Immunosuppressive Agent

GlaxoSmithKline Inc. 7333 Mississauga Road Mississauga, Ontario L5N 6L4

Date of Revision: February 27, 2007 Control No: 109525

(c)

2007 GlaxoSmithKline Inc., All Rights Reserved

(r)

IMURAN and ZYLOPRIM are registered trademarks, GlaxoSmithKline Inc.

Table of Contents

PART I: HEALTH PROFESSIONAL INFORMATION 3

SUMMARY PRODUCT INFORMATION 3 INDICATIONS AND CLINICAL USE 3 CONTRAINDICATIONS 3 WARNINGS AND PRECAUTIONS 4 ADVERSE REACTIONS 8 DRUG INTERACTIONS 10 DOSAGE AND ADMINISTRATION 11 OVERDOSAGE 12 ACTION AND CLINICAL PHARMACOLOGY 13 STORAGE AND STABILITY 14 SPECIAL HANDLING INSTRUCTIONS 15 DOSAGE FORMS, COMPOSITION AND PACKAGING 15

PART II: SCIENTIFIC INFORMATION 16

PHARMACEUTICAL INFORMATION 16 CLINICAL TRIALS 17 TOXICOLOGY 17 REFERENCES 20

PART III: CONSUMER INFORMATION. 23

PrIMURAN(r)

Azathioprine Tablets, USP (50 mg azathioprine)

Azathioprine sodium for Injection, Manufacturer's Standard (50 mg azathioprine per vial)

PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION

CONTRAINDICATIONS

• IMURAN(r) (azathioprine) should not be given to patients who have shown hypersensitivity to the drug.

WARNINGS AND PRECAUTIONS

IMURAN(r) is mutagenic and carcinogenic and may increase the patients' risk of neoplasia, in particular lymphoma and skin cancer (see Carcinogenesis and Mutagenesis section).

Severe leukopenia and/or thrombocytopenia may occur in patients on IMURAN(r) (see Hematologic section).

Increased susceptibility to infection. (See Warnings and Precautions).

IMURAN(r) can cause fetal harm when administered to a pregnant woman (see Pregnant Women section).

Transplantation

Only physicians experienced in immunosuppressive therapy and management of organ transplant should prescribe Imuran(r) (Azathioprine). Patients receiving the drug should be managed in facilities equipped and staffed with adequate laboratory and supportive medical resources. The physician responsible for maintenance therapy should have complete information requisite for the follow-up of the patient.

Rheumatiod Arthritis

Careful monitoring of Imuran(r) treated patients is mandatory. Imuran(r) should only be prescribed for rheumatoid arthritis by physicians experienced with the use of immunosuppressants.

General

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

Carcinogenesis and Mutagenesis

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(r). IMURAN(r) 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(r). 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(r) can be found under ADVERSE REACTIONS.

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

Hematologic

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

Immune

Patients receiving IMURAN(r) 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.

Sexual Function/Reproduction

IMURAN(r) 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.

Special Populations

Pregnant Women: There are no adequate and well-controlled studies in pregnant women therefore IMURAN(r) 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(r) can cause fetal harm when administered to a pregnant woman. IMURAN(r) should not be given during pregnancy or in patients of reproductive potential without careful weighing of risk versus benefit. Use of IMURAN(r) 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(r) 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(r). 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. Nursing Women: The use of IMURAN(r) 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.

Pediatrics (< 18 years of age)

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

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

Geriatrics (> 65 years of age):

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

DRUG INTERACTIONS

Overview

Drug-Drug Interactions

Allopurinol: The principal pathway for detoxification of IMURAN(r) is inhibited by allopurinol. In patients receiving IMURAN(r), the concomitant administration of ZYLOPRIM(r) (allopurinol) will require a reduction in dose to approximately 1/3 to 1/4 of the usual dose of IMURAN(r). Subsequent adjustment of doses of IMURAN(r) 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: IMURAN(r) may inhibit the anticoagulant effect of warfarin. Non-depolarizing muscle relaxants: There is clinical evidence that IMURAN(r) 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).

