Imuran

There is clinical evidence that IMURAN antagonizes the effect of non-depolarizing 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.

As there is in vitro evidence that aminosalicylate derivatives (e.g. olsalazine, mesalazine or sulphasalazine) inhibit the TPMT enzyme, they should be administered with caution to patients receiving concurrent azathioprine therapy (see Warnings and Precautions).

The use of angiotensin converting enzyme inhibitors to control hypertension in patients on azathioprine has been reported to induce anemia and severe leukopenia.

The principal pathway for detoxification of IMURAN is inhibited by allopurinol. In patients receiving IMURAN, the concomitant administration of ZYLOPRIM (allopurinol) will require a reduction in dose to approximately 1/3 to 1/4 of the usual dose of IMURAN. Subsequent adjustment of doses of IMURAN 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.

IMURAN may inhibit the anticoagulant effect of warfarin.

The dose of IMURAN (azathioprine) required to prevent rejection and minimize toxicity will vary with individual patients; this necessitates careful management. The initial dose is usually 3-5 mg/kg daily, beginning at the time of transplant. IMURAN is usually given as a single daily dose on the day of, and in a minority of cases one to three days before, transplantation. IMURAN is often initiated with the intravenous administration of the sodium salt, with subsequent use of tablets (at the same dose level) after the post-operative period. Intravenous administration of the sodium salt is indicated only in patients unable to tolerate oral medications. Dose reduction to maintenance levels of 1-3 mg/kg daily is usually possible. The dose of IMURAN 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.

Further dilution into sterile saline is usually made for infusion. The final volume depends on the time for the infusion, usually 30-60 minutes, but as short as five minutes and as long as eight hours for the daily dose.

As with all parenteral drug products, intravenous admixtures should be inspected visually for clarity, particulate matter, precipitate, discolouration and leakage prior to administration whenever solution and container permit. Solutions showing haziness, particulate matter, precipitate, discolouration or leakage should not be used. Discard unused portion.

For intravenous use only. A 50 mg vial should be reconstituted with 5 to 15 mL Sterile Water for Injection, however to obtain a nominal concentration of 10 mg/mL, 5mL of Sterile Water for Injection should be used. Once the Sterile Water for Injection has been added, swirl until a clear solution results. This solution has a pH of approximately 10-12. No antimicrobial preservative is included. Therefore reconstitution and dilution must be carried out under full aseptic conditions, preferably immediately before use. Any unused solution should be discarded. Further dilution into sterile saline is usually made for infusion; the final volume depends on time for the infusion, usually 30-60 minutes but as short as five minutes and as long as eight hours for the daily dose.

Shake until complete dissolution.

No antimicrobial preservative is included. Therefore reconstitution and dilution must be carried out under full aseptic conditions, preferably immediately before use. Any unused solution should be discarded.

Relatively oliguric patients, especially those with tubular necrosis in the immediate post-cadaveric transplant period, may have delayed clearance of IMURAN or its metabolites, or be particularly sensitive to this drug, and are usually given lower doses.

IMURAN is usually given on a daily basis. The initial dose should be approximately 1.0 mg/kg (50-100 mg) given as a single dose or on a twice daily schedule. The dose may be increased, beginning at six to eight weeks and thereafter by steps at four-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 six to eight; an adequate trial should be a minimum of 12 weeks. Patients not improved after twelve weeks can be considered refractory. IMURAN 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 four weeks, while other therapy is kept constant. The optimum duration of maintenance IMURAN has not been determined. IMURAN can be discontinued abruptly, but delayed effects are possible.

Rest, physiotherapy and salicylates should be continued while IMURAN is given, but it may be possible to reduce the dose of corticosteroids in patients on IMURAN.

Nausea and vomiting may occur within the first few months of IMURAN 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, vasculitis, hepatic dysfunction, cholestatis and myalgias (see Warnings and Precautions). Vomiting with abdominal pain may occur rarely with a hypersensitivity pancreatitis.

Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported very rarely in post-marketing surveillance.

