NEW ZEALAND DATA SHEET - Medsafe

1 Version pfdrapaa10818 Supersedes: pfdrapaa10817 Page 1 of 28 NEW ZEALAND data SHEET 1. PRODUCT NAME RAPAMUNE mg, 1 mg and 2 mg tablets RAPAMUNE 1 mg/mL oral so lut ion. 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each mg tablet contains mg 1 mg tablet contains 1 mg sirolimus. Each 2 mg tablet contains 2 mg sirolimus. Each mL of oral so lution contains 1 mg sirolimus. Excipients with known effect: Rapamune tablets contains lactose and sucrose Rapamune oral solution contains ethanol For the full list of excipients, see section 3.

2 PHARMACEUTICAL FORM Rapamune mg tablets: Tan triangular-shaped sugar coated tablet marked RAPAMUNE mg on one side Rapamune 1 mg tablets: White triangular-shaped sugar coated tablet marked RAPAMUNE 1 mg on one side Rapamune 2 mg tablets: Yellow to beige triangular-shaped sugar coated tablet marked RAPAMUNE 2 mg on one side Rapamune oral so lut ion: Pale yellow to yello w solution. 4. CLINICAL PARTICULARS Therapeutic Indications Rapamune is indicated for the prophylaxis of organ rejection in patients at mild to moderate immunological risk receiving renal transplants.

3 Therapeutic drug monitoring of sirolimus is required. Dose and Method of Administration Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation. Bioavailability has not been determined for tablets after they have been crushed, chewed, or split and therefore this cannot be recommended. Patients unable to take the tablets should be Version pfdrapaa10818 Supersedes: pfdrapaa10817 Page 2 of 28 prescribed the solution and instructed in its use. Do not halve tablet. Dose equivalence when the tablet is divided has not been established.

4 Therapeutic drug monitoring is recommended for all patients receiving Rapamune (see Therapeutic Drug Monitoring subsection below). Adults De Novo Use It is recommended that Rapamune be used initially in a regimen with cyclosporin and corticosteroids (see section , De novo Use Without Calcineurin Inhibitor (CNI)). Elimination of cyclosporin 2 to 4 months after transplantation should be considered. Rapamune with Cyclosporin Therapy (2 to 4 Months Post-Transplantation) The usual dosage regimen for Rapamune is a 6 mg oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily.

5 The Rapamune dose should then be individualised, to obtain whole blood trough levels of 4 to 12 ng/mL (chromatographic assay; see Therapeutic Drug Monitoring subsection below). Two mg of Rapamune oral solution has been demonstrated to be clinically equivalent to 2 mg of Rapamune tablets and hence are interchangeable on a mg to mg basis. However, it is not known if higher doses of Rapamune oral solution are clinically equivalent to higher doses of tablets on a mg to mg basis. It is recommended that sirolimus be taken 4 hours after administration of cyclosporin oral solution and/or cyclosporin capsules (see section , Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4), Cyclosporin (CYP3A4 substrate)).

6 Rapamune should be taken consistently either with or without food. It should not be taken with grapefruit juice. Rapamune Maintenance Regimen with Cyclosporin Withdrawal After 2 to 4 months, cyclosporin should be progressively discontinued over a period of 4 to 8 weeks and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/mL (LC/MS/MS; see Therapeutic Drug Monitoring subsection below). Sirolimus has a lo ng half-life and patients should be retained on their daily maintenance dose for at least 3 days (with a loading dose) or 7-14 days (without a loading dose) before assuming that blood samples drawn at 20-24 hours after dose administration reflect a steady-state level.

7 Dose adjustments based on non-steady-state concentrations may lead to over-dosing. A loading dose should be added to the new maintenance dose when it is necessary to considerably increase sirolimus trough levels: sirolimus loading dose = 3 x [new maintenance dose current maintenance dose]. Dose adjustments can be based on simple proportion: new sirolimus dose = current dose x (new concentration/current concentration). The maximum sirolimus dose administered on any day should not exceed 40 mg. If the estimated dose exceeds 40 mg, then the loading dose should be administered over 2 days.

8 Any significant increase or decrease in sirolimus levels after reaching steady state should be verified by a check on compliance and the use of more than a single trough blood sample. Use in Children and Adolescents There is insufficient experience to recommend the use of sirolimus in children and adolescents. Limited pharmacokinetic information is available in children. Elderly Patients (> 65 years) Clinical studies of Rapamune did not include a sufficient number of patients >65 years of age to determine whether they will respond differently than younger patients.

9 Sirolimus trough concentration data in 35 renal transplant patients >65 years of age were similar to those in the adult population (n=822) from 18 to 65 years of age. Rapamune tablets administered to 12 renal Version pfdrapaa10818 Supersedes: pfdrapaa10817 Page 3 of 28 transplant patients >65 years of age also gave similar results to adult patients (n = 167) 18 to 65 years of age. Patients with Renal Impairment No dosage adjustment is required. Patients with Hepatic Impairment In patients with hepatic impairment, it is recommended that the maintenance dose of sirolimus be reduced by approximately one third to one half.

10 It is not necessary to modify the Rapamune loading dose (see section , Special Populations, Hepatic Impairment). It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function. Therapeutic Drug Monitoring Most patients who received 2 mg of Rapamune 4 hours after cyclosporin had whole blood trough concentrations of sirolimus within the 4 to 12 ng/mL target range (chromatographic assay). Optimal therapy requires therapeutic drug concentration monitoring in all patients. Whole blood sirolimus levels should be closely monitored in the following populations (see Assay Methodology subsect ion below): 1.