DOSAGE AND ADMINISTRATION

Recommended Dose and Dosage Adjustment

Renal Homotransplantation

The dose of IMURAN(r) (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(r) 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(r) 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(r) 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

IMURAN(r) is usually given on a daily basis. The initial dose should be approximately 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(r) 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(r) has not been determined. IMURAN(r) can be discontinued abruptly, but delayed effects are possible. Rest, physiotherapy and salicylates should be continued while IMURAN(r) is given, but it may be possible to reduce the dose of corticosteroids in patients on IMURAN(r).

Use in Renal Dysfunction

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

Parenteral Administration

FOR INTRAVENOUS USE ONLY. A 50mg vial should be reconstituted with 5 to 15 mL Sterile Water for Injection, however to obtain a nominal concentration of 10mg/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.

Reconstitution:

Parenteral Products:

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.

Intravenous Infusion

: 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.

OVERDOSAGE

Initial symptoms are nausea and vomiting; and symptoms appearing later are leukopenia, thrombocytopenia, hepatic necrosis and anorexia. For the treatment of overdosage, administer gastric lavage and fluids; blood transfusions may be needed due to suppression of the proliferation of granulocytes. About 30% of IMURAN(r) (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 IMURAN(r). The immediate toxic reactions were nausea, vomiting, and diarrhea, followed by mild leukopenia and mild abnormalities in liver function. The white blood cell count, SGOT, and bilirubin returned to normal 6 days after the overdose.

ACTION AND CLINICAL PHARMACOLOGY

Mechanism of Action

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 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.

Pharmacodynamics

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(r) (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.

Pharmacokinetics

Metabolism

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 ug/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(r) (allopurinol) is the basis for the azathioprine dosage reduction required in these patients (see Drug Interactions under PRECAUTIONS). 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.

STORAGE AND STABILITY

IMURAN(r) Tablets should be stored in a dry place between 15 and 25 C, protected from light. IMURAN(r) for Injection should be stored between 15 and 25 C and protected from light. Single dose vials. Discard unused portion.

SPECIAL HANDLING 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 1000 C or more. Sealed containers may explode. Personnel regularly involved in the preparation and handling of cytotoxic agents should have bi-annual blood examinations.

DOSAGE FORMS, COMPOSITION AND PACKAGING

IMURAN(r) (azathioprine) Tablet 50 mg is a yellow to off-white tablet with an overlapping circle (dumbell) shape, imprinted "IMURAN(r) 50" on one side and with converging scored lines on the other side. IMURAN(r) Tablets are available in bottles of 100 tablets. IMURAN(r) Tablets contain 50 mg azathioprine and the following non-medicinal ingredients: lactose, magnesium stearate, potato starch, povidone, and stearic acid. IMURAN(r) for Injection is available as sterile lyophilized material. Each 17 mL single dose vial contains the equivalent of 50 mg azathioprine as sodium salt. IMURAN(r) for Injection vials contain 50 mg azathioprine sterile lyophilized material as the sodium salt, and sodium hydroxide to adjust pH.

PART II: SCIENTIFIC INFORMATION

PHARMACEUTICAL INFORMATION

Drug Substance

Proper name:

Azathioprine

Chemical name: 1H-Purine, 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]- [USAN] Chemical Name: 6-[(1-methyl-4-nitro-1H-imidazol-5-yl)thio]-1H-purine [Chem. Abstr.] Molecular formula and molecular mass: Molecular formula: Base: C9H7N7O2S Sodium salt: C9H6N7NaO2S Molecular weight: Base: 277.27 Sodium salt: 299.24 Structural formula: Physicochemical properties:

Description:

Azathioprine, a pale yellow, odorless powder, is insoluble in water, but may be dissolved with addition of one molar equivalent of alkali. The sodium salt of azathioprine is sufficiently soluble to make a 10 mg/mL water solution. Azathioprine is stable in solution at neutral or acid pH, but hydrolysis to mercaptopurine occurs in excess sodium hydroxide (0.1 N), especially on warming. Conversion to mercaptopurine also occurs in the presence of sulfhydryl compounds such as cysteine, glutathione and hydrogen sulfide.

CLINICAL TRIALS

Renal Homotransplantation

IMURAN(r) (azathioprine) is indicated as an adjunct for the prevention of rejection in renal homotransplantation. Experience with over 16 000 transplants shows a five-year patient survival of 35% to 55%, but this is dependent on donor, match for HLA antigens, antidonor or anti B-cell alloantigen antibody and other variables. The effect of IMURAN(r) on these variables has not been tested in controlled trials.

