Imuran

Imuran is an immunosuppressant medication with an active component of azathioprine.

[1]

Indications of the 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 certain organs (heart, kidney or liver), and in addition - to reduce the need for the presence of corticosteroids in the body after kidney transplantation.

As a monotherapeutic drug, either simultaneously with SCS or other medications, it is often used to treat the following diseases:

• rheumatoid arthritis in severe degree;
• SLE;
• polymyositis with dermatomyositis;
• Active hepatitis of the autoimmune type in the chronic stage of development;
• vulgar pemphigus;
• polyarteritis of nodular type;
• hemolytic form of anemia of autoimmune origin;
• refractory ITP of chronic type;
• Multiple sclerosis in relapsing form.

Release form

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

[2], [3]

Pharmacodynamics

Azathioprine is a derivative of 6-MP substance that does not have activity, but acts as a purine antagonist, and for the process of immunosuppression it needs absorption through cells and subsequent intracellular anabolism with the formation of NTG elements in its process. These components, together with other decay products (eg, 6-MP ribonucleotides) inhibit the purine binding of the purine during the de novo process, as well as the mutual conversion of purine nucleotides. In addition, NTG is incorporated into nucleic acids, which helps to strengthen the immunosuppressive properties of tablets.

Among other possible mechanisms of action are suppression of the majority of biosynthetic pathways within nucleic acids, which causes a delay in cell proliferation (those cells that participate in amplification, as well as the determination of immune responses).

Taking into account this mechanism of influence, the medicinal effect of taking tablets develops after several weeks or even months.

How does methylnitroimidazole (a product of the disintegration of azathioprine, and not 6-MP), was not completely elucidated. But in individual systems, it affects the degree of activity of azathioprine substance in comparison with the 6-MP element.

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Pharmacokinetics

The indices of 6-MP and azathioprine inside the plasma do not have a clear match between the drug efficacy or the toxicity of the drug.

Absorption.

Azathioprine is absorbed variably and not completely. The average bioavailability of the 6-MP element with 50 mg of medication is 47% (range in the range 27-80%). Absorption volume is uniform throughout the digestive tract (this includes the stomach together with the blind and small intestine). But the index of the absorption volume of 6-MP after the use of azathioprine is variable, so it can differ in different sites of absorption. The highest in this case will be absorption within the small intestine, moderate inside the stomach, and the lowest inside the blind intestine.

Although no tests have been conducted on the effects of food during the use of azathioprine, 6-MP pharmacokinetic parameters have been performed that relate to azathioprine. The average value of the relative bioavailability of the 6-MP element is reduced by approximately 26% after eating milk or food compared to the refusal to eat at night. The instability of the 6-MP substance inside the milk is due to xanthine oxidase (30% decay in the half hour period). It is required to drink tablets at least 60 minutes before eating milk / meals or after 3 hours after this.

Distribution.

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

When ingesting or intravenously injecting drugs, the concentrations of the 6-MP component inside the CSF are sufficiently low or generally minor.

Metabolic processes.

Azathioprine during in vivo tests disintegrates fairly quickly under the influence of GST substance, transforming into 6-MP, as well as methylnitroimidazole. The 6-MP element rapidly penetrates through the cell membrane and, passing along the multi-level pathways, undergoes extensive metabolism with conversion to active as well as inactive decay products (it should be noted that none of the enzymes are considered to be predominant). In connection with the complex metabolism, inhibition of one enzyme, it is impossible to explain all the existing cases of mild effects or powerful myelosuppression.

Most often, for the metabolism of a 6-MP substance or its subsequent degradation products, enzymes: TPMT with xanthine oxidase, as well as GFRT and IMPDG. Other enzymes that are involved in the formation of active and inactive decay products are GMFs, which contribute to the formation of NTG, as well as ITF-ase.

The azathioprine component is also metabolized by aldehyde oxidase, forming an element of 8-hydroxyazathioprine, which may have drug activity. At the same time, there are many decay products of the inactive type, which are formed in other ways.

There is evidence proving that gene polymorphism (genes that encode different enzyme systems involved in the metabolism of active drug LS) is able to predict the side effects of using tablets.

Excretion.

When 100 mg of  ³⁵ S-azathioprine is used, about 50% of the radioactivity was excreted together with urine, and another 12% - with feces after 24 hours. Inside the urine, the main element is often the oxidized degradation product of thiourea that does not have activity. Less than 2% of the substance is excreted together with urine in the form of 6-MP or azathioprine. Azathioprine has a high excretion level with a total clearance rate of 3 liters per minute in volunteers. Regarding the clearance within the kidneys or the half-life of the component - no information. The clearance of the 6-MP element inside the kidneys, as well as the half-life of it, are 191 ml / minute / m ²  and 0.9 hours, respectively .

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Dosing and administration

Tablets are consumed at least 20 minutes before eating or after 3 hours after this (milk also includes milk).

Adults dosage in case of organ transplant.

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

Test indications show that treatment with Imuran should be long, without a certain time frame, even when taking drugs in small doses, because there is a probability of rejection of the transplanted organ.

