Instructions for use Imuran film-coated tablets 50 mg No. 100
Composition
active ingredient: azathioprine;
1 tablet contains azathioprine 50 mg;
Excipients: lactose monohydrate; corn starch; pregelatinized starch; magnesium stearate; stearic acid; hypromellose; macrogol 400.
Dosage form
Film-coated tablets.
Main physicochemical properties: round, biconvex, yellow tablets, film-coated, with a score and marking GX CH1.
Pharmacotherapeutic group
Immunosuppressants, azathioprine. ATX code L04A X01.
Pharmacological properties
Pharmacodynamics.
Azathioprine is a derivative of 6-mercaptopurine (6-MP). 6-MP is inactive, but it acts as a purine antagonist and requires cellular uptake and intracellular anabolism to thioguanine nucleotides (TGN) for immunosuppression. TGN and other metabolites (e.g. 6-methyl-mercaptopurine ribonucleotides) inhibit de novo purine synthesis and purine nucleotide interconversion. TGN is also incorporated into nucleic acids, contributing to the immunosuppressive effects of the drug.
Other potential mechanisms of action include:
- inhibition of many pathways of nucleic acid biosynthesis, resulting in a delay in the proliferation of cells involved in the process of determination and amplification of the immune response.
Given this mechanism of action, the therapeutic effect of Imuran occurs after several weeks or months.
The action of methylnitroimidazole, a metabolite of azathioprine but not of 6-MP, is not fully understood. However, in some systems it interferes with the activity of azathioprine when compared to 6-MP.
Pharmacokinetics.
Plasma levels of azathioprine and 6-mercaptopurine do not have a clear relationship with the therapeutic efficacy or toxicity of Imuran.
Absorption.
Absorption of azathioprine is incomplete and variable. The mean absolute bioavailability (range) of 6-MP following a 50 mg dose of azathioprine is 47% (27-80%). The extent of absorption of azathioprine is similar throughout the gastrointestinal tract, including the stomach, small intestine, and cecum. However, the extent of absorption of 6-MP following azathioprine is variable and may differ at different sites of absorption, with the highest extent of absorption observed in the small intestine, the lowest in the stomach, and the lowest in the cecum.
Although no studies have been conducted on the effect of food on azathioprine treatment, pharmacokinetic studies of 6-MP have been conducted that are specific to azathioprine. The mean relative bioavailability of 6-MP was approximately 26% lower after food or milk compared with overnight fasting. 6-MP is unstable in milk due to the presence of xanthine oxidase (30% degradation within 30 minutes) (see Pharmacokinetics: Metabolism). Azathioprine should be taken at least 1 hour before or 3 hours after food or milk (see Dosage and Administration).
Distribution.
The steady-state volume of distribution of azathioprine is unknown. The mean steady-state volume of distribution (± standard deviation) observed for 6-MP is 0.9 (± 0.8) L/kg, although this may be an underestimate as 6-MP is excreted throughout the body (not just in the liver).
After intravenous or oral administration of 6-MP, 6-MP concentrations in the cerebrospinal fluid are low or negligible.
Metabolism.
Azathioprine is rapidly broken down in vivo into 6-MP and methylnitroimidazole by glutathione-S-transferase. 6-MP rapidly crosses the cell membrane and is extensively metabolized to active and inactive metabolites by multiple pathways, with no single enzyme being predominant. Because of the complex metabolism, inhibition of a single enzyme cannot explain all cases of lack of efficacy and/or severe myelosuppression. The main enzymes responsible for the metabolism of 6-MP or its further metabolites are: the polymorphic enzyme thiopurine S-methyltransferase (TPMT) (see "Features of use", "Interaction with other medicinal products and other forms of interaction: Aminosalicylates"), xanthine oxidase (see "Interaction with other medicinal products and other forms of interaction: Allopurinol/oxypurinol/thiopurinol" and "Pharmacokinetics: Absorption"), inosine monophosphate dehydrogenase (IMPDH) (see "Interaction with other medicinal products and other forms of interaction: Ribavirin") and hypoxanthineguanine phosphoribosyltransferase (HPRT). Other enzymes involved in the formation of active and inactive metabolites are: guanosine monophosphate synthetase (GMPS, which forms NTG) and inosine triphosphate pyrophosphatase (ITP-ase). Azathioprine itself is also metabolized by aldehyde oxidase to form 8-hydroxyazathioprine, which may be active. There are also numerous inactive metabolites formed by other pathways.