Rheumatoid Arthritis

IMURAN(r) is indicated only in adult patients meeting criteria for classic or definite rheumatoid arthritis as specified by the American Rheumatism Association. IMURAN(r) 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). Rest, physiotherapy and salicylates should be continued while IMURAN(r) is given, but it may be possible to reduce the dose of corticosteroids in patients on IMURAN(r). The combined use of IMURAN(r) with DMARD's have not been studied for either added benefit or unexpected adverse effects. The use of IMURAN(r) with these agents cannot be recommended.

TOXICOLOGY

Acute toxicity studies in mice and rats showed a species variation and a somewhat lower toxicity when azathioprine was administered orally than when it was given intraperitoneally. The single LD50 dose in mice is 650 mg/kg, intraperitoneally, and about 2500 mg/kg, orally. In rats, the single LD50 is 310 mg/kg, intraperitoneally, and 400 mg/kg, orally. Death after an LD50 dose, and even after an LD100 dose, was delayed two to seven days. Subacute toxicity studies also demonstrated the cumulative toxicity. When the drug was given to mice for five successive days, the maximum tolerated daily dose was 100 mg/kg intraperitoneally and 200 mg/kg orally. In rats given five consecutive daily doses, the LD50 was 100 mg/kg whether the drug was given intraperitoneally or orally, and in these animals death occurred within a day or two of the last dose. Chronic toxicity studies in rats revealed that all the animals that died of drug toxicity at the two highest dosage levels (60 mg/kg body weight/day and 180 mg/kg body weight/day incorporated in the diet) showed agranulocytic spleens and bone marrows and hemorrhagic lungs. There was also some colloid depletion of the thyroid and failure of spermatogenesis. None of the animals that survived the six-month period showed blood dyscrasias or histological abnormalities. Dogs receiving 1 or 2 mg/kg body weight/day orally for 18 weeks showed a normal weight gain and no hematologic changes. Of four dogs receiving 4 mg/kg/day orally for 18 weeks, two had episodes of fever during the last six weeks and one of these died of pneumonia and had evidence of bone marrow depression. The other two dogs maintained a normal hematologic picture. Two dogs (including the one that died) showed reduced weight gain; the other two dogs that survived the dosage of 4 mg/kg/day showed at autopsy discolored and mottled lungs but no histological abnormalities in the liver, spleen, kidneys, testes, adrenals, pancreas or myocardium. Bone marrows showed normal cellularity. A dog given ten doses of 10 mg/kg, orally, over a 12-day period became moribund four days after the last dose and had agranulocytosis and acute ulcers of the anal and rectal region with tissue necrosis. At a dose of 7.5 mg/kg given orally for ten doses, a dog maintained its weight and showed a normal white blood cell count for several months after the study; the red blood cell count was slightly depressed to 3.7 million two weeks after the final dose, but the count gradually returned to normal. At a dose of 5 mg/kg for ten doses, a dog maintained its weight and continued to show a normal blood picture for several months. Dogs with kidney homografts generally tolerated doses of 10 mg/kg/day, orally, for two days followed by maintenance doses of 2.5 mg to 4 mg/kg/day. The hepatotoxic potential of azathioprine was studied by Starzl et al. in 18 normal dogs. Azathioprine alone was administered for 40 days in the same dosage as used for prevention of homograft rejection. There were declines in hematocrit, weight loss and elevations of SGOT, SGPT and alkaline phosphatase. These changes tended to occur early suggesting that the liver injury was due to direct hepatotoxicity. Although there was usually a partial recovery from these biochemical abnormalities, 13 of the 18 dogs had histologic evidence of liver injury at the end of 40 days. The principal histologic alterations were usually in the centrilobular area. As Starzl pointed out, the hepatotoxicity of azathioprine is greater in dogs than in man. This is borne out by the 3% incidence of hepatitis in the cases reported in the Registry.

Carcinogenicity Studies

Rats:

Azathioprine was administered orally in the diet at doses of 0, 3 or 10 mg/kg/day to groups of 70 male and 70 female Sprague-Dawley rats for 90 and 97 consecutive weeks, respectively.

