Action And Clinical Pharmacology: Metabolism: Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at 1 to 2 hours after oral 5-azathioprine and decays with a half-life of 5 hours. This is not an estimate of the half-life of azathioprine itself but is the decay rate for all 5-containing metabolites of the drug. Because of extensive metabolism, only a fraction of the radioactivity is present as azathioprine. Usual doses produce blood levels of azathioprine, and of mercaptopurine derived from it, which are low.
Azathioprine is cleaved in vivo to mercaptopurine. Both compounds are rapidly eliminated from blood and are oxidized or methylated in erythrocytes and liver; no azathioprine or mercaptopurine is detectable in urine after 8 hours. Conversion to inactive 6-thiouric acid by xanthine oxidase is an important degradative pathway, and the inhibition of this pathway in patients receiving allopurinol is the basis for the azathioprine dosage reduction required in these patients (see Precautions, Drug Interactions). Proportions of metabolites are different in individual patients, and this presumably accounts for variable magnitude and duration of drug effects. Renal clearance is probably not important in predicting biological effectiveness or toxicities, although dose reduction is practiced in patients with poor renal function.
In view of the observations by Schwartz et al. that mercaptopurine suppressed the antibody response in rabbits injected with bovine serum albumin, the effects of azathioprine on the formation of antibodies were investigated. In the suppression of the formation of antibodies in mice to sheep red cells, as determined by hemagglutinin titres, azathioprine was found to be superior to mercaptopurine. Whereas mercaptopurine was active only at its maximum tolerated dose of 75 mg/kg, azathioprine was active at 25 mg/kg and was tolerated in doses up to 60 mg/kg for the dosage schedule employed (intraperitoneal injection for 4 successive days beginning at the time of the antigenic stimulus). The anti-immune effects of azathioprine are not due entirely to the mercaptopurine derived therefrom by splitting in vivo.
Another line of evidence which suggests that part of the activity of azathioprine may be due to its reaction with sulfhydryl compounds is the potentiation of its anti-immune effect by the simultaneous administration of busulfan. (Busulfan is also known to react with sulfhydryl groups in tissues.) Thus the combination of azathioprine (10 mg/kg) and busulfan (30 mg/kg) produced a marked suppression of the antibody response whereas the minimum effective dose of azathioprine alone is 25 mg/kg; busulfan alone is inactive at its maximum tolerated dose of 40 mg/kg. The combination of mercaptopurine (25 mg/kg) and busulfan (25 mg/kg) is inactive.
Homograft Survival: Although the use of azathioprine for inhibition of renal homograft rejection is well established, the mechanism(s) for this action are somewhat obscure. The drug suppresses hypersensitivities of the cell-mediated type and causes variable alterations in antibody production. Suppression of T-cell effects, including ablation of T-cell suppression, is dependent on the temporal relationship to antigenic stimulus or engraftment. This agent has little effect on established graft rejections or secondary responses.
Alterations in specific immune responses or immunologic functions in transplant recipients are difficult to relate specifically to immunosuppression by azathioprine. These patients have subnormal responses to vaccines, low numbers of T-cells, and abnormal phagocytosis by peripheral blood cells, but their mitogenic responses, serum immunoglobulins and secondary antibody responses are usually normal.
Immunoinflammatory Response: Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of autoimmune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine.
The mechanisms whereby azathioprine affects autoimmune diseases are not known. Azathioprine is immunosuppressive, delayed hypersensitivity and cellular cytotoxicity tests being suppressed to a greater degree than are antibody responses. In the rat model of adjuvant arthritis, azathioprine has been shown to inhibit the lymph node hyperplasia which precedes the onset of the signs of the disease. Both the immunosuppressive and therapeutic effects in animal models are dose-related. Azathioprine is considered a slow-acting drug and effects may persist after the drug has been discontinued.
Indications And Clinical Uses: Chronic immunosuppression with this purine antimetabolite may increase risk of neoplasia. Physicians using this drug should be very familiar with this risk as well as with possible hemotologic toxicities. See below under warnings.
Renal homotransplantation: Azathioprine is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16 000 transplants shows a 5-year patient survival of 35 to 55%, but this is dependent on donor, match for HLA antigens, anti-donor or anti B-cell alloantigen antibody and other variables. The effect of azathioprine on these variables has not been tested in controlled trials.
