Azathioprine (Azathioprine)

Composition Pharmacodynamics Indications Carefully Contraindications Dosing and Administration Side effects Form release / dosage
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Active substanceAzathioprineAzathioprine
Dosage form: & nbsppills
Composition:

For one tablet:

Active substance: azathioprine - 50 mg.

Excipients: gelatin - 0.26 mg, potato starch - 10 mg, lactose monohydrate (sugar milk) - 38.24 mg, crospovidone (polyplasdone XL-10) - 0.5 mg, calcium stearate - 1 mg.
Description:Tablets of light yellow or light yellow with a greenish tinge, colors, round, flat-cylindrical, with a bevel.

Pharmacotherapeutic group:Immunosuppressive remedy
Pharmacodynamics:Azathioprine is a thiol derivative, a competitive antagonist of hypoxanthine, in chemical structure and biological action close to purine bases; has an immunosuppressive and cytostatic effect.
Incorporating metabolic reactions, disrupts the synthesis of nucleic acids, competes with hypoxanthine and guanine for hypoxanthine-guanine-phosphoribosyltransferase, which converts purinethol to thioinosinic acid (TEC). TEC suppresses a number of reactions involving inosinic acid (IR), including the conversion of IR into xanthic and adenylic acids. During the methylation of TEC, a metabolite is formed blocking glutamine-5-phosphorylbosyl pyrophosphate aminotransferase, an enzyme that initiates the purine synthesis of ribonucleotides.In connection with the loss of the ability of cells to form TECs, the development of resistance of tumor cells to azathioprine is possible.
Immunodepressivnoe effect due to hypoplasia of lymphoid tissue, a decrease in the number of T-lymphocytes, a violation of the synthesis Ig, the appearance in the blood of atypical phagocytes and suppression of cell-mediated allergic reactions. In comparison with mercaptopurine, the immunosuppressive effect is relatively more pronounced (with less cytostatic activity). In large doses (10 mg / kg) inhibits the function of the bone marrow, suppresses the proliferation of granulocytes, causes leukopenia.
Pharmacokinetics:

ATsating: azathioprine well absorbed in the upper gastrointestinal tract. Time of approach Cmax - 1-2 hours.

Distribution: the connection with plasma proteins is low. Penetrates through the placenta, accumulates in breast milk. The average therapeutic dose creates very low concentrations (less than 1 μg / ml) in the blood, which do not correlate with the severity and duration of the effect.

Metabolism: after the "first passage" through the liver is metabolized in mercaptopurine (active metabolite), is quickly captured from the blood by tissues. Oxidation and methylation - in the liver, erythrocytes with the formation of a pharmacologically inactive metabolite (6-thiocaric acid) under the influence of xanthine oxidase. Half-life T1/2 - 5 hours

Excretion: azathioprine is mainly excreted as 6-thiouracilic acid in urine. In urine is also determined in a small amount of 1-methyl-4-nitro-5-thioimidazole. Only a small amount of the accepted dose of azathioprine is excreted c urine in unchanged form. Removed during hemodialysis, quickly disappears from the bloodstream.

Indications:

Prevention of rejection reaction in renal transplantation, rheumatoid arthritis, chronic active hepatitis, systemic lupus erythematosus, dermatomyositis, periarteritis nodosa, acquired hemolytic anemia, idiopathic thrombocytopenic purpura, gangrenous pyoderma, psoriasis, Crohn's disease, ulcerative colitis, myasthenia gravis, pemphigus, Reiter's syndrome, radiation dermatitis, pseudohypertrophic myopathy.

Ineffectiveness and contraindications to the appointment of glucocorticosteroids or the need to reduce their dosage (in patients with side effects from their use and / or a high risk of their development).

Azathioprine is used as a monotherapy or in combination with corticosteroids and / or other immunosuppressants.

Contraindications:Hypersensitivity, suppression of hemopoiesis (hypoplastic and aplastic anemia, leukopenia, lymphopenia, thrombocytopenia), hepatic insufficiency, pregnancy, lactation.
Pregnancy and lactation:

Azathioprine is contraindicated in pregnant women or planning a pregnancy in the near future without a thorough assessment of the relationship between risk and benefit.

Teratogenicity of azathioprine concerns men and women. As with any cytotoxic chemotherapy, adequate contraception should be recommended if one of the partners receives azathioprine.