A life-table analysis indicated comparable cumulative survival of the control and 3 mg/kg/day female group. Survival of the male 3 mg/kg/day group began to diverge from the control group by day 600. Reduced cumulative survival of the male and female 10 mg/kg/day groups compared to the controls began by 450 and 350 days respectively. There were no effects on food consumption. The mean weight of the 10 mg/kg group was lower than the untreated control group mean. There was a marked depletion of body fat in the 10 mg/kg/day rats. An increased incidence of neoplasms of the skin, ear canal (including the auditory sebaceous or Zymbal's gland) and preputial gland was associated with azathioprine administration. The presence of a few neoplasms of the nonglandular stomach in the treated males was considered potentially significant due to their rare spontaneous occurrence. Two mucinous adenocarcinomas of the duodenum, which were noted in the male 3 mg/kg/day group, were considered possibly significant.

Mice:

A study was carried out to determine the carcinogenic effects of azathioprine when given orally in the diet to mice during an 18-month period. Six hundred (300 males and 300 females) clinically healthy 21-day-old mice were used in this study. Mice were randomly assigned to 1 of the 3 following dose groups of 100 males and 100 females: 0 mg/kg/day, 3 mg/kg/day and 10 mg/kg/day.

Mice in the high dose group (10 mg/kg/day) were fed a drug-free diet during dose weeks 21 through 38 because high mortality due to drug toxicity was observed. Otherwise the drug-diet mixture was fed until there was 10 to 20% survival of that sex in any treatment groups. Surviving females were sacrificed after 524 to 530 days on study and surviving males after 600 to 602 days on study. Mice were observed daily and palpated weekly for tumors. Complete necropsies were performed on each mouse after death or sacrifice. Representative sections of all major organs and all tumors were fixed, prepared, and examined histologically from high dose (10 mg/kg/day) and control mice. Target organs and all tumors were examined from low dose (3 mg/kg/day) mice. Azathioprine in the diet significantly reduced the survival of 3 mg/kg/ day females and 10 mg/kg/day males and females. Paleness of the mucous membranes, probably due to anemia, was observed. Significant differences in food consumption and body weights were periodically observed, but they were not consistently present throughout the study. The number of clinically palpable nodules was similar in control and treated mice. At necropsy enlarged thymuses, lymph nodes, and spleens were observed, especially in the high dose group. Cystic endometrial hyperplasia was present in the majority of control and treated females. Histologically, both male and female mice had a dose-related increase (p<.01) in lymphosarcomas. This increased incidence of lymphosarcoma in azathioprine-dose females was also responsible for a significant (p<.01) increase in total malignant and/or malignant plus benign tumors. In treated male mice, the incidence of malignant or malignant plus benign tumors was not significantly increased. Synergistic immunosuppression with N-nitrosobutylurea and azathioprine induced leukemia, mean latent period of 189 days, in 14 of 24 (58%) C57BL mice. Immunosuppression with azathioprine of NZB X NZW mice that had lupus nephritis also increased the incidence of lymphosarcoma. In view of the above, lymphosarcoma as observed in this current study in treated mice may have been secondary to azathioprine immunosuppression. An increased number of squamous cell carcinomas was observed in the preputial area of treated mice, and for purposes of statistical comparison were considered to be of preputial gland origin. Although the total number of these tumors in either treated group of male mice was not significantly greater than the number in controls, a positive dose response was detected statistically. The incidence of spontaneous preputial gland carcinomas reported in the literature is low; therefore, these tumors may have been induced by azathioprine.

Teratology Studies

Reproductive studies have been performed in a variety of species. The administration of azathioprine to pregnant rats and one strain of mice did not produce significant congenital anomalies. However, studies with pregnant rabbits and Swiss-Webster mice have shown that azathioprine has significant teratogenic potential producing resorptions and skeletal anomalies even when administered as late as the midpoint of gestation.

REFERENCES

1. Advisory Committee to the Renal Transplant Registry. The 12th report on the Human Renal Transplant Registry. JAMA 1975; 233:787-796.

2. Cox J, Daneshmend TK, Hawkey CJ, et al. Devastating diarrhoea caused by azathioprine: management difficulty in inflammatory bowel disease. Gut 1988; 29:686-688.

3. Davis JD, Muss HB, Turner RA. Cytotoxic agents in the treatment of rheumatoid arthritis. South Med J 1978; 71(1):58-64.

