TEVA-AZATHIOPRINE

2 Recommended Dose and Dosage Adjustment Renal Homotransplantation The dose of TEVA-AZATHIOPRINE (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. TEVA-AZATHIOPRINE is usually given as a single daily dose on the day of, and in a minority of cases one to three days before, transplantation. TEVA-AZATHIOPRINE 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 TEVA-AZATHIOPRINE should not be increased to toxic levels because of threatened rejection.

Discontinuation may be necessary for severe TEVA-AZATHIOPRINE Product Monograph Page 6 of 35 hematologic or other toxicity, even if rejection of the homograft may be a consequence of drug withdrawal. Rheumatoid Arthritis TEVA-AZATHIOPRINE is usually given on a daily basis.

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.

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. TEVA-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.

5 mg/kg or approximately 25 mg daily every four weeks, while other therapy is kept constant. The optimum duration of maintenance TEVA-AZATHIOPRINE has not been determined. TEVA- AZATHIOPRINE can be discontinued abruptly, but delayed effects are possible.

Rest, physiotherapy and salicylates should be continued while TEVA-AZATHIOPRINE is given, but it may be possible to reduce the dose of corticosteroids in patients on TEVA- AZATHIOPRINE. Use in Renal Dysfunction Relatively oliguric patients, especially those with tubular necrosis in the immediate post- cadaveric transplant period, may have delayed clearance of TEVA-AZATHIOPRINE or its metabolites, or be particularly sensitive to this drug, and are usually given lower doses.

). 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 TEVA-AZATHIOPRINE Product Monograph Page 11 of 35 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. Hypersensitivity Patients with a history of hypersensitivity reaction to 6-mercaptopurine should not be prescribed azathioprine.

Macrophage activation syndrome Macrophage activation syndrome (MAS) is a known, life-threatening disorder that may develop in patients with autoimmune conditions, in particular with inflammatory bowel disease (IBD), and there could potentially be an increased susceptibility for developing the condition with the use of azathioprine.

If MAS occurs, or is suspected, evaluation and treatment should be started as early as possible, and treatment with azathioprine should be discontinued. Physicians should be attentive to symptoms of infection such as EBV and cytomegalovirus (CMV), as these are known triggers for MAS.

1 Pregnant Women 04/2024 TABLE OF CONTENTS Sections or subsections that are not applicable at the time of authorization are not listed. 1 Pediatrics ......................................................................................................................

2 Geriatrics…………………………………………………………………………………………………………………….. 2 Breast-feeding…………………………………………………………………………………………………….. 3 Pediatrics……………………………………………………………………………………………………………. 4 Geriatrics…………………………………………………………………………………………………………….. 14 8 ADVERSE REACTIONS .....................................................................................................

1 Adverse Reaction Overview……………………………………………………………………………………. 2 Clinical Trial Adverse Reactions…………………………………………………………………………………. 5 Post-Market Adverse Reactions……………………………………………………………………………… 16 9 DRUG INTERACTIONS .....................................................................................................

7 Drug-Laboratory Test Interactions………………………………………………………………………….. 18 10 CLINICAL PHARMACOLOGY ............................................................................................ 1 Mechanism of Action……………………………………………………………………………………………..

2 Pharmacodynamics……………………………………………………………………………………………….. 3 Pharmacokinetics………………………………………………………………………………………………….. 19 11 STORAGE, STABILITY AND DISPOSAL .............................................................................. 21 12 SPECIAL HANDLING INSTRUCTIONS................................................................................

21 PART II: SCIENTIFIC INFORMATION.......................................................................................... 22 13 PHARMACEUTICAL INFORMATION.................................................................................

22 14 CLINICAL TRIALS ............................................................................................................. 3 Comparative Bioavailability Studies……………………………………………………………………….. Error! Bookmark not defined. 16 NON-CLINICAL TOXICOLOGY...........................................................................................

TEVA-AZATHIOPRINE is contraindicated in patients who are hypersensitive to this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.