Dimensions of dosages for the treatment of multiple sclerosis.

With an alternating form of multiple sclerosis (relapsing type), 2-3 mg / kg / day should be taken 2-3 times. In order for the treatment to work, you may need to take the medicine for more than 12 months. To start to supervise progression of a pathology it is possible after the lapse of 2 years of a therapeutic course.

Dimensions of dosages with other pathologies.

The standard size of the initial dosage is 1-3 mg / kg / day, but it needs to be specified, taking into account the clinical response (it manifests itself after several weeks or months of therapy), and with it hematological tolerance.

After the development of the drug effect, it is required to reduce the maintenance dosage to the minimum maintenance sizes. If after 3 months of the course of improvement is not observed, it is necessary to decide the question of the appropriateness of using drugs.

The size of the maintenance dose of the drug is in the range of 1-3 mg / kg / day. A more accurate dose depends on the individual reaction of the patient, as well as his condition and hematologic tolerance.

Children.

The sizes of children's dosages for the prevention of development of rejection after organ transplantation do not differ from adults.

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Use of the imurana during pregnancy

When kidneys are transplanted to people with kidney failure, with which Imuran is taken, an increase in fertility is observed in both women and men.

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

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

There is information about premature birth, as well as the birth of infants with low weight, when a woman took the medicine during pregnancy, especially when combining it with the SCS. In addition, there are data on cases of miscarriages after imuran application by the mother or father.

There was also a significant transfer of the active component with its decay products from the mother to the baby through the placenta.

Some infants, whose mothers used the drug during pregnancy, developed thrombocytopenia and leukopenia. In this regard, you need to closely monitor blood levels in pregnant women.

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

Breastfeeding mothers should be aware that after taking the medicine, the 6-MP element penetrates into the mother's milk. Therefore, it is recommended to abandon breastfeeding for the time of drug use.

Contraindications

Among the contraindications: the presence of hypersensitivity to 6-MP, as well as azathioprine and other elements of the medication. You can not also prescribe a medicine for children suffering from multiple sclerosis.

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Side effects of the imurana

The taking of tablets is capable of provoking the development of certain side effects:

• complications of invasive or infectious type: often people after transplanting organs treated with Imuran in combination with other immunosuppressors develop fungal, viral or bacterial infections. Sometimes the sensitivity of patients to bacteria and viruses with fungi increases (this includes severe infections and atypical disorders caused by chickenpox viruses, herpes zoster and other infectious strains). Subcortical encephalopathy of the progressive type, associated with the JC virus, was noted singly;
• tumors of an evil and benign type (polyps with cysts are also included): occasionally there are tumors, among them melanoma (and other types of skin cancer), NHL, sarcomas (including Kaposi and other species), uterine neck cancer, and in addition acute stage of myeloid leukemia, as well as myelodysplasia. The likelihood of the appearance of NHL and other malignant tumors (mainly skin cancer), uterine neck cancer or sarcoma is increased in persons treated with immunosuppressors, especially after organ transplants. In this regard, treatment should be carried out in minimally effective dosages. The increased likelihood of occurrence of NHL in people with rheumatoid arthritis who take immunosuppressors is most likely associated with the very disease itself;
• lymph and systemic blood flow: leukopenia or suppression of bone marrow function is often observed. Quite often thrombocytopenia develops. Sometimes there is anemia. Occasionally there is pancytopenia, anemia of megaloblastic or aplastic type, as well as agranulocytosis and erythroid hypoplasia. In particular, these disorders are typical for people with a tendency to develop myelotoxicity - for example, in people with a deficiency of the TPMT element, and in addition to kidney / liver failure. In addition, such disorders can develop in those who, when combined with allopurinol, did not reduce the Imuran dosage. During treatment, a curable increase in erythrocyte volume (depending on the size of the dose), as well as an increase in the content of hemoglobin inside erythrocytes, was detected. Along with this, changes in the megaloblastic type of medullar function have been noted, although irregularities in severe form develop quite infrequently;
• Immune disorders: sometimes there are reactions of intolerance. There is a TEN or Stevens-Johnson syndrome. Periodically taking pills causes the development of certain clinical manifestations, which are symptoms of hypersensitivity. Among them, vomiting, chills, dizziness, diarrhea, a feeling of general malaise, nausea, rashes, fever, vasculitis with exanthema, and in addition arthralgia with myalgia, functional renal / hepatic disorders, lowering blood pressure and cholestasis. Quite often after repeated application of drugs, these side effects appeared again. Often, immediate withdrawal of the medication and (if necessary) holding supportive treatment activities helped the patient recover. With the development of other significant changes in the body, deaths were reported sporadically. If the patient develops intolerance, it is required to carefully evaluate the feasibility of continuing the treatment course;
• lesions in the lungs, as well as the sternum: single note the development of a treatable pneumonitis;
• lesions of the gastrointestinal tract: often there is nausea (this can be avoided by eating a medicine after eating). Sometimes pancreatitis develops. Single diverticulitis or colitis is observed, as well as intestinal perforation after organ transplantation and diarrhea in severe form in individuals with intestinal inflammations;
• disorders of the function of the hepatobiliary system: sometimes there are likely to be associated with manifestations of hypersensitivity disorders in the liver or cholestasis (in the case of the appearance of these disorders, the condition usually normalizes after withdrawal of the drug). Occasionally, life-threatening liver damage (with chronic drug administration, especially after organ transplants) develops. Histological tests demonstrate hepatic purpura, enlargement of sinusoids, and in addition thrombosis and nodular hyperplasia of the regenerative type. There were cases when the cancellation of Imuran administration caused a transient or stable improvement in histological manifestations in the liver region. Hepatotoxic properties are manifested in the form of increased values of bilirubin, APF and serum transaminases of blood;
• defeat of the subcutaneous layer and skin: occasionally appears alopecia. Often, such a violation disappeared on its own, even under conditions of 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: the development of arrhythmia, meningitis, the appearance of headaches or paresthesias, the occurrence of lesions on the lips and mouth, the deterioration of the course of diseases such as dermatomyositis or myasthenia gravis, as well as a disorder of taste or olfactory receptors.