There is evidence that polymorphisms in genes encoding various enzyme systems involved in azathioprine metabolism may predict adverse effects of azathioprine treatment.
Thiopurine S-methyltransferase (TPMT).
Genotyping studies can determine the allelic profile of a patient. Currently, 3 alleles TPMT*2, TPMT*3A and TPMT*3C are
responsible for the decreased TPMT activity in 95% of patients. Approximately 0.3% (1:300) of patients have two non-functioning alleles (homozygous deficiency) of the TPMT gene and have weak or undetectable enzyme activity. Approximately 10% of patients have one non-functioning allele (heterozygous deficiency), resulting in low or intermediate TPMT activity, and 90% of patients have normal TPMT activity with two functioning alleles. There is also a group of patients (approximately 2%) who have very high TPMT activity. Phenotypic testing determines the level of thiopurine nucleotides or TPMT activity in erythrocytes and may also be informative (see “Special instructions”).
Breeding.
Following oral administration of 100 mg 35S-azathioprine, 50% of the radioactivity was excreted in the urine and 12% in the feces after 24 hours. The major component in the urine was the largely inactive oxidized metabolite of thiouric acid. Less than 2% was excreted in the urine as azathioprine or 6-MP. Azathioprine has a high elimination rate with a total clearance exceeding 3 L/min in healthy volunteers. No data are available on the renal clearance or half-life of azathioprine. The renal clearance of 6-MP and the half-life of 6-MP are 191 mL/min/m2 and 0.9 hours, respectively.
Special patient groups.
Elderly patients.
Studies have not been conducted in elderly patients (see "Method of administration and dosage").
Children with excess body weight.
In a clinical study in the United States, 18 children (aged 3 to 14 years) were equally divided into two groups, with a weight-for-height ratio above or below the 75th percentile. Each child received maintenance treatment with 6-MP, and the dosage was calculated based on the child's body surface area. The mean AUC (0-¥
) 6-MP in the group where the ratio was above the 75th percentile was 2.4 times lower than in the group where the ratio was below the 75th percentile. Thus, higher tolerated doses of azathioprine may be required for overweight children, and monitoring of their response to treatment is recommended (see “Method of administration and dosage”).
Kidney failure.
Studies of azathioprine have not shown differences in the pharmacokinetics of 6-MP in uremic patients compared with renal transplant patients. Due to the lack of data on the active metabolites of azathioprine in renal failure, the possibility of dose reduction in patients with impaired renal function should be considered (see Dosage and Administration).
Azathioprine and/or its metabolites are removed by hemodialysis, with 45% of the radioactive metabolites removed within 8 hours of dialysis.
Liver failure.
Azathioprine was studied in three groups of renal transplant patients: patients without hepatic insufficiency, patients with hepatic insufficiency (but without cirrhosis), and patients with hepatic insufficiency and cirrhosis. The study showed that the exposure to 6-mercaptopurine was 1.6 times higher in patients with hepatic insufficiency (but without cirrhosis) and 6 times higher in patients with hepatic insufficiency and cirrhosis compared to patients without hepatic insufficiency. Therefore, a dose reduction should be considered in patients with impaired hepatic function (see Dosage and Administration).
Indication
In combination with corticosteroids and/or other immunosuppressive drugs for the prevention of organ rejection in kidney, heart, and liver transplantation, as well as to reduce the need for corticosteroids in kidney transplantation.
As monotherapy or in combination with corticosteroids and/or other drugs (which may include dose reduction or withdrawal of corticosteroids) it is used for the following diseases:
- severe rheumatoid arthritis;
- systemic lupus erythematosus;
- dermatomyositis and polymyositis;
- autoimmune chronic active hepatitis;
- pemphigus vulgaris;
- polyarteritis nodosa;
- autoimmune hemolytic anemia;
- chronic refractory idiopathic thrombocytopenic purpura;
- relapsing-remitting multiple sclerosis.