Rheumatoid arthritis: Azathioprine is indicated only in adult patients meeting criteria for classic or definite rheumatoid arthritis as specified by the American Rheumatism Association. Azathioprine should be restricted to patients with severe, active and erosive disease not responsive to conventional management including rest, ASA or other nonsteroidal drugs or to agents in the class of which gold is an example. Rest, physiotherapy and salicylates should be continued while azathioprine is given, but it may be possible to reduce the dose of corticosteroids in patients on azathioprine. The combined use of azathioprine with gold, antimalarials or penicillamine has not been studied for either added benefit or unexpected adverse effects. The use of azathioprine with these agents cannot be recommended.
Contra-Indications: Hypersensitivity to the drug.
Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive risk of neoplasia if treated with azathioprine.
Azathioprine should not be used in treating rheumatoid arthritis in pregnant women. Azathioprine should not be used to treat children with rheumatoid arthritis.
Manufacturers’ Warnings In Clinical States: Severe leukopenia and/or thrombocytopenia may occur in patients on azathioprine. Macrocytic anemia and severe bone marrow depression may also occur. Hematologic toxicities are dose related and may be more severe in renal transplant patients whose homograft is undergoing rejection. It is suggested that patients on azathioprine have complete blood counts, including platelet counts, weekly during the first month, twice monthly for the second and third months of treatment, then monthly or more frequently if dosage alterations or other therapy changes are necessary. Delayed hematologic suppression may occur. Prompt reduction in dosage or temporary withdrawal of the drug may be necessary if there is a rapid fall in, or persistently low leukocyte count or other evidence of bone marrow depression. Leukopenia does not correlate with therapeutic effect; therefore the dose should not be increased intentionally to lower the white blood cell count.
Serious infections are a constant hazard for patients receiving chronic immunosuppression, especially for homograft recipients. Fungal, viral, bacterial and protozoal infections may be fatal and should be treated vigorously. Reduction of azathioprine dosage and/or use of other drugs should be considered.
Azathioprine is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient’s risk of neoplasia. Renal transplant patients are known to have an increased risk of malignancy, predominantly skin cancer and reticulum cell or lymphomatous tumors. The risk of post-transplant lymphomas may be increased in patients who receive aggressive treatment with immunosuppressive drugs. The degree of immunosuppression is determined not only by the immunosuppressive regimen, but also by a number of other patient factors. The number of immunosuppressive agents may not necessarily increase the risk of post-transplant lymphomas. However, transplant patients who receive multiple immunosuppressive agents may be at risk for over-immunosuppression; therefore, immunosuppressive drug therapy should be maintained at the lowest effective levels. Information is available on the spontaneous neoplasia risk in rheumatoid arthritis, and on neoplasia following immunosuppressive therapy of other auto-immune diseases. It has not been possible to define the precise risk of neoplasia due to azathioprine. The data suggest the risk may be elevated in patients with rheumatoid arthritis, though lower than for renal transplant patients. However, acute myelogenous leukemia as well as solid tumors have been reported in patients with rheumatoid arthritis who have received azathioprine. Data on neoplasia in patients receiving azathioprine can be found under Adverse Effects.
Azathioprine has been reported to cause temporary depression in spermatogenesis and reduction in sperm viability and sperm count in mice at doses 10 times the human therapeutic dose; a reduced percentage of fertile matings occurred when animals received 5 mg/kg.
A persistent negative nitrogen balance has been observed in some patients on continuous azathioprine dosage; if this should occur, the dose should be reduced as this has been found to correct the situation.
Pregnancy : Azathioprine can cause fetal harm when administered to a pregnant woman.
Azathioprine should not be given during pregnancy or in patients of reproductive potential without careful weighing of risk versus benefit. Use of azathioprine in pregnant patients should be avoided whenever possible. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing age should be advised to avoid becoming pregnant.
Azathioprine is teratogenic in rabbits and mice when given in doses equivalent to the human dose (5 mg/kg daily). Abnormalities included skeletal malformations and visceral anomalies.
There are no adequate and well-controlled studies in pregnant women.
Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on azathioprine. In a detailed case report, documented lymphopenia, diminished IgG and IgM levels, CMV infection, and a decreased thymic shadow were noted in an infant born to a mother receiving 150 mg azathioprine and 30 mg prednisone daily throughout pregnancy. At 10 weeks most features were normalized. DeWitte et al. reported pancytopenia and severe immune deficiency in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. There have been 2 published reports of abnormal physical findings. Williamson and Karp described an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. Tallent et al. described an infant with a large myelomeningocele in the upper lumbar region, bilateral dislocated hips, and bilateral talipes equinovarus. The father was on long-term azathioprine therapy.
