PRODUCT MONOGRAPH Pr ® RAPAMUNE (Sirolimus Oral Solution and Tablets) Oral Solution: 1mg/mL; Tablets: 1 mg, 2 mg and 5 mg Professed Immunosuppressive agent ®T.M. Wyeth. Date of Revision: Pfizer Canada Inc., Licensee 25 October 2017 17,300 Trans-Canada Highway Kirkland, Quebec H9J 2M5 Control Number: 208129 ©Pfizer Canada Inc. TABLE OF CONTENTS PART I: HEALTH PROFESSIONAL INFORMATION...............................................................3 SUMMARY PRODUCT INFORMATION ...........................................................................3 INDICATIONS AND CLINICAL USE ................................................................................3 CONTRAINDICATIONS ......................................................................................................4 WARNINGS AND PRECAUTIONS ....................................................................................4 ADVERSE REACTIONS ....................................................................................................13 DRUG INTERACTIONS ....................................................................................................25 DOSAGE AND ADMINISTRATION ................................................................................30 OVERDOSAGE ...................................................................................................................35 ACTION AND CLINICAL PHARMACOLOGY ...............................................................36 STORAGE AND STABILITY ............................................................................................46 SPECIAL HANDLING INSTRUCTIONS ..........................................................................46 DOSAGE FORMS, COMPOSITION AND PACKAGING ................................................47 PART II: SCIENTIFIC INFORMATION ....................................................................................49 PHARMACEUTICAL INFORMATION ............................................................................49 CLINICAL TRIALS ............................................................................................................50 DETAILED PHARMACOLOGY .......................................................................................62 TOXICOLOGY ....................................................................................................................64 REFERENCES .....................................................................................................................68 PART III: CONSUMER INFORMATION ..................................................................................72 Rapamune® (sirolimus) Product Monograph Page 2 of 75 Rapamune (Sirolimus Oral Solution and Tablets) PART I: HEALTH PROFESSIONAL INFORMATION SUMMARY PRODUCT INFORMATION Route of Dosage Form / Clinically Relevant Nonmedicinal Administration Strength Ingredients Oral Solution: 1 mg/mL Ethanol Oral Tablets: 1 mg, 2 mg Lactose Monohydrate and 5 mg For a complete listing see DOSAGE FORMS, COMPOSITION AND PACKAGING section. INDICATIONS AND CLINICAL USE Rapamune (sirolimus oral solution and tablets) is indicated for the prophylaxis of organ rejection in patients receiving allogeneic renal transplants: In patients at low to moderate immunological risk, it is recommended that Rapamune be used initially in a regimen with cyclosporine and corticosteroids. Cyclosporine should be withdrawn 2 to 4 months after transplantation and the Rapamune dose should be increased to reach recommended blood concentrations (See DOSAGE AND ADMINISTRATION). In patients at high immunologic risk (defined as Black transplant recipients and/or repeat renal transplant recipients who lost a previous allograft for immunologic reason and/or patients with high-panel reactive antibodies (PRA; peak PRA level > 80%), it is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation (See DOSAGE AND ADMINISTRATION and CLINICAL TRIALS). Thereafter, any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient. Rapamune® (sirolimus) Product Monograph Page 3 of 75 Geriatrics (> 65 years of age): Clinical studies of Rapamune did not include sufficient numbers of patients aged 65 and over to determine whether safety and efficacy differ in this population from younger patients. Based on the finding that blood clearance decreases linearly with age, consideration should be given to reducing the Rapamune dose in patients 65 years of age and over. Pediatrics (< 13 years of age): THE SAFETY AND EFFICACY OF RAPAMUNE IN PEDIATRIC PATIENTS BELOW THE AGE OF 13 YEARS HAVE NOT BEEN ESTABLISHED. CONTRAINDICATIONS Rapamune is contraindicated in patients with a hypersensitivity to sirolimus or its derivatives or any component* of the drug product. *For a complete listing, see the DOSAGE FORMS, COMPOSITION AND PACKAGING section of the Product Monograph. WARNINGS AND PRECAUTIONS Serious Warnings and Precautions Increased susceptibility to infection and the possible development of lymphoma may result from immunosuppression. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should use Rapamune. 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. Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus. The safety and efficacy of sirolimus as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore, such use is not recommended. Rapamune® (sirolimus) Product Monograph Page 4 of 75 General Rapamune is intended for oral administration only. Rapamune has been approved to be administered concurrently with cyclosporine (liquid and microemulsion) and corticosteroids. The efficacy and safety of the use of Rapamune in combination with other immunosuppressive agents has not been established. Use in High Risk Patients The safety and efficacy of cyclosporine withdrawal in high-risk patients have not been adequately studied and it is therefore not recommended. This includes patients with Banff grade III acute rejection or vascular rejection prior to cyclosporine withdrawal, those who are dialysis- dependent, or with serum creatinine > 400 µmol/L (4.5 mg/dL), black patients, re-transplants, multi-organ transplants, and patients with high panel of reactive antibodies. It is recommended that Rapamune be used in combination with cyclosporine and corticosteroids for the first year following transplantation. The safety and efficacy of this combination in high-risk renal transplant patients have not been studied beyond one year. Therefore, after the first year following transplantation any adjustments to the immunosuppressive regimen should be considered on the basis of the clinical status of the patient (See INDICATIONS AND CLINICAL USE, DOSAGE AND ADMINISTRATION, and CLINICAL TRIALS). Antimicrobial Prophylaxis Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly for patients at increased risk for CMV infection. Cases of Pneumocystis carinii pneumonia have been reported in patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for 1 year following transplantation. Carcinogenesis and Mutagenesis Patients receiving immunosuppression regimens involving combinations of drugs, including Rapamune, as part of an immunosuppression regimen are at increased risk of developing lymphomas and other malignancies, particularly of the skin. The risk appears to be related to the intensity and duration of immunosuppression rather than to the use of any specific agent. As Rapamune® (sirolimus) Product Monograph Page 5 of 75 with all patients at an increased risk for skin cancer, exposure to sunlight and UV light should be limited by wearing protective clothing and using a sunscreen with a high protection factor. Also, see TOXICOLOGY - Chronic Toxicology - Carcinogenicity, Mutagenesis, and Impairment of Fertility. Cardiovascular Hyperlipidemia: Increased serum cholesterol and triglycerides requiring treatment may occur in patients treated with Rapamune. The risk/benefit should be considered in patients with established hyperlipidemia before initiating an immunosuppressive regimen including Rapamune. Endocrine and Metabolism Co-administration of Rapamune with strong inhibitors of CYP3A4 and/or P-glycoprotein (P-gp) (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) or strong inducers of CYP3A4 and/or P-gp (such as rifampicin or rifabutin) is not recommended. Sirolimus is extensively metabolized by the CYP3A4 isozyme in the intestinal wall and liver. Inhibitors of CYP3A4 decrease the metabolism of sirolimus and increase sirolimus whole blood concentrations. Inducers of CYP3A4 increase the metabolism of sirolimus and decrease sirolimus whole blood concentrations (see DRUG INTERACTIONS). Hematologic Patients receiving immunosuppressive agents such as Rapamune may develop leukopenia. The development of leukopenia may be related to Rapamune itself, concomitant medications, viral infection, or some