, occurrence of headaches or paresthesia, occurrence of lesions on the lips and in the mouth, worsening of diseases such as dermatomyositis or myasthenia gravis, as well as disorders of taste or olfactory receptors.

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Overdose

Among the manifestations of an overdose: the occurrence of ulcers inside the throat, as well as bleeding with bruises and infections - these are the main signs of intoxication with the drug, developing due to the suppression of bone marrow function. The maximum effect occurs after 9-14 days. Such symptoms more often occur with chronic poisoning than as a result of acute poisoning. There is information about a victim who took a single dose of 7.5 g of the drug. The result was immediate vomiting with nausea and diarrhea. Then leukopenia and liver dysfunction developed. No complications arose during recovery.

Because the drug has no antidote, it is necessary to closely monitor blood counts, as well as perform general supportive procedures. Such active measures as the use of activated carbon may be ineffective if they are not taken within 1 hour after poisoning.

Supportive treatment is carried out in accordance with the condition of the victim and national recommendations for therapy in cases of intoxication.

There is no information on how effective dialysis is in treating drug poisoning, but azathioprine is known to be partially dialyzable.

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Interactions with other drugs

Vaccines.

The immunosuppressive properties of the drug may have an atypical and potentially negative effect on the activity of live vaccines, and therefore vaccination of people who are being treated with Imuran is prohibited.

A mild reaction to non-live vaccines may occur - this has been noted with the hepatitis B vaccine when it was injected into people being treated with a combination of the drug and corticosteroids.

The results of a small clinical trial showed that when taking standard medicinal doses of the drug, there is no impairment of the body's response to the injection of a polyvalent pneumococcal vaccine (based on the assessment of the average values of specific antibodies of the anticapsular type).

Combinations of the drug with other medications.

Ribavirin.

Ribavirin inhibits the enzyme IMPDH, which results in a decrease in the amount of active 6-TGN produced. During the combined use of Imuran with this drug, the development of severe myelosuppression was observed. Therefore, combining these drugs is prohibited.

Myelosuppressants with cytostatics.

It is recommended to try to avoid the combined use of drugs with drugs that have myelosuppressive properties (for example, penicillamine), as well as with cytostatics. There is information about the development of severe hematological disorders when using the drug with co-trimoxazole.

There is also evidence of the possible occurrence of hematological abnormalities during the combined use of azathioprine with ACE inhibitors.

It is also possible to expect potentiation of the myelosuppressive properties of indomethacin with cimetidine in case of combined administration with Imuran.

Allopurinol with thiopurinol and oxypurinol.

The activity of xanthine oxidase is inhibited by the above substances, resulting in a decrease in the degree of conversion of bioactive 6-thioinosinic acid into 6-thiouric acid, which has no biological activity. Therefore, when combining the above drugs with azathioprine or 6-MP, the dosage of the latter should be reduced by 25%.

Aminosalicylates.

There is evidence that aminosalicylate derivatives in vitro, as well as in vivo (such as meslazine with olsalazine or sulfosalazine), inhibit the TPMT enzyme. Because of this, when combined with these components, it is necessary to take into account the possible need to reduce the dose of Imuran.

Methotrexate.

Oral administration of 20 mg/m2 ^increased mean urinary 6-MP levels by approximately 31%, and intravenous methotrexate injection at 2 or 5 g/m2 ^increased these values by 69% and 93%, respectively. Therefore, when using azathioprine in combination with methotrexate at high doses, it is necessary to adjust the dosage of the drug to maintain the required white blood cell count in the blood.

The effect of the drug on other medications.

Anticoagulants.

There is information about the suppression of the anticoagulant effect of acenocoumarol and warfarin when combined with azathioprine. This may require taking anticoagulants in higher doses. In this regard, when combining these drugs, it is necessary to carefully monitor the readings of coagulation tests.

Storage conditions

Imuran is kept out of the reach of children at a temperature not exceeding 25°C.

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Special instructions

Reviews

Imuran has quite mixed reviews. There are patients who took the drug to eliminate autoimmune diseases and were completely satisfied with the effect of the drug. They also noted the absence of severe negative reactions (in comparison with the use of hormonal agents). But there is also another group of patients who were not helped by the drug at all, as a result of which they switched to using other drugs.

It should be noted that Imuran is indicated for the treatment of quite serious diseases, so it can only be prescribed by a qualified specialist with experience in treating such disorders. In this regard, self-medication using this drug is strictly prohibited. Before prescribing the drug, you must undergo a comprehensive examination, based on the results of which the doctor will determine the appropriateness of using this drug.

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Shelf life

Imuran is allowed to be used for a period of 5 years from the date of release of the drug.

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