Leukopenia and/or thrombocytopenia and rarely as agranulocytosis, pancytopenia and aplastic anemia are dose dependent and may occur late in the course of IMURAN therapy. Dose reduction or temporary withdrawal allows reversal of these toxicities. These adverse events occur particularly in patients predisposed to myelotoxicity, such as those with TPMT deficiency (see Warnings and Precautions) and renal or hepatic insufficiency and in patients failing to reduce the dose of IMURAN when receiving concurrent allopurinol therapy (see Warnings and Precautions). 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 IMURAN.

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

The relative incidences in clinical studies are summarized below:

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.

There have been rare reports of neoplasms including non-Hodgkins lymphomas, skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's), uterine cervical cancer in situ, acute myeloid leukaemia and myelodysplasia (some in association with chromosomal abnormalities).

The principal and potentially serious toxic effects of IMURAN (azathioprine) are hematologic and gastrointestinal. The risks of secondary infection and neoplasia are also significant (see Warnings and Precautions). The frequency and severity of adverse reactions depend on the dose and duration of IMURAN 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 IMURAN for rheumatoid arthritis.

Infections (i.e. viral, fungal and bacterial) occur very commonly in transplant patients receiving azathioprine in combination with other immunosuppressants and uncommonly in other patient populations (see Warnings and Precautions).

Hepatotoxicity manifested by elevation of serum alkaline phosphatase, bilirubin and/or serum transaminases is known to occur with thiopurines including IMURAN and PURINETHOL (6-mercaptopurine). This toxic hepatitis with biliary stasis is known to occur in homograft recipients. Hepatotoxicity has been uncommon in rheumatoid arthritis patients on IMURAN (less than 1%). Hepatotoxicity following transplantation most often occurs within 6 months of transplantation and is generally reversible after interruption of IMURAN. Rare, but life-threatening hepatic damage associated with chronic administration of azathioprine has been described primarily in transplant patients and in one patient receiving IMURAN for panuveitis. Histological findings include sinusoidal dilation, peliosis hepatis, veno-occlusive disease and nodular regenerative hyperplasia. Periodic measurement of serum transaminases, alkaline phosphatase, and bilirubin is indicated for early detection of hepatotoxicity. If hepatic veno-occlusive disease is clinically suspected, IMURAN should be permanently withdrawn. In some cases withdrawal of azathioprine has resulted in either a temporary or permanent improvement in liver histology and symptoms.

No data are available.

No data are available.

IMURAN (azathioprine) is indicated as an adjunct for the prevention of rejection in renal homotransplantation.

IMURAN is indicated only in adult patients meeting criteria for classic or definite rheumatoid arthritis as specified by the American Rheumatism Association. IMURAN should be restricted to patients with severe, active and erosive disease not responsive to conventional management including rest, acetylsalicylic acid or other non-steroidal drugs, or with disease-modifying antirheumatic drugs (DMARD’s).

Each yellow to off-white, overlapping circle (dumbbell) shape tablet, imprinted 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.

Each vial contains: the equivalent of azathioprine 50 mg as the sodium salt, and sodium hydroxide to adjust pH. Single dose vials of 17 mL.

Safety and efficacy of azathioprine in geriatrics have not been established.

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, vasculitis, hepatic dysfunction, cholestatis and occasionally, hypotension. Symptoms of gastrointestinal toxicity may often develop within the first several weeks of IMURAN therapy and are reversible upon discontinuation of the drug. The reaction can recur within hours after rechallenge with a single dose of IMURAN.

Severe leukopenia and/or thrombocytopenia may occur in patients on IMURAN (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 IMURAN 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.

There are individuals with an inherited deficiency of the enzyme thiopurine methyl-transferase (TPMT) who may be unusually sensitive to the myelosuppressive effect of azathioprine and prone to developing rapid bone marrow depression following the initiation of treatment with IMURAN (azathioprine). This problem could be exacerbated by coadministration with drugs that inhibit TPMT, such as olsalazine, mesalazine or sulphasalazine. Also a possible association between decreased TPMT activity and secondary leukemias and myelodysplasia has been reported in individuals receiving 6-mercaptopurine (the active metabolite of azathioprine) in combination with other cytotoxics. Some laboratories offer testing for TPMT deficiency, although these tests have not been shown to identify all patients at risk of severe toxicity. Therefore close monitoring of blood counts is still necessary.