Contraindication
Imuran is contraindicated in patients with known hypersensitivity to azathioprine or other components of the drug. Hypersensitivity to 6-mercaptopurine.
Special safety measures.
Healthcare professionals handling uncoated tablets should follow instructions for handling cytotoxic drugs according to local guidelines and/or requirements.
If the film coating is not damaged, there is no risk when handling Imuran film-coated tablets. Imuran film-coated tablets should be used undivided, therefore, if the integrity of the coating is maintained, no additional precautions are required when handling the drug.
Disposal: Imuran tablets should be disposed of in accordance with existing local regulations for the disposal of hazardous substances.
Interaction with other medicinal products and other types of interactions
The immunosuppressive activity of Imuran may have an atypical and potentially negative effect on the efficacy of live vaccines, therefore the use of live vaccines in patients treated with Imuran is not recommended (see section "Special warnings and precautions for use").
A reduced response to inactivated vaccines is possible; a similar response has been observed to hepatitis B vaccine when administered to patients treated with a combination of azathioprine and corticosteroids.
A small clinical study found that standard therapeutic doses of azathioprine did not impair the response to polyvalent pneumococcal vaccine as assessed by mean anticapsular specific antibody concentrations.
Concomitant use of azathioprine with other drugs.
Ribavirin.
Ribavirin inhibits the enzyme, inosine monophosphate dehydrogenase (IMPDH), resulting in a decrease in the production of the active nucleotide 6-thioguanine. Severe myelosuppression has been reported with concomitant administration of azathioprine and ribavirin; therefore, their concomitant administration is not recommended (see section 4.4 and section 5.2).
Cytostatics/myelosuppressants (see section "Special instructions").
If possible, simultaneous use with cytostatics and drugs with myelosuppressive effects, such as penicillamine, should be avoided. There are reports of serious hematological changes with the simultaneous use of Imuran and co-trimoxazole.
There are also reports of the possible development of hematological abnormalities with the simultaneous use of azathioprine and ACE inhibitors.
It is also likely that cimetidine and indomethacin may have a myelosuppressive effect, which would be enhanced by the simultaneous use of azathioprine.
Allopurinol/oxypurinol/thiopurinol.
The action of xanthine oxidase is inhibited by allopurinol, oxypurinol and thiopurinol, which leads to a decrease in the conversion of biologically active 6-thioinosinic acid to biologically inactive 6-thiouric acid. When allopurinol, oxypurinol and thiopurinol are used simultaneously with 6-mercaptopurine or azathioprine, the doses of the latter should be reduced to 25% of the usual ones (see sections "Method of administration and dosage", "Interaction with other medicinal products and other types of interactions").
Aminosalicylates.
There is evidence that aminosalicylate derivatives (olsalazine, meslazine or sulfosalazine) inhibit the TPMT enzyme in vitro and in vivo. Therefore, when co-administered with aminosalicylate derivatives, a reduced dose of azathioprine should be considered (see also section 4.4).
Methotrexate.
Methotrexate (20 mg/m2 orally) increased the mean urinary 6-mercaptopurine concentration by approximately 31% and methotrexate (2 or 5 g/m2 IV) increased the mean urinary 6-mercaptopurine concentration by 69 and 93%, respectively. Therefore, when azathioprine is given with high-dose methotrexate, dosage adjustments should be made to maintain adequate leukocyte counts.
The effect of azathioprine on other drugs.
Anticoagulants.
The anticoagulant effect of warfarin and acenocoumarol has been reported to be reduced when given concomitantly with azathioprine; therefore, higher doses of anticoagulants may be required. Therefore, careful coagulation tests are recommended when anticoagulants are given concomitantly with azathioprine.
Application features
Immunization with live vaccines may potentially lead to infectious disease in immunocompromised patients. Therefore, immunization with live vaccines is not recommended (see section 4.5).
The concomitant use of ribavirin and azathioprine is not recommended. Ribavirin may reduce the efficacy and increase the toxicity of azathioprine (see section "Interaction with other medicinal products and other types of interactions").