4. DeWitte DB, Buick MK, Cyran SE, et al. Neonatal pancytopenia and severe combined immunodeficiency associated with antenatal administration of azathioprine and prednisone. J Pediatr 1984; 105(4):625-628.

5. Elion GB, Hitchings GH. Azathioprine, in Handbook of Experimental Pharmacology, Vol. 38/2. Sartorelli and Johns (eds). Springer Verlag, New York, 1975; pp.404-425.

6. Fye K, Talal N. Cytotoxic drugs in the treatment of rheumatoid arthritis.

Rational Drug Ther 1975; 9(4):1-5. Hoover R, Fraumeni JF. Risk of cancer in renal transplant recipients. Lancet 1973; 2:55-57. Hunter T, Urowitz MB, Gordon DA, et al. Azathioprine in rheumatoid arthritis. A long-term follow-up study. Arthritis Rheum 1975; 18(1):15- 20. International Agency for Research on Cancer: Azathioprine. IARC Monographs on the Evaluation of the Carcinogenic Risk of Chemicals to Humans 1981; 26:47-78. Katzka DA, Saul SH, Jorkasky D, et al. Azathioprine and hepatic venocclusive disease in renal transplant patients. Gastroenterology 1986; 90:446-454. Lewis RB, Castor CW, Knisley RE, et al. Frequency of neoplasia in systemic lupus erythematosus and rheumatoid arthritis. Arthritis Rheum 1976; 19(6):1256-1260. Louie S, Schwartz RS. Immunodeficiency and the pathogenesis of lymphoma and leukemia. Semin Hematol 1978; 15(2):117-138. McEwen C. The diagnosis and differential diagnosis of rheumatoid arthritis, in Arthritis and Allied Conditions. Lea and Febiger, Philadelphia, 1972; pp.403-418. McGeown M. Immunosuppression for kidney transplantation. Lancet 1978; 2:310-312. McIntosh J, Hansen P, Ziegler J, et al. Defective immune and phagocytic functions in uremia and renal transplantation. Int Arch Allergy Appl Immunol 1976; 51:544-559. Saarikoski S, Seppalla M. Immunosuppression during pregnancy: Transmission of azathioprine and its metabolites from the mother to the fetus. Am J Obstet Gynec 1973; 115(8):1100-1106. Schusziarra V, Ziekursch V, Schlamp R, et al. Pharmacokinetics of azathioprine under haemodialysis. Int J Clin Pharmacol Biopharm 1976: 14(4):298-302. Schwartz R, Stack J, Dameshek W. Effect of 6-Mercaptopurine on Antibody Production. Proc Soc Exp Biol & Med 1958; 99:164-167. Sieber SM, Adamson RH. Toxicity of antineoplastic agents in man. Adv Cancer Res 1975; 22:57-155. Silman AJ, Petrie J, Hazelman B, et al. Lymphoproliferative cancer and other malignancy in patients with rheumatoid arthritis treated with azathioprine: a 20 year follow up study. Ann Rheum Dis 1988; 47:988- 992. Simmons RL, Thompson EJ, Yunis EJ, et al. 115 patients with first cadaver kidney transplants followed two to seven and a half years. Am J Med 1977; 62:234-242. Starzl TE, Marchioro TL, Porter KA, et al. Factors determining short- and long-term survival after orthotopic liver homotransplantation in the dog. Surgery 1965; 58(1): 131-155. Tagatz GE, Simmons RL. Pregnancy after renal transplantation. Ann Intern Med 1975; 82:113-114. (Editorial) Tallent MB, Simmons RL, Najarian JS. Birth defects in child of male recipient of kidney transplant. JAMA 1970; 211(11):1854-1855. Urowitz MB, Smythe HA, Abel T, et al. Long-term effects of azathioprine in rheumatoid arthritis. Ann Rheum Dis 1982; 41(Suppl):18- 22. Williamson RA, Karp LE. Azathioprine teratogenicity: review of the literature and case report. Obstet Gynecol 1981; 58(2):247-250.

PART III: CONSUMER INFORMATION

PrIMURAN(r) Tablets and Injection azathioprine

This leaflet is part III of a three-part "Product Monograph" published when IMURAN(r) was approved for sale in Canada and is designed specifically for Consumers. This leaflet is a summary and will not tell you everything about IMURAN(r). Contact your doctor or pharmacist if you have any questions about the drug.

