Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation.

Posology

Initial therapy (2 to 3 months post-transplantation)

The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose adjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of 4 to 12 ng/mL (chromatographic assay). Rapamune therapy should be optimised with a tapering regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges for the first 2-3 months after transplantation are 150-400 ng/mL (monoclonal assay or equivalent technique) (see section 4.5).

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).

Maintenance therapy

Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/mL (chromatographic assay; see Therapeutic monitoring of the medicinal product and dose adjustment). Rapamune should be given with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted.

Therapeutic monitoring of the medicinal product and dose adjustment

Whole blood sirolimus levels should be closely monitored in the following populations:

(1) in patients with hepatic impairment

(2) when inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5) and/or

(3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements.

Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory parameters.

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 (expressed as chromatographic assay values). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all patients.

Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained more than 5 days after a previous dosing change.

Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis. It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or tablet strength 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.

If further dose adjustment(s) are required during maintenance therapy (after discontinuation of ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune dose = current dose x (target concentration/current concentration). A loading dose should be considered in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough concentrations: Rapamune loading dose = 3 x (new maintenance dose – current maintenance dose). The maximum Rapamune dose administered on any day should not exceed 40 mg. If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading dose(s).

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