The use of Imuran is potentially dangerous. Therefore, it should be prescribed only if there is a possibility of adequate monitoring of the patient in order to detect toxic effects throughout the entire period of treatment.
Hematological response should be closely monitored and maintenance dosage should be reduced to the minimum necessary to obtain a clinical response.
It is recommended that during the first 8 weeks of treatment with Imuran, a complete blood count, including platelet count, be performed weekly or more frequently (when using high doses or in the presence of severe renal and hepatic insufficiency). Subsequently, the frequency of blood tests can be reduced, but not less than once a month, and in extreme cases, not less than once every 3 months.
At the first signs of pathological deterioration of the blood picture, treatment should be discontinued immediately, as the level of leukocytes and platelets may fall after discontinuation of treatment.
Azathioprine is a hepatotoxic drug and liver function tests should be performed periodically during treatment. More frequent monitoring is recommended in patients with pre-existing liver disease or those receiving other potentially hepatotoxic therapy. The patient should be advised to discontinue azathioprine immediately if severe jaundice occurs.
Very rarely, some patients with thiopurine methyltransferase (TPMT) deficiency may be unusually sensitive to the myelosuppressive effects of azathioprine, which may lead to rapid bone marrow suppression during treatment with Imuran. These effects may be exacerbated by concomitant administration of drugs that inhibit TPMT, such as olsalazine, mesalazine and sulfasalazine. A possible association between decreased TPMT activity and the development of secondary leukemia and myelodysplasia has also been reported in some patients treated with 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxic drugs. Although some laboratories perform tests for TPMT deficiency, such tests do not identify all patients at risk of severe toxicity. Therefore, careful monitoring of the patient's blood count should be performed.
A reduction in the dosage of azathioprine may be required when this agent is administered concomitantly with other medicinal products whose primary or secondary toxicity includes myelosuppression (see section “Interaction with other medicinal products and other forms of interaction: Cytostatics/myelosuppressants”).
Imuran contains lactose, therefore patients with rare hereditary forms of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption syndrome should not take this medicine.
Renal and/or hepatic insufficiency
Caution should be exercised when administering azathioprine to patients with renal and/or hepatic impairment. Dosage reduction should be considered in such patients and haematological response should be closely monitored (see section 4.2).
Lesch-Nyhan syndrome
Limited data suggest that Imuran is harmful to patients with hypoxanthine-guanine phosphoribosyltransferase deficiency (Lesch-Nyhan syndrome). Therefore, given the metabolic abnormalities in these patients, Imuran is not recommended.
Mutagenicity
Chromosomal abnormalities have been observed in both males and females treated with Imuran, but it is difficult to assess the role of Imuran in the development of these abnormalities. Chromosomal abnormalities, which resolved over time, have been observed in lymphocytes of offspring of patients treated with Imuran. Except in very rare cases, no apparent physical abnormalities have been observed in offspring of patients treated with Imuran. A synergistic clastogenic effect has been observed in the treatment of a number of diseases with azathioprine and UV radiation.
Fertility
Recovery from chronic renal failure after kidney transplantation and the use of Imuran was accompanied by an increase in fertility in women and men (see section "Use during pregnancy or lactation").
Carcinogenicity (see section "Adverse reactions").
The risk of non-Hodgkin lymphoma and other malignancies, mainly skin cancers (melanoma and other types), sarcomas (Kaposi and other types), and cervical cancer, is increased in patients treated with immunosuppressive drugs. This risk is more related to the intensity and duration of immunosuppressive therapy than to the specific drug administered. There are reports that reducing or withdrawing immunosuppressive treatment has resulted in partial or complete regression of non-Hodgkin lymphoma and Kaposi's sarcoma.
Patients receiving multiple immunosuppressive drugs are at high risk of oversuppression of the immune system, so Imuran therapy should be maintained at the lowest effective dose. As with all patients at increased risk of skin cancer, exposure to sunlight and UV radiation should be limited, appropriate clothing should be worn, and sunscreen with a high protection factor should be used.