ABOUT THIS MEDICATION

"IMURAN(r) 50" on one side and with converging scored lines on the other side. IMURAN(r) Tablets are available in bottles of 100 tablets.

IMURAN(r) for Injection is available as sterile lyophilized powder. Each 17 mL single dose vial contains the equivalent of 50 mg azathioprine as sodium salt.

WARNINGS AND PRECAUTIONS

Serious Warnings and Precautions

IMURAN(r) may increase your risk of developing cancer, especially skin cancer and lymphoma

(r)

What the medication is used for:

IMURAN

can cause a severe decrease in the number of

IMURAN(r), an immunosuppressant agent is used in the

white blood cells and platelets thereby increases your

risk of having infection and unusual bleeding or bruising

(r)

following conditions:

IMURAN

can cause harm to an unborn child when

taken by a pregnant woman

(r)

Renal Homotransplantations: as an adjunct (with other

IMURAN

should be prescribed by doctors who are

medications) in the prevention of rejection of kidney transplants.

• Rheumatoid Arthritis in adult patients who cannot be treated with other medications and treatments.

What it does:

IMURAN(r) belongs to a group of medicines called immunosuppressants. This means that it reduces the strength

of your immune system.

Immunosuppressant medicines are sometimes necessary to help your body accept an organ transplant, such as a new kidney or to treat rheumatoid arthritis where your immune system is reacting against your own body (autoimmune diseases).

When it should not be used:

You should NOT take IMURAN(r) if you:

• are allergic to azathioprine or any of the other ingredients of IMURAN(r)

What the medicinal ingredient is:

Azathioprine

experienced in immunosuppressive therapy and

management of organ transplant

Patients taking immunosuppressive medicines may have an increased risk of developing tumours including skin cancer. Therefore while taking IMURAN(r)tablets you should avoid too much exposure to sunlight. You are advised to wear protective clothing and to use a sunscreen with a high protection factor.

Patients receiving IMURAN(r) alone or in combination with other immunosuppressants, particularly corticosteroids, have shown increased susceptibility to infections.

Infection with chickenpox or shingles can become severe in patients taking immunosuppressive medicine. Therefore you should avoid contact with anyone suffering from chickenpox or shingles.

Patients receiving IMURAN(r) have experienced gastrointestinal hypersensitivity reactions including severe nausea and vomiting.

BEFORE you use IMURAN(r) talk to your doctor or pharmacist if:

What the important non-medicinal ingredients are: IMURAN(r) 50 mg tablets contain the following non-medicinal ingredients: lactose, magnesium stearate, potato starch, povidone, and stearic acid.

IMURAN(r) 50 mg for injection contains the following non- medicinal ingredients: sodium hydroxide to adjust pH.

What dosage forms it comes in:

The IMURAN(r) tablet 50 mg is a yellow to off-white tablet with an overlapping circle (dumbbell) shape, imprinted

you have rheumatoid arthritis and have been previously treated with alkylating agents (cyclophosphamide, chlorambucil, melphalan or others)

are under 18 years of age

you are pregnant or breast feeding

you are planning to have a baby - discuss this with your doctor whether you are male or female

you suffer from liver or kidney disease

you have been told you have any type of cancer

• you have a condition where your body produces too little of a natural chemical called thiopurine methyltransferase (TPMT)

• you have never suffered from chickenpox or shingles

INTERACTIONS WITH THIS MEDICATION

Please inform your doctor or pharmacist if you are taking or have recently taken any other medicines, even those that you have bought yourself without a doctor's prescription.

Certain medicines can interact with IMURAN(r) such as those listed below:

angiotensin-converting enzyme inhibitors such as captopril (used mainly to treat high blood pressure and heart failure)

co-trimoxazole also known as SEPTRA(r) (used to treat infections).

allopurinol (used mainly to treat gout)

curare, d-tubocurarine, tubocurarine, succinylcholine (used during anaesthesia and as muscle relaxants)

warfarin (used to prevent blood clots)

mesalazine, olsalazine or sulphasalazine (used mainly to treat ulcerative colitis).