Patients receiving IMURAN alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to infections (e.g. fungal, viral and bacterial), including severe or atypical infection with varicella, herpes zoster and other infections agents (see Adverse Reactions). 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. 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 VZV, special care must be taken to avoid patients developing chickenpox or herpes zoster, and passive immunisation with varicella-zoster immunoglobulin (VZIG) may be considered.

If the patient is infected with VZV, appropriate measures should be taken, which may include antiviral therapy and supportive care.

Patients with rheumatoid arthritis previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan or others) may have a prohibitive risk of neoplasia if treated with IMURAN.

IMURAN is mutagenic in animals and humans, carcinogenic in animals, and may increase the patient's risk of neoplasia. Patients receiving immunosupressive drugs, particularly transplant patients receiving aggressive therapy, are known to have an increased risk of developing non-Hodgkin's lymphomas and other malignancies, notably skin cancers (melanoma and non-melanoma), sarcomas (Kaposi's and non-Kaposi's), uterine cervical cancer in situ, and reticulum cell or lymphomatous tumors. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. It has been reported that reduction or discontinuation of immunosuppression may be associated with partial or complete regression of non-Hodgkin's lymphomas and Kaposi's sarcomas. 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 lymphomas. However, 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. As is usual for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited, and patients should wear protective clothing and use a sunscreen with a high protection factor. 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 IMURAN. The increased risk of developing non-Hodgkin's lymphomas in immunosuppressed rheumatoid arthritis patients compared with the general population appears to be related at least in part to the disease itself. 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 IMURAN can be found under Adverse Reactions.

The dosage that will be tolerated or effective will vary from patient to patient. 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.

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.

The combined use of IMURAN with DMARD’s have not been studied for either added benefit or unexpected adverse effects. The use of IMURAN with these agents cannot be recommended.

Safety and efficacy of azathioprine in children have not been established.

IMURAN should not be used to treat children with rheumatoid arthritis.

IMURAN 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.

There are no adequate and well-controlled studies in pregnant women therefore IMURAN should not be given to patients who are pregnant or likely to become pregnant in the near future without careful assessment of risk versus benefit.

IMURAN can cause fetal harm when administered to a pregnant woman.

IMURAN should not be given during pregnancy or in patients of reproductive potential without careful weighing of risk versus benefit. Use of IMURAN 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.

There have been reports of premature birth and low birth weight following maternal exposure to azathioprine, particularly in combination with corticosteroids. There have also been reports of spontaneous abortion following either maternal or paternal exposure. IMURAN 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.

Leukopenia and/or thrombocytopenia have been reported in a proportion of neonates whose mothers took azathioprine throughout their pregnancies. Extra care in hematological monitoring is advised during pregnancy.

Limited immunologic and other abnormalities have occurred in a few infants born of renal allograft recipients on IMURAN. 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. Pancytopenia and severe immune deficiency has been reported in a preterm infant whose mother received 125 mg azathioprine and 12.5 mg prednisone daily. There have been two published reports of abnormal physical findings. In one study an infant born with preaxial polydactyly whose mother received azathioprine 200 mg daily and prednisone 20 mg every other day during pregnancy. The second study 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.

The use of IMURAN 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.

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 titers, 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 MYLERAN (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, and 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.

Azathioprine suppresses disease manifestations as well as underlying pathology in animal models of auto-immune disease. For example, the severity of adjuvant arthritis is reduced by azathioprine.

The mechanisms whereby azathioprine affects auto-immune 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.

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.

Azathioprine is well absorbed following oral administration. Maximum serum radioactivity occurs at one to two hours after oral 35S-azathioprine and decays with a half-life of five hours. This is not an estimate of the half-life of azathioprine itself but is the decay rate for all 35S-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 (<1 μg/mL). Blood levels are of little predictive value for therapy since the magnitude and duration of clinical effects correlate with thiopurine nucleotide levels in tissues rather than with plasma drug levels. Azathioprine and mercaptopurine are moderately bound to serum proteins (30%) and are partially dialyzable.

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 eight hours. Conversion to inactive 6-thiouric acid by xanthine oxidase is an important degradative pathway, and the inhibition of this pathway in patients receiving ZYLOPRIM (allopurinol) is the basis for the azathioprine dosage reduction required in these patients (see 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.