Patients with rheumatoid arthritis who have previously been treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan, etc.) may have an excessively high risk of neoplasia when treated with azathioprine.
Infections caused by the Varicella Zoster virus (see section "Adverse reactions").
Infections caused by the Varicella Zoster virus (chickenpox or herpes zoster) may become more severe during treatment with immunosuppressants. Caution should be exercised, especially in the following regard: Before prescribing immunosuppressants, it should be checked whether the patient has had diseases caused by the Varicella Zoster virus. Serological testing will be useful for this. In the absence of a history of exposure to this virus, contact with individuals with varicella or herpes zoster should be avoided. In the presence of exposure to the virus, contact with patients with varicella or herpes zoster should be avoided and passive immunization with Varicella Zoster immunoglobulin should be considered. In case of infection with the Varicella Zoster virus, appropriate measures should be taken, including antiviral and supportive therapy.
Cases of progressive multifocal leukoencephalopathy, an opportunistic infection caused by the JC (John Cunningham) virus, have been reported in patients treated with azathioprine in combination with other immunosuppressive agents. Immunosuppressive therapy should be discontinued at the first signs or symptoms that would suggest progressive multifocal leukoencephalopathy and appropriate diagnostic testing should be performed (see section 4.8).
Use during pregnancy or breastfeeding
Kidney transplantation in patients with renal failure, accompanied by the administration of Imuran, increases fertility in both male and female patients.
Imuran should not be prescribed during pregnancy without careful assessment of the expected benefit outweighing the possible risk of using the drug.
The evidence for teratogenicity of Imuran in humans is mixed. Animal studies have shown that use of the drug during the period of organogenesis results in birth defects of varying severity. As with other cytotoxic drugs, adequate contraception should be used by both partners if at least one of them is being treated with Imuran.
There have been reports of premature birth and low birth weight babies when Imuran was used in pregnant women, especially in combination with corticosteroids. There have also been reports of spontaneous abortions following maternal or paternal treatment with Imuran.
Significant transplacental and transamniotic transfer of azathioprine and its metabolites from mother to fetus has been demonstrated.
Leukopenia and thrombocytopenia have been observed in a number of infants born to mothers treated with azathioprine during pregnancy. Therefore, special attention should be paid to monitoring the blood status of women during pregnancy.
Use of the drug during pregnancy should be avoided as much as possible. The drug may harm the fetus. The drug should not be used in pregnant patients with rheumatoid arthritis. If the drug is used during pregnancy or the patient becomes pregnant during treatment, she should be warned of the potential risks to the fetus.
6-mercaptopurine has been detected in breast milk in women who breastfeed while receiving azathioprine. It is recommended that mothers taking azathioprine refrain from breastfeeding.
Fertility.
Recovery from chronic renal failure after kidney transplantation and the use of Imuran was accompanied by increased fertility in women and men.
Ability to influence reaction speed when driving vehicles or other mechanisms
There is no data on the effect of azathioprine on the ability to drive and use machines and it cannot be due to the pharmacological properties of the drug.
Method of administration and doses
General remark.
Imuran tablets should be taken at least 1 hour before or 3 hours after food (including milk) (see section "Pharmacokinetics: Absorption").
Use in adults.
Transplantation doses.
Depending on the immunosuppressive regimen, a dose of up to 5 mg/kg body weight per day in 2-3 divided doses may be used on the first day. The maintenance dose is 1-4 mg/kg body weight per day and should be adjusted according to clinical status and hematological tolerance.
Research data suggest that Imuran therapy should be continued indefinitely, even at low doses, due to the risk of transplant rejection.
Dosages for treating multiple sclerosis
The recommended dose for the treatment of relapsing-remitting multiple sclerosis is 2-3 mg/kg body weight per day in 2-3 divided doses. It may take more than a year to achieve treatment effectiveness. Control of disease progression can be established after two years of treatment.
Doses for other diseases.
In general, the initial dose is 1-3 mg/kg body weight per day and should be adjusted within this range depending on the clinical response (which is evident over weeks or months of treatment) and hematological tolerance.
