Azathioprine Pharmachemie

Azathioprine.

Azathioprine, 50 mg tablet.
Excipients/Inactive Ingredients: Potato starch, Lactose, Povidone K25, Magnesium Stearate, Colloidal Silicon Dioxide.

Pharmacology: Pharmacodynamics: Azathioprine mainly exhibits immunosuppressive activity. The exact mechanism of immunosuppressive activity of the drug has not been determined. The action of azathioprine probably depends on several factors. Azathioprine, which is an antagonist to purine metabolism, may inhibit RNA and DNA synthesis. The drug may also be incorporated into nucleic acids resulting in chromosome breaks, malfunctioning of the nucleic acids, or synthesis of fraudulent proteins. The drug may also inhibit coenzyme formation and function thereby interfering with cellular metabolism. Mitosis may also be inhibited by the drug.
Pharmacokinetics: Absorption: Azathioprine is readily absorbed from GI tract.
Distribution: Distribution of azathioprine has not been fully characterized, but the drug is rapidly cleared from blood. Both mercaptopurine and azathioprine are approximately 30% bound to serum proteins, but both appear to be dialyzable. Azathioprine and its metabolites have been shown to cross the placenta.
Metabolism: Azathioprine is metabolized in vivo to 6-mercaptopurine and a methylnitroimidazole moiety. The 6-MP easily passes cell membranes and is converted intracellularly into a number of thio-analogs of purines, amongst which the most important active nucleotide, 6-thioinosinic acid. The conversion rate varies from person to person. The formed 6-mercaptopurine is mainly excreted as the inactive (oxidized) metabolite thio-uric acid. This oxidation occurs through xanthine-oxidase. This enzyme is inhibited by allopurinol.
Elimination: The metabolites of azathioprine are excreted by the kidneys; only small amounts of azathioprine and mercaptopurine are excreted intact.

Azathioprine is used as an immunosuppressant antimetabolite either alone or more commonly, in combination with other agents (usually corticosteroids), and procedures which influence the immune response. Therapeutic effect may be evident only after weeks or months and can include a steroid-sparing effect, thereby reducing the toxicity associated with high dosage and prolonged usage of corticosteroids.
Azathioprine, in combination with corticosteroids and/or other immunosuppressive agent and procedures, is indicated to enhance the survival organ transplants, such as renal transplants, cardiac transplants and hepatic transplants. It also reduces the corticosteroid requirements of renal transplant recipients.
Azathioprine, either alone or more usually in combination with corticosteroids and/or other drugs and procedures, has been used with clinical benefit (which may include reduction of dosage or discontinuation of corticosteroids) in a proportion of patients suffering from severe rheumatoid arthritis.

Specialist medical literature should be consulted for guidance as to clinical experience in particular conditions.
Dosage: Adults: With transplantations: Depending on the immunosuppressive regimen employed, a dosage of 3-5 mg/kg of body weight per day, one to three days before or at the time of surgery.
Maintenance dosage should range from 1-3 mg/kg of body weight per day and must be adjusted according to clinical requirements and haematological tolerance.
Evidence indicates that Azathioprine therapy should be maintained indefinitely, even if only low doses are necessary, because of the risk of graft rejection.
Rheumatoid arthritis: Usually given daily. Initial dose is approximately 1 mg/kg (50 to 100 mg) given as a single dose or twice daily. The dose may be increased, beginning at 6 to weeks and thereafter by steps at 4 week intervals, if there are no serious toxicities and initial response is unsatisfactory. Use dose increments of 0.5 mg/kg/day up to a maximum dose of 2.5 mg/kg/day.
Therapeutic response occurs after 6 to 8 weeks of treatment; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks are refractory. Continue the drug in patients with clinical response, but monitor carefully, and attempt gradual dosage reduction to reduce risk of toxicity. Optimum duration of therapy has not been determined. Use the lowest effective dose for maintenance therapy; lower decremental with changes of 0.5 mg/kg or approximately 25 mg/day every 4 weeks while other therapy is kept constant. Azathioprine can be discontinued abruptly, but delayed effects are possible.
Children: With transplantation and other indications: See Adults as previously mentioned.
Elderly: There is limited experience of the administration of Azathioprine to elderly patients. Although the available data do not provide evidence that the incidence of side effects among elderly patients is higher than that among other patients treated with Azathioprine, it is recommended that the dosages used should be at the lower end of the range.
Particular care should be taken to monitor haematological response and to reduce the maintenance dosage to the minimum required for clinical response.
Renal or Hepatic Impairment: In patients, dosage should be given at the lower end of the normal range (see Precautions).