There are reports of premature birth and weight deficit in children born to mothers receiving azathioprine, especially in combination with corticosteroids. It is known about spontaneous abortion due to the use of azathioprine by any of the parents.

Azathioprine and / or its metabolites are found in low concentrations in fetal blood and amniotic fluid in women receiving azathioprine.

Leukopenia and / or thrombocytopenia were detected in newborns whose mothers took azathioprine during pregnancy. Increased attention should be paid to monitoring the hematological parameters during pregnancy.

Azathioprine is contraindicated during lactation. 6-MP is found in breast milk of women receiving azathioprine.

Dosing and Administration:

Inside.

Adults

Transplantation

Up to 5 mg / kg / day on the first day of therapy.

A maintenance dose of 1 to 4 mg / kg / day, depending on clinical indications and hematological tolerability.

Even with low doses, maintenance therapy with azathioprine should be performed indefinitely, as there is a risk of graft rejection.

Other diseases

The initial dose is 1-3 mg / kg / day and should be selected in this dose range depending on the clinical effect (which can be obtained after several weeks and months from the start of treatment) and hematological tolerability.

If the therapeutic effect is obtained, then it is necessary to reduce the maintenance dose to a minimum level, which preserves the effect.If within 3 months the clinical effect is not achieved, then azathioprine should be canceled. However, in inflammatory bowel diseases, treatment should be performed for at least 12 months, and the therapeutic effect can be achieved after 3-4 months.

The maintenance dose may range from less than 1 mg / kg / day to 3 mg / kg / day and is determined by the disease, the patient's individual response and hematologic tolerability.

Application in elderly patients

The experience with azathioprine in elderly patients is limited. Minimum dosages of the recommended dose range should be used. Particular attention should be paid to monitoring hematological parameters, reducing the maintenance dose to the minimum allowable to maintain the therapeutic effect.

Children

Transplantation

See dosages for adults during transplantation.

Other diseases

See dosages for adults for other diseases.

Renal / hepatic impairment

In patients with renal and / or liver failure, minimal doses of the therapeutic range should be used.
Side effects:

The frequency of occurrence of side effects with the use of azathioprine varies depending on the pathology that serves as the basis for its appointment.

Classification of undesirable side reactions in frequency:

Very frequent: ≥ 1/10 appointments

Frequent: ≥1 / 100 - <1/10 appointments

Infrequent: ≥1 / 1000 - <1/100 assignments

Rare: ≥1 / 10000 - <1/1000 assignments

Very rare: <1/10000 prescriptions

Infectious and parasitic diseases

Infrequent: viral, fungal and bacterial infections.

Benign, malignant and unspecified neoplasms (including cysts and polyps)

Rare: neoplasms, including lymphomas, skin cancer, acute myeloid leukemia and myelodysplasia.

The risk of developing lymphomas and other malignant tumors, mainly skin cancer, increases in patients who are immunosuppressed; especially in transplant recipients of organs receiving aggressive therapy. Therefore, such therapy should be maintained at the minimum acceptable level of doses necessary to maintain its effectiveness. The increased risk of developing lymphomas compared with the general population in patients with rheumatoid arthritis who take immunosuppressants is associated, at least in part, with the disease itself.

Violations of the blood and lymphatic system

Very Frequent: bone marrow depression, leukopenia.

Frequent: thrombocytopenia.

Infrequent: anemia.

Rare: agranulocytosis, pancytopenia, aplastic anemia, megaloblastic anemia, erythroid hypoplasia.

Azathioprine can cause a reversible dose-dependent bone marrow depression, most often manifested by leukopenia, sometimes anemia and thrombocytopenia and rarely agranulocytosis, pancytopenia and aplastic anemia. This is observed in patients with thiopurin methyltransferase enzyme deficiency, renal and hepatic insufficiency, which are predisposed to toxic reactions from the bone marrow, and in patients who failed to reduce the dose of azathioprine while taking it with allopurinol.

A reversible dose-dependent increase in the mean volume of blood cells and hemoglobin in erythrocytes occurred with the administration of azathioprine.

Immune system disorders

Infrequent: hypersensitivity reactions.

With the use of azathioprine, some clinical manifestations of idiosyncrasy are sometimes developed within the framework of hypersensitivity syndrome.These include general weakness, dizziness, nausea, vomiting, diarrhea, fever, exanthema, rash, myalgia, arthralgia, impaired renal function and hypotension.