When a therapeutic effect appears, the maintenance dose is reduced to a level at which this therapeutic effect is maintained. In the absence of a therapeutic effect after 3 months of treatment, the appropriateness of prescribing Imuran should be reconsidered.
The maintenance dose may range from less than 1 mg/kg body weight to 3 mg/kg body weight per day depending on the clinical condition and individual patient response, including hematological tolerance.
Children.
For the prevention of rejection reactions in children during transplantation, the method of administration and doses are the same as for adults.
Children with excess body weight.
Children with overweight may require higher tolerated doses, so their response to such treatment should be carefully monitored (see section “Pharmacokinetics: Special patient groups. Children with overweight”).
Experience with the use of Imuran in elderly patients is limited. Although available data suggest that the incidence of adverse reactions in elderly patients treated with Imuran is not different from that in other patients, it is recommended to monitor renal and hepatic function and reduce the dosage in case of impairment (see section "Method of administration and dosage: Use in patients with renal and/or hepatic impairment").
Use in patients with renal and/or hepatic insufficiency.
For patients with renal and/or hepatic insufficiency, the dosage should be reduced and lower tolerated doses should be maintained (see section "Special warnings and precautions for use").
Combined treatment.
When concomitantly taking xanthine oxidase inhibitors, such as allopurinol and azathioprine, only 25% of the usual dose should be used, as allopurinol reduces the rate of azathioprine catabolism (see section "Interaction with other medicinal products and other types of interactions").
Patients with thiopurine S-methyltransferase (TPMT) deficiency.
Patients with partial or complete hereditary TPMT deficiency are at increased risk of severe toxicity from azathioprine at normal doses and generally require a significantly reduced dose. The optimal starting dose for patients with homozygous deficiency has not been established (see sections 4.4 and 5.2).
Most patients with heterozygous TPMT deficiency can tolerate recommended doses of azathioprine, but some may require a reduced dosage. Genotypic and phenotypic TPMT tests are available (see sections 4.4 and 5.2).
Children. The drug can be used to treat children, with the exception of the treatment of multiple sclerosis, in which the use of Imuran for the treatment of children is not recommended.
Overdose
Symptoms
Unexplained infections, sore throat, bruising, and bleeding are the main symptoms of Imuran overdose and are the result of bone marrow suppression, which peaks after 9 to 14 days. These symptoms are more common in chronic overdose than in acute overdose. There is a report of a patient who took a single dose of 7.5 g of azathioprine, which immediately caused nausea, vomiting, and diarrhea, followed by mild leukopenia and liver dysfunction. Recovery was uneventful.
Treatment
Since there is no specific antidote, careful monitoring of the blood count and general supportive measures are necessary. Active measures (e.g., activated charcoal) may be ineffective in azathioprine overdose if they are not administered within 60 minutes of ingestion.
Supportive therapy is provided according to the clinical condition and in accordance with national recommendations for the treatment of poisoning.
The therapeutic value of dialysis for patients who have taken an excessive dose of Imuran is unknown, although azathioprine is partially dialysable.
Adverse reactions
Adverse reactions are classified according to frequency as follows: very common (>1/10), common (>1/100, <1/10), uncommon (>1/1000, <1/100), rare (>1/10000, <1/1000), very rare (<1/10000).
Infectious and invasive complications
Very common: viral, fungal and bacterial infections in transplant patients receiving azathioprine treatment in combination with other immunosuppressants.
Uncommon: viral, fungal and bacterial infections in other patients.
Patients treated with Imuran alone or in combination with other immunosuppressants, especially corticosteroids, are susceptible to viral, fungal and bacterial infections, including severe or atypical infections caused by Varicella, herpes zoster and other infectious agents (see section 4.4).
Very rare: Cases of progressive multifocal leukoencephalopathy associated with JC (John Cunningham) virus have been reported following the use of azathioprine in combination with other immunosuppressants (see section 4.4).
Neoplasms, benign and malignant (including cysts and polyps)
Rare: neoplasms, including non-Hodgkin lymphomas, skin cancers (melanoma and other types), sarcomas (Kaposi and other types), cervical cancer, acute myeloid leukemia and myelodysplasia (see section "Special warnings and precautions for use").