Symptoms: The main signs of an overdose with azathioprine are inexplicable infections, ulceration of the throat, bruises and bleeding. They are the result of bone marrow suppression, which can be at a maximum after just 9-14 days. These symptoms will probably occur sooner with chronic overdosing, than with a single acute overdose.
There has been a report concerning a patient who ingested a single overdose of 7.5 g of azathioprine. The acute toxic effects of this overdose were nausea, vomiting and diarrhea, followed by a mild leucopoenia and mild abnormalities in the liver function. The recovery was uncomplicated.
Treatment: There is no specific antidote. Lavage was applied. Further monitoring, including haematology, is necessary to make the immediate treatment of any side effects that might occur possible. Azathioprine can be dialysed, but this is of questionable value as the substance is rapidly metabolized and the metabolites are absorbed in the tissue cells.

Azathioprine is contraindicated in patients with a known hypersensitivity to azathioprine or to 6-mercaptopurine or to one of the excipients of the product.

Monitoring: There are potential hazards involved with the use of the medicinal product; therefore it should only be prescribed if the patients can be sufficient for toxic effects during the entire therapy.
At least once a week for the first eight weeks of the treatment a complete blood count, including thrombocytes, should be done. This needs to be done more frequently with higher doses or with severe renal and/or liver dysfunction. After this period of time the monitoring may be done in a reducing frequency and it is recommended to repeat a complete blood count monthly, or at least with intervals of no more than three months.
Patients who receive azathioprine, should be instructed to immediately report to the doctor any sign of infection; unexplained bruising, bleeding or other expression of bone marrow depression. In rare cases people have an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT). They may be unusually sensitive to the myelosuppressive effect of azathioprine and may be increased risk of developing myelotoxicity. This problem may be increased by the co-administration of TPMT inhibiting medicinal products such as: olsalazine, mesalamine or sulfasalazine.
Renal and/or hepatic insufficiency: It has been suggested that the toxicity of azathioprine would be increased in the presence of renal insufficiency, but controlled studies do not support this point of view. Nevertheless it is recommended to choose doses on the low end of the normal dose ranging scale and to carefully do the haematological check ups. The dose should be reduced further in case of the occurrence of haematological toxicity.
Caution is needed with administration of azathioprine to patients with a liver function disorder and complete blood counts and liver function tests should be done regularly. In such patients the metabolism of azathioprine may be reduced and therefore the dose of azathioprine should be reduced to the low end of the recommended dose range. The dose should be further reduced in case of the occurrence of haematological or liver toxicity.
Mutagenicity: In both male and female patients who were treated with azathioprine, chromosome aberrations have been shown, but the abnormalities were reversed following discontinuance of the drug.
Teratogenicity: Indications for teratogenicity in humans are doubtful. As is true for all treatments with cytotoxic chemotherapeutic agents, adequate contraceptive measures should be advised when one of the parents is treated with azathioprine.
Carcinogenicity: Patients receiving immunosuppressive therapy are at an increased risk of Neoplasia.
Patients receiving multiple immunosuppressive agents may be at risk of over-immunosuppression, therefore such therapy should be maintained at the lowest effective level.
Varicella zoster virus infection: Infection with varicella zoster virus (VZV; chickenpox and herpes zoster) may become severe during the administration of immunosuppressants. Caution should be exercised especially with respect to the following: Before starting the administration of immunosuppressants, the prescriber should check to see if the patient has a history of VZV. Serologic testing may be useful in determining previous exposure. Patients who have no history of exposure should avoid contact with individuals with chickenpox or herpes zoster. If the patient is exposed to ZVZ, special care must be taken to avoid patients developing chickenpox or herpes zoster, and passive immunization with varicella-zoster immunoglobin (VZIG) may be considered.
If the patient is infected with ZVZ, appropriate measures should taken, which may include antiviral therapy and supportive care.

