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Rapamune Data Sheet. Medsafe

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Rapamune Data Sheet. Medsafe NEW ZEALAND DATA SHEET 1. PRODUCT NAME RAPAMUNE® 0.5 mg, 1 mg and 2 mg tablets RAPAMUNE® 1 mg/mL oral solution 2. QUALITATIVE AND QUANTITATIVE COMPOSITION Each 0.5 mg tablet contains 0.5 mg sirolimus. Each 1 mg tablet contains 1 mg sirolimus. Each 2 mg tablet contains 2 mg sirolimus. Each mL of oral solution 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 6.1. 3. PHARMACEUTICAL FORM Rapamune 0.5 mg tablets: Tan triangular-shaped sugar coated tablet marked “RAPAMUNE 0.5 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 solution: Pale yellow to yellow solution. 4. CLINICAL PARTICULARS 4.1 Therapeutic Indications Rapamune is indicated for the prophylaxis of organ rejection in patients at mild to moderate immunological risk receiving renal transplants. Therapeutic drug monitoring of sirolimus is required. Version: pfdrapaa10919 Supersedes: pfdrapaa10619 Page 1 of 34 4.2 Dose and Method of Administration Dose 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 prescribed the solution and instructed in its use. Do not halve tablet. Dose equivalence when the tablet is divided has not been established. Only physicians experienced in immunosuppressive therapy and management of organ transplant patients should prescribe 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. 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 ciclosporin and corticosteroids (see section 4.4, De novo Use without Calcineurin Inhibitor (CNI)). Elimination of ciclosporin 2 to 4 months after transplantation should be considered. Rapamune with Ciclosporin 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. 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 ciclosporin oral solution and/or ciclosporin capsules (see section 4.5, Inhibitors and Inducers of Cytochrome P450 3A4 (CYP3A4), Ciclosporin (CYP3A4 substrate)). Rapamune should be taken consistently either with or without food. It should not be taken with grapefruit juice. Rapamune Maintenance Regimen with Ciclosporin Withdrawal After 2 to 4 months, ciclosporin 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 long half-life and patients should be retained on their daily maintenance Version: pfdrapaa10919 Supersedes: pfdrapaa10619 Page 2 of 34 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. 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. 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. Dose Adjustment 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. 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 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. It is not necessary to modify the Rapamune loading dose (see section 5.2, 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 ciclosporin 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 subsection below): Version: pfdrapaa10919 Supersedes: pfdrapaa10619 Page 3 of 34 1. in patients receiving concentration-controlled Rapamune 2. in patients with hepatic impairment 3. when inducers (e.g. rifampicin, rifabutin) or inhibitors (e.g. ketoconazole) of CYP3A4 and P-glycoprotein (P-gp) are concurrently administered and after their discontinuation and/or 4. if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements. Therapeutic drug monitoring should not be the sole basis for adjusting sirolimus therapy. Careful attention should also be paid to clinical signs/symptoms, tissue biopsies, and laboratory parameters. To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours after the ciclosporin dose and consistently either with or without food (see section 5.2, Effect of Food). Optimally, adjustments in Rapamune dosage should be based on more than a single trough level obtained >5 days after a previous dosing change. Patients can be switched from the oral solution to the tablet formulation on a mg per mg basis; however, it is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations to confirm that the trough concentration is within the recommended target range. Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/ml (chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and consequently, sirolimus levels will decrease when ciclosporin is discontinued unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of ciclosporin elimination. Assay Methodology The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. Adjustments to the targeted range should be made according to the assay utilised to determine sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. Version: pfdrapaa10919 Supersedes: pfdrapaa10619 Page 4 of 34 Monitoring Advice Monitoring of triglycerides should be included as part of routine post-transplant patient management (see section 4.4, Hyperlipidaemia) Method of Administration Instructions for Dilution and Administration of Rapamune Oral Solution The dosing syringe
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