The risk of non-Hodgkin's lymphoma and other malignancies, mainly skin cancer (melanoma and other types), sarcoma (Kaposi and other types) and cervical cancer, is increased in patients treated with immunosuppressive drugs, especially in patients after transplantation. Therefore, therapy with Imuran should be maintained at the minimum effective dose. The increased risk of non-Hodgkin's lymphoma in patients with rheumatoid arthritis treated with immunosuppressive drugs, compared with the general population, is most likely related to the disease itself. There are isolated reports of cases of acute myeloid leukemia and myelodysplasia (sometimes associated with chromosomal aberrations).
Blood and lymphatic system
Very common: bone marrow depression, leukopenia.
Common: thrombocytopenia.
Uncommon: anemia.
The use of Imuran may be associated with dose-dependent and generally reversible bone marrow depression, most commonly manifested as leukopenia, occasionally as anemia and thrombocytopenia, and rarely as agranulocytosis, pancytopenia, and aplastic anemia. This is particularly true in patients predisposed to myelotoxicity, such as those with thiopurine methyltransferase (TPMT) deficiency, renal failure, or hepatic impairment. This also applies to patients in whom the dose of Imuran has not been reduced while allopurinol is being administered concomitantly.
Reversible dose-dependent increases in red blood cell volume and hemoglobin content have been observed with Imuran therapy. Megaloblastic changes in the bone marrow have also been observed, but severe megaloblastic anemia and erythroid hypoplasia are rare.
Immune system
Uncommon: hypersensitivity reactions.
Very rare: Stevens-Johnson syndrome and toxic epidermal necrolysis.
A variety of clinical syndromes, which are manifestations of hypersensitivity, have occurred occasionally following the use of Imuran. Clinical symptoms have included malaise, dizziness, nausea, vomiting, diarrhoea, fever, chills, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal impairment, hepatic impairment and cholestasis (see Gastrointestinal reactions).
In many cases, when Imuran was re-administered, side effects recurred.
In most cases, immediate discontinuation of the drug and the administration of supportive therapy, if necessary, leads to recovery.
In the case of other significant pathological changes in the body, there have been isolated reports of fatalities.
Following a hypersensitivity reaction, the need for continued therapy with Imuran should be carefully considered on an individual basis.
Lungs and chest
Very rare: reversible pneumonitis.
Digestive tract
Common: nausea.
Uncommon: pancreatitis.
Very rare: colitis, diverticulitis and intestinal perforation in transplant patients, severe diarrhea in patients with inflammatory bowel disease.
Some patients may experience nausea after the first dose of Imuran, which can be avoided by taking the tablets after meals.
Serious complications such as colitis, diverticulitis and intestinal perforation have been described in organ transplant patients receiving immunosuppressive therapy. Severe diarrhoea, which recurred with rechallenge, has been observed in patients with inflammatory bowel disease treated with Imuran. The possibility that exacerbations of symptoms may be dose-related should be considered when treating such patients.
Pancreatitis has been reported in a small number of patients, particularly in renal transplant recipients and patients with inflammatory bowel disease. It is difficult to establish a definitive relationship between pancreatitis and the use of any particular drug, although in some cases symptoms have recurred when Imuran is re-administered.
Hepatobiliary system
Uncommon: cholestasis and liver dysfunction.
Rare: life-threatening liver damage.
Cholestasis and hepatic dysfunction have been occasionally reported during treatment with Imuran, which usually resolve after discontinuation of the drug. These may be associated with symptoms of a hypersensitivity reaction (see Immune System Disorders).
Life-threatening liver damage has been reported very rarely with chronic use of azathioprine, particularly in organ transplant patients. Histological findings include sinusoidal dilation, hepatic purpura, veno-occlusive status, and nodular regenerative hyperplasia. In some cases, withdrawal of azathioprine has resulted in transient or sustained improvement in hepatic histological findings and symptoms.
Hepatotoxicity may be manifested by increased levels of alkaline phosphatase, bilirubin, and serum transaminases.
Skin and subcutaneous tissue
Rare: alopecia.
It is observed in some people