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Overdose

Among the manifestations of an overdose: the occurrence of ulcers inside the throat, and besides bleeding with bruises and infections - these are the main signs of drug intoxication, developing in connection with the suppression of bone marrow function. The maximum impact occurs after a lapse of 9-14 days. Similar symptoms often occur with chronic poisoning, than as a result of acute. There is information about the victim who took a single dose of 7.5 grams of medication. The result was immediate vomiting with nausea and diarrhea. Further development of leukopenia and a disorder of the hepatic function. When recovering, there were no complications.

Because the drug does not have an antidote, you need to closely monitor blood counts, as well as perform supportive procedures of a general nature. Such active measures as the use of activated charcoal may prove ineffective if they are not taken within the first hour after poisoning.

Supportive treatment is carried out in accordance with the condition of the victim, as well as national recommendations for therapy for intoxication.

There is no information on how effective dialysis is in case of drug poisoning, but it is known that azathioprine is partially dialyzed.

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Interactions with other drugs

Vaccines.

Immunosuppressive properties of the drug may have an atypical and potentially negative effect on the activity of live vaccines, and therefore it is forbidden to vaccinate people who are treated with Imuran.

There may be a weak response to non-living vaccines - this was noted for a type B hepatitis B vaccine during injection to people who are being treated, combining the drug with GCS.

The results of a small clinical trial showed that when taking standard medicinal dosages of drugs, there is no violation of the body's response to the injection of the polyvalent pneumococcal vaccine (based on an average anti-capsular antibody).

Combinations of the drug with other medications.

Ribavirin.

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

Myelosuppressors with cytostatics.

It is recommended to try to avoid 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 hematologic disorders when using a drug with co-trimoxazole.

There are also data on the likely appearance of hematological abnormalities during the combined use of azathioprine with ACE inhibitors.

One can also expect potentiation of the myelosuppressive properties of indomethacin with cimetidine in the case of combined treatment with Imuran.

Allopurinol with thiopurinol and oxypurinol.

The activity of xanthine oxidase is suppressed by the aforementioned substances, as a result of which the degree of conversion of bioactive 6-thioinosinic acid to 6-thiocaric acid, which does not have biological activity, is reduced. Therefore, when combining the above medicines with azathioprine or 6-MP dosages, the latter should be reduced by 25%.

Aminosalicylates.

There is evidence that derivatives of aminosalicylates 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 ingestion of 20 mg / m ² increased the mean 6-MW within the urine by approximately 31%, and methotrexate injection of 2 or 5 g / m ² increased these values by 69% and 93%, respectively. In this regard, when using azathioprine in combination with methotrexate in a large dose, it is necessary to adjust the portions of the drug to maintain the necessary white blood cell count.

The effect of the drug on other medicines.

Anticoagulants.

There is information on the suppression of anticoagulant effects of acenocoumarol and warfarin when combined with azathioprine. This may require taking anticoagulants at higher dosages. In this regard, when combining the drug data, it is required to carefully monitor the indications of coagulation samples.

Storage conditions

Imuran is kept out of reach of children, at a temperature that does not exceed 25 ° C.

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Special instructions

Reviews

The imuran has rather mixed reviews. There are patients who took the medicine to eliminate diseases of autoimmune origin, and were completely satisfied with the effect of the medication. They also noted the absence of severe adverse reactions (in comparison with the use of hormonal drugs). But there is also another group of patients who did not help the drug completely, so they switched to using other drugs.

It should be noted that the Imuran is indicated for the elimination of serious enough diseases, therefore it can be appointed exclusively by a qualified specialist who has experience in the treatment of such disorders. In connection with this, self-medication with the use of this remedy is forbidden to engage categorically. Before the appointment of a drug it is required to undergo a comprehensive examination, according to the results of which the doctor will determine the expediency of using this drug.

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Shelf life

Imuran is allowed to be used in the period of 5 years after the release of the drug.

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