PROPER USE OF THIS MEDICATION

It is important to take your medicine at the right times. You must take it in the way your doctor has told you to. Swallow the tablet whole, do not break the tablet.

It is important that you and/or your caregivers are aware of the need for safe handling of this medicine. Please consult your pharmacist or doctor for advice.

IMURAN(r) for injection should be given in the hospital through the vein (intravenous infusion).

The amount of IMURAN(r) people take can be very different. Your dose will depend on the condition your doctor is treating.

Your doctor will tell you how long your treatment will last. Do not stop treatment early.

From time to time, while you are taking IMURAN(r), your doctor will want you to have a blood test. This is to check your blood cell count and to change your dose if necessary.

Usual dose for adults for Renal Homotransplantation:

A starting dose of up to 5 mg/kg of your bodyweight is usually given on the first day of therapy.

You will then be given a maintenance dose of IMURAN(r). This is likely to be between 1 to 3 mg/kg bodyweight per day.

Usual dose for adults for Rheumatoid Arthritis:

If you are receiving IMURAN(r) for rheumatoid arthritis the dose given is likely to start at approximately 1 mg/kg of your

bodyweight. Depending on how your treatment is working, your dose may be adjusted, until an optimal maintenance dose

is determined.

Overdose:

If you accidentally take too many tablets tell your doctor or

pharmacist, or contact your nearest hospital emergency department without delay.

Missed Dose:

If you forget to take a dose, do not take extra tablets to make up

for the dose or doses you have missed. When you remember take your next dose at the usual time and continue as before. Speak to your doctor as soon as you can about the doses you may have missed.

SIDE EFFECTS AND WHAT TO DO ABOUT THEM

Like all medicines, IMURAN(r) can cause side effects.

Some people can be allergic to medicines. If you have any of the following symptoms soon after taking IMURAN(r) STOP taking this medicine and tell your doctor immediately or go to the nearest hospital emergency department:

• you develop muscle or bone pain

• you develop kidney problems

• you start feeling faint especially on standing up

• you develop bad diarrhoea and/or abdominal pain

• you develop a serious skin reaction (e.g. blistering and/or peeling)

Tell your doctor immediately if any of the following happen to you while you are taking IMURAN(r):

you start to notice any signs of a fever or an infection

you have any unexpected bruising or bleeding

you develop any new marks on your skin or any change to marks that you may have had previously

you develop a cough or difficulty breathing similar to a chest infection

you have nausea and vomiting

you feel tired, dizzy or generally unwell

you come into contact with anyone who is suffering from chickenpox or shingles.

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

You may notice some hair loss while taking IMURAN(r). Often hair does grow again, even if you carry on taking IMURAN(r). If you are worried ask your doctor.

HOW TO STORE IT

Store between 15degC and 25degC. Protect from light.

Do not take the medicine after the expiry date shown on the tablet pack.

If your doctor tells you to stop taking the tablets, please return any which are left over to your pharmacist. Only keep them if your doctor tells you to.

As with all medicines, keep IMURAN(r) tablets out of reach of children.

REPORTING SUSPECTED SIDE EFFECTS

To monitor drug safety, Health Canada collects information on serious and unexpected effects of drugs . If you suspect you have had a serious or unexpected reaction to this drug you may notify Health Canada by:

toll-free telephone: 866-234-2345

toll-free fax 866-678-6789 By email: cadrmp @hc-sc.gc.ca

By regular mail: National AR Centre

Marketed Health Products Safety and Effectiveness Information Division

Marketed Health Products Directorate Tunney's Pasture, AL 0701C

Ottawa ON K1A 0K9

NOTE: Before contacting Health Canada, you should contact your physician or pharmacist.

MORE INFORMATION

This document plus the full product monograph, prepared for health professionals can be found at:

http://www.gsk.ca or by contacting the sponsor, GlaxoSmithKline Inc.

7333 Mississauga Road Mississauga, Ontario

L5N 6L4

1-800-387-7374

If you notice any side effects not mentioned in this leaflet, tell your doctor or pharmacist.

This leaflet was prepared by GlaxoSmithKline Inc. Last revised: February 27, 2007

(c)

2007 GlaxoSmithKline Inc. All Rights Reserved

(r) IMURAN and SEPTRA are registered trademarks, GlaxoSmithKline Inc.