Precautions: General: The dosage which will be tolerated or will be effective will vary from patient to patient and, therefore, careful management is necessary to obtain the optimum therapeutic effect and to reduce toxicity. Caution must be exercised to observe early signs of depression of the bone marrow which may result in leukopenia and eventually thrombocytopenia and bleeding. Since this drug may have a delayed action, it is important to withdraw the medication temporarily at the first sign of an abnormally large fall in the white cell count or of abnormal depression of the bone marrow. It must be kept in mind that patients with impaired renal function may have slower elimination of the drug and a greater cumulative effect. Lower dose if there is impaired renal function. It is recommended that the drug be withheld if there is evidence of toxic hepatitis or biliary stasis.
Hematologic: There are rare individuals with an inherited deficiency of the enzyme thiopurine methyltransferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow suppression following the initiation of treatment with azathioprine.
Gastrointestinal: A gastrointestinal hypersensitivity reaction characterized by severe nausea and vomiting has been reported. These symptoms may also be accompanied by diarrhea, rash, fever, malaise, myalgias, elevations in liver enzymes, and occasionally, hypotension. Symptoms of gastrointestinal toxicity may often develop within the first several weeks of azathioprine therapy and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of azathioprine.
Drug Interactions: Allopurinol: The principal pathway for detoxification of azathioprine is inhibited by allopurinol. In patients receiving azathioprine, the concomitant administration of allopurinol will require a reduction in dose to approximately 1/3 to 1/4 of the usual dose of azathioprine. Subsequent adjustment of doses of azathioprine should be made on the basis of therapeutic response and any toxic effects.
Other Agents Affecting Myelopoesis: Drugs which may affect leukocyte production, including co-trimoxazole, may lead to exaggerated leukopenia, especially in renal transplant recipients.
Angiotensin Converting Enzyme Inhibitors: The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.
Warfarin: Azathioprine may inhibit the anticoagulant effect of warfarin.
Nondepolarizing Muscle Relaxants: There is clinical evidence that azathioprine antagonizes the effect of nondepolarizing muscle relaxants such as curare, d-tubocurarine and pancuronium. Experimental data confirm that azathioprine reverses the neuromuscular blockade caused by d-tubocurarine, and show that azathioprine potentiates the neuromuscular blockade caused by succinylcholine.
Pregnancy: See Warnings.
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 on whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.
Children: Safety and efficacy of azathioprine in children have not been established.
Information for the Patient: Patients being started on azathioprine should be informed of the necessity of periodic blood counts while they are receiving the drug and should be encouraged to report any unusual bleeding or bruising to their physician. They should be informed of the danger of infection while receiving azathioprine and asked to report signs and symptoms of infection to their physician. Careful dosage instructions should be given to the patient, especially when azathioprine is being administered in the presence of impaired renal function or concomitantly with allopurinol (see Drug Interactions and Dosage).
Patients should be advised of the potential risks of the use of azathioprine during pregnancy and during the nursing period. The increased risk of neoplasia following azathioprine therapy should be explained to the patient.
Adverse Reactions: The principal and potentially serious toxic effects of azathioprine are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see Warnings). The frequency and severity of adverse reactions depend on the dose and duration of azathioprine as well as on the patient’s underlying disease or concomitant therapies. The incidence of hematologic toxicities and neoplasia encountered in groups of renal homograft recipients is significantly higher than that in studies employing azathioprine for rheumatoid arthritis.
Hematologic: Leukopenia and/or thrombocytopenia are dose dependent and may occur late in the course of azathioprine therapy. Dose reduction or temporary withdrawal allow reversal of these toxicities. Infection may occur as a secondary manifestation of bone marrow suppression or leukopenia, but the incidence of infection is 30 to 60 times greater in renal homotransplantation than in rheumatoid arthritis. Macrocytic anemia and/or bleeding have been reported in patients on azathioprine.
Gastrointestinal: Nausea and vomiting may occur within the first few months of azathioprine therapy, and occurred in approximately 12% of 676 rheumatoid arthritis patients. The frequency of gastric disturbance can often be reduced by administration of the drug in divided doses and/or after meals. However, in some patients, nausea and vomiting may be severe and may be accompanied by symptoms such as diarrhea, fever, malaise, and myalgias (see Precautions). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis.
Hepatic: Hepatotoxicity manifest by elevation of serum alkaline phosphatase, bilirubin and/or serum transaminases is known to occur with thiopurines including azathioprine and 6-mercaptopurine. This toxic hepatitis with biliary stasis is known to occur in homograft recipients. Hepatotoxicity has been uncommon in rheumatoid arthritis patients on azathioprine (less than 1%). Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of azathioprine. A rare, but life-threatening hepatic veno-occlusive disease associated with chronic administration of azathioprine has been described in transplant patients and in one patient receiving azathioprine for panuveitis. Periodic measurement of serum transaminases, alkaline phosphatase and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, azathioprine should be permanently withdrawn.