Pregnancy: Category D. Azathioprine can cause fetal harm when administered to a pregnant woman. Azathioprine should not be given during pregnancy without careful weighing of risk versus benefit. Whenever possible, use of azathioprine in pregnant patients should be avoided. This drug should not be used for treating rheumatoid arthritis in pregnant women.
Lactation: The use of azathioprine in nursing mothers is not recommended. Azathioprine or its metabolites are transferred at low levels, both transplacentally and in breast milk. Because of the potential for tumorigenicity shown for azathioprine, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Infections and infestations: Patients receiving Azathioprine alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to viral, fungal and bacterial infections, including severe or atypical infection with varicella, herpes zoster and other infectious agents.
Neoplasms benign and malignant (including cysts and polyps): The risk of developing malignancy (e.g. skin cancer, reticulum cell sarcoma, lymphomas), is increased in patients who receive immunosuppressive drugs, particularly in transplant recipients receiving aggressive treatment and such therapy should be maintained at the lowest effective levels. Evidence suggests that the risk also may be evaluated in patients with rheumatoid arthritis patients. The increase risk of neoplasia following Azathioprine therapy should be explained to patients.
There have been reports of acute myelogenous leukemia and solid tumors in patients with rheumatoid arthritis.
Blood and lymphatic system disorders: Azathioprine may be associated with a dose-related, generally reversible, depression of bone marrow function, most frequently expressed as leucopenia, but also sometimes as anaemia and thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anaemia.
These occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency and renal or hepatic insufficiency and in patients failing to reduce the dose of Azathioprine when receiving concurrent allopurinol therapy.
Reversible, dose-related increases in mean corpuscular volume and red cell haemoglobin content have occurred in association with Azathioprine therapy. Megaloblastic bone marrow changes have also been observed but severe megaloblastic anaemia and erythroid hypoplasia are rare.
Immune system disorders: Several different clinical syndromes, which appear to be idiosyncratic manifestations of hypersensitivity, have been described occasionally following administration of Azathioprine.
Clinical features include general malaise, dizziness, nausea, vomiting, diarrhoea, fever, rigors, exanthema, rash, vasculitis, myalgia, arthralgia, hypotension, renal dysfunction, hepatic dysfunction.
In many cases, rechallenge has confirmed an association with Azathioprine.
Immediate withdrawal of Azathioprine and institution of circulatory support where appropriate have led to recovery in the majority of cases.
Other marked underlying pathology has contributed to the very rare deaths reported.
Following a hypersensitivity reaction to Azathioprine, the necessity for continued administration of Azathioprine should be carefully considered on an individual basis.
Respiratory thoracic and mediastinal disorders: Reversible pneumonitis.
Gastrointestinal disorders: Nausea, vomiting, anorexia and diarrhea may occur in patients receiving large dosages of Azathioprine when first given. This appears to be relieved by administering the tablets after meals. Vomiting with abdominal pain may occur rarely with hypersensitivity pancreatitis.
Symptoms of GI toxicity must often develop within the first several weeks of Azathioprine therapy and reversible upon discontinuance of the drug. The reaction can occur within several hours after rechallenge with a single dose of the drug.
Other adverse GI effects include ulceration of the mucous membranes of the mouth, esophagitis with possible ulceration, and steatorrhea.
Hepatotoxicity and biliary stasis: Biliary stasis has been reported in less frequent and is dose-related.
Azathioprine-induced hepatotoxicity and is usually reversible on withdrawal of therapy.
Rare, but life-threatening hepatic damage associated with chronic administration of Azathioprine has been described, primarily in transplant patients. Periodic measurement, serum transaminases, alkaline phosphatase and bilirubin are indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, it is recommended that Azathioprine be permanently withdrawn.
Skin and subcutaneous tissue disorders: Hair loss has been described on a low frequency in patients receiving Azathioprine.

Allopurinol: Allopurinol inhibits one of the metabolic pathways of azathioprine (i.e., the oxidative metabolism of mercaptopurine by xanthine oxidase), thus increasing the possibility of toxic effects of azathioprine, particularly bone marrow depression. When azathioprine and allopurinol are administered concomitantly, dosage of azathioprine should be reduced to 25-33% of the usual dosage, and subsequent dosage adjusted according to the patient response and toxic effects.
Angiotensin-converting enzyme inhibition: Anemia and severe leucopenia may occur when angiotensin-converting enzyme (ACE) inhibitors are administered concomitantly with azathioprine.
Aminosalicylates: In vitro, aminosalicylates (mesalamine, olsalazine, sulfasalazine) have been shown to inhibit the enzyme thioprine methyl transferase (TPMT), an enzyme involved in the methylation of 6-mercaptopurine (a metabolite of azathioprine). Caution should be used during concomitant administration of azathioprine with aminosalicylates.
Drug affecting Myelopoiesis: Concomitant use of drugs affecting myelopoiesis (e.g., co-trimoxazole) with azathioprine may result in severe leucopenia, especially in patients who have undergone renal transplantation.
Warfarin: Azathioprine may inhibit the anticoagulant effect of warfarin.
Vaccines: Killed virus: Because normal defense mechanisms may be suppressed by Azathioprine therapy, the patient's antibody response to the vaccine may be decreased.
Live virus: Concurrent use with a live virus vaccine may potentiate the replication of the vaccine virus, may increase the side/adverse effect of the vaccine virus, and/or may decrease the patient's antibody response to the vaccine. Immunization of these patients should be undertaken only with extreme caution after careful review of the patient's hematologic status and only with the knowledge and consent of the physician managing the Azathioprine therapy.

Store below 30°C.

Disease-Modifying Anti-Rheumatic Drugs (DMARDs) / Immunosuppressants

L04AX01 - azathioprine ; Belongs to the class of other immunosuppressants.

D

Tab 50 mg (yellow, bi-convex, scored, inscription: AZP 50) x 10 x 10's.