In many cases, the analysis showed the association of these symptoms with azathioprine. Immediate withdrawal of azathioprine and, if necessary, the appointment of maintenance hemodynamic therapy led to recovery in most cases.

In the case of development of hypersensitivity reactions on azathioprine it is necessary to evaluate the possibility of continuing further therapy individually.

Disturbances from the respiratory system, chest and mediastinal organs

Very rare: reversible pneumonitis.

Disorders from the gastrointestinal tract

Frequent: nausea.

Infrequent: pancreatitis.

Rare: when organ transplantation occurs colitis, diverticulitis; with inflammatory bowel diseases - intestinal perforation, severe diarrhea.

A small number of patients experience nausea with the first use of azathioprine, which is facilitated when taking the drug after a meal.

Serious complications, including colitis, diverticulitis and intestinal perforation, have been described in recipients, organ transplants receiving immunosuppressive therapy.However, the etiology of these complications is not yet established, and, perhaps, they are caused by high doses of corticosteroids. Severe diarrhea developed in patients receiving azathioprine inflammatory bowel disease. It is necessary to take into account the possibility of developing in these patients an exacerbation of symptoms associated with the dose of the drug.

The histological manifestations, such as dilation sine liver, hepatic purpura, venookklyuzionnaya disease and nodular regenerative hyperplasia, partially or completely disappear when canceling azathioprine.

Disturbances from the skin and subcutaneous tissues

Rare: alopecia.

In many cases, hair loss stops, despite the continuation of therapy. The relationship of this symptom with the administration of azathioprine is not defined.

Overdose:

Symptoms: dyspepsia, pancytopenia, increased activity of "hepatic" transaminases, hyperbilirubinemia. Ulceration of the mucous membrane of the throat, bruising and bleeding - are the main symptoms of bone marrow depression resulting from an overdose of azathioprine, which reach a maximum after 9-14 days of treatment.Their appearance is more likely in chronic than in acute single overdose. A patient is reported to have taken a single overdose of 7.5 g of azathioprine. Immediate toxic manifestations of this overdose were nausea, vomiting and diarrhea, followed by a slight leukopenia and mild violations of liver function. Recovery was incomplete.

Treatment: gastric lavage. There is no specific antidote. Follow-up with hematological monitoring is necessary to provide rapid assistance in the development of adverse reactions. The efficacy of dialysis is unknown, although azathioprine partially excreted by hemodialysis.

Interaction:

Allopurinol / oxypurinol / thiopurinol

The activity of xanthine oxidase is inhibited by allopurinol, oxipurinol to thiopurinol, which is accompanied by a decrease in the conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouracilic acid. When allopurinol, oxypurinol and / or thiopurinol is given concomitantly with 6-MP or azathioprine, the dose of the latter should be reduced by one-quarter of the original dose.

Neuromuscular blockers

Azathioprine can enhance neuromuscular blockade caused by depolarizing drugs (succinylcholine), and can reduce blockade caused by non-depolarizing drugs (tubocurarine). The strength of these interactions varies considerably.

Warfarin

It is reported on the suppression of the anticoagulant effect of warfarin in its appointment with azathioprine.

Cytotoxic / myelodepressive drugs

If possible, simultaneous use with azathioprine of cytotoxic drugs or drugs with a mielodepressive effect should be avoided, such as penicillamine.

There are clinical data on the interaction of azathioprine and cotrimoxazole with the development of hematological disorders.

A case is described that allows one to assume a connection between hematological abnormalities and simultaneous administration of azathioprine and captopril.

There is a presumption that cimetidine and indomethacin can enhance the myelodepressant effect of azathioprine with simultaneous administration.

Aminosalicylates

Aminosalicylic derivatives (olsalazine, mesalazine or sulfasalazine) in vitro inhibit the TPMT enzyme, so they should be administered with caution in patients receiving azathioprine therapy.

Other interactions

Furosemide in vitro Disrupts the metabolism of azathioprine with liver tissue. The clinical significance of this interaction is unknown.

Vaccines

Immunosuppressive activity of azathioprine can cause an atypical or potentially unfavorable response to live vaccines, so live vaccines are theoretically contraindicated in patients taking azathioprine.

A decrease in the response to killed vaccines is likely and was observed for the hepatitis B vaccine in patients receiving combination therapy with azathioprine and corticosteroids.