Others: Additional side effects of low frequency have been reported. These include skin rashes, alopecia, fever, arthralgias, diarrhea, steatorrhea, negative nitrogen balance and reversible interstitial pneumonitis.
Symptoms And Treatment Of Overdose: Symptoms: Initial symptoms are nausea and vomiting; and symptoms appearing later are leukopenia, thrombocytopenia, hepatic necrosis and anorexia.
Treatment: Administer gastric lavage and fluids; blood transfusions may be needed due to suppression of the proliferation of granulocytes.
About 30% of azathioprine is bound to serum proteins, but approximately 45% is removed during an 8-hour hemodialysis. A single case has been reported of a renal transplant patient who ingested a single dose of 7500 mg azathioprine. The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, AST, and bilirubin returned to normal 6 days after the overdose.
Dosage And Administration: Renal Homotransplantation: The dose of azathioprine required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. Initial dose is usually 3 to 5 mg/kg daily, beginning at the time of transplant. Azathioprine is usually given as a single daily dose on the day of, and in a minority of cases 1 to 3 days before, transplantation. Azathioprine is often initiated with the i.v. administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the post-operative period. I.V. administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1 to 3 mg/kg daily is usually possible. The dose of azathioprine should not be increased to toxic levels because of threatened rejection. Discontinuation may be necessary for severe hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal.
Rheumatoid Arthritis: Azathioprine is usually given on a daily basis. The initial dose should be approximately 1 mg/kg (50 to 100 mg) given as a single dose or on a twice daily schedule. The dose may be increased, beginning at 6 to 8 weeks and thereafter by steps at 4-week intervals, if there are no serious toxicities and if initial response is unsatisfactory. Dose increments should be 0.5 mg/kg daily, up to a maximum dose of 2.5 mg/kg/day. Therapeutic response occurs after several weeks of treatment, usually 6 to 8; an adequate trial should be a minimum of 12 weeks. Patients not improved after 12 weeks can be considered refractory. Azathioprine may be continued long-term in patients with clinical response, but patients should be monitored carefully, and gradual dosage reduction should be attempted to reduce risk of toxicities. Maintenance therapy should be at the lowest, effective dose, and the dose given can be lowered with decremental changes of 0.5 mg/kg or approximately 25 mg daily every 4 weeks while other therapy is kept constant. The optimum duration of maintenance azathioprine has not been determined. Azathioprine can be discontinued abruptly, but delayed effects are possible.
Renal Dysfunction: Relatively oliguric patients, especially those with tubular necrosis in the immediate post-cadaveric transplant period, may have delayed clearance of azathioprine or its metabolites or be particularly sensitive to this drug and are usually given lower doses.
Parenteral Administration: For i.v. use only. Add 10 mL of sterile water for injection, and swirl until a clear solution results. This solution, equivalent to 100 mg azathioprine, has a pH of approximately 9.6. The solution should be prepared immediately before use and any remainder discarded. Further dilution into sterile saline or dextrose is usually made for infusion; the final volume depends on time for the infusion, usually 30 to 60 minutes but as short as 5 minutes and as long as 8 hours for the daily dose.
Shake until complete dissolution.
The solution should be prepared immediately before use and any remainder discarded.
Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration, whenever solution and container permit.
I.V. Infusion: Further dilution into sterile saline or dextrose is usually made for infusion. The final volume depends on the time for the infusion, usually 30 to 60 minutes, but as short as 5 minutes and as long as 8 hours for the daily dose.
Special Instructions: Tablets and intact vials should be returned to the manufacturer for destruction. Proper precautions should be taken in packaging these materials for transport.
All materials which have come in contact with cytotoxic drugs should be segregated and incinerated at 1 000°C or more. Sealed containers may explode.
Personnel regularly involved in the preparation and handling of cytotoxic agents should have biannual blood examinations.
Availability And Storage: Injection: Each 20 mL vial contains: the equivalent of azathioprine 100 mg as the sodium salt. Store between 15 and 25°C, protected from light.
Tablets: Each yellow to off-white, dumbbell-shaped tablet, with code number IMURAN 50 on one side and with converging scored lines on the other contains: azathioprine 50 mg. Nonmedicinal ingredients: lactose, magnesium stearate, potato starch, povidone, and stearic acid. Bottles of 100. Store in a dry place between 15 and 25°C, protected from light.
IMURAN® Glaxo Wellcome Azathioprine Immunosuppressive Agent