It has been shown that the standard therapeutic doses of azathioprine do not cause an adverse response to the polyvalent pneumococcal vaccine, which was evaluated based on the average concentration of the anti- capsular specific antibody.

Special instructions:

Monitoring

With the use of azathioprine, there is a potential danger of developing toxic complications, so it can be prescribed only if the patient receives adequate observation during therapy.

It is suggested that during the first 8 weeks of therapy, a complete blood count, including platelet count, should be performed weekly or more often,if a high dose of the drug is used or the patient has severe renal and / or hepatic impairment. In the future, blood tests can be controlled less often, but a complete blood test should be repeated monthly or, at least, with an interval of not more than 3 months.

Patients receiving azathioprine, should be instructed to immediately report all cases of infection, sudden bruising, bleeding, or other signs of bone marrow depression.

Some individuals with congenital enzyme deficiency, thiopurin methyltransferase (TPMT) may be hypersensitive to the myelodepressant effect of azathioprine and be prone to rapid development of bone marrow depression after initiation of azathioprine treatment. This problem can be aggravated by a combination with drugs that suppress TPMT (olsalazine, mesalazine or sulfasalazine).

Renal and / or hepatic impairment

It is assumed that the toxicity of azathioprine is enhanced in renal failure, but controlled studies have not confirmed this assumption.Nevertheless, dosages are recommended at the lower end of the dose range and careful monitoring of hematologic parameters. With the development of hematological toxicity, doses should be reduced.

Caution is necessary for the administration of azathioprine in liver failure, with regular complete blood tests and liver tests. In some patients, the metabolism of azathioprine may be impaired and, consequently, its dose should be reduced if signs of hepatic and hematologic toxicity develop.

A few data indicate that azathioprine is unfavorable for patients with deficiency of hypoxanthine-guanine-phosphoribosyltransferase (Lesch-Nijhen syndrome), and they should not be recommended azathioprine.

Mutagenicity

Chromosomal abnormalities were found in men and women receiving azathioprine. But the role of azathioprine in their occurrence is difficult to assess.

Chromosomal abnormalities disappearing with time were detected in children of patients receiving azathioprine. Except in extremely rare cases, they had no obvious physical signs of these disorders.

Synergism of the action of azathioprine and prolonged ultraviolet irradiation in patients taking azathioprine.

Influence on reproductive function

Reduction of renal failure as a result of kidney transplantation followed by the appointment of azathioprine was accompanied by increased reproductive function in both men and women who are transplant recipients.

Carcinogenicity

Patients receiving azathioprine, have an increased risk of developing lymphomas and other malignancies, mainly skin cancer. The risk is related to the intensity and duration of immunosuppressive therapy to a greater extent than with the use of a specific drug. It has been reported that lowering the dose or canceling an immunosuppressant can cause the reverse development of lymphoma.

Patients who receive several immunosuppressants have a risk of over-immunodepression, so the lowest effective doses of drugs should be used. As is customary in patients with an increased risk of skin cancer, exposure to sunlight and exposure to ultraviolet irradiation with protective clothing and the use of sunscreens with a high degree of protection should be limited.
Effect on the ability to drive transp. cf. and fur:

No data. However, it is impossible to predict the disruption of the ability to drive, the car / mechanisms, based on the pharmacokinetics of azathioprine.

Form release / dosage:Tablets, 50 mg.
Packaging:

10 tablets are placed in a contour mesh package made of a polyvinylchloride film and aluminum foil.

5 contour mesh packages together with the instruction for use are placed in a pack of cardboard.

Storage conditions:

In a dry, the dark place at a temperature of no higher than 25 ° C.

Keep out of the reach of children.

Shelf life:

5 years.

Do not use after the expiration date printed on the package.
Terms of leave from pharmacies:On prescription
Registration number:P N001426 / 01
Date of registration:04.12.2008 / 19.03.2012
Expiration Date:Unlimited
The owner of the registration certificate:MOSHIMFARM PREPARATES them. N.А.Semashko, OJSC MOSHIMFARM PREPARATES them. N.А.Semashko, OJSC Russia
Manufacturer: & nbsp
Representation: & nbspMOSHIMFARM PREPARATES them. NA Semashko OJSC MOSHIMFARM PREPARATES them. NA Semashko OJSC Russia
Information update date: & nbsp10.02.2017
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