RAPAMUNE Coated tablet Ref.[8468] Active ingredients: Sirolimus

Posology

Prophylaxis of organ rejection

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

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:

• in patients with hepatic impairment
• when inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5) and/or
• 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 chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents. Adjustments to the targeted range should be made according to the assay being utilised to determine the 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. Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus.

Patients with sporadic lymphangioleiomyomatosis (S-LAM)

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

For patients with S-LAM, the initial Rapamune dose should be 2 mg/day. Sirolimus whole blood trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain concentrations between 5 to 15 ng/mL.

In most patients, dose adjustments can be based on simple proportion: new Rapamune dose=current dose x (target concentration/current concentration). Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once Rapamune maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every 3 months.

Data from controlled studies for treatment of S-LAM longer than one year are currently not available, therefore the benefit of treatment should be reassessed when used long-term.

Special populations

Black population

There is limited information indicating that Black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-Black patients. The efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in Black recipients.

Elderly

Clinical studies with Rapamune oral solution did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2). In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune be reduced by approximately one-half.

It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function (see Therapeutic monitoring of the medicinal product and dose adjustment). It is not necessary to modify the Rapamune loading dose.

In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until 3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or after loading dose due to the delay in reaching steady-state because of the prolonged half-life.

Paediatric population

The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not been established.

Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a posology can be made.

Method of administration

Rapamune is for oral use only.

Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and therefore this cannot be recommended.

To minimise variability, Rapamune should consistently be taken either with or without food.

Grapefruit juice should be avoided (see section 4.5).

Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths (see section 5.2).

At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. In general, the adverse effects of overdose are consistent with those listed in section 4.8. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte and plasma protein binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent.

Rapamune 0.5 mg coated tablets: 2 years.

Rapamune 1 mg coated tablets: 3 years.

Rapamune 2 mg coated tablets: 3 years.

Do not store above 25°C.

Keep the blister in the outer carton in order to protect from light.

Clear polyvinyl chloride (PVC)/polyethylene (PE)/polychlorotrifluoroethylene (Aclar) aluminium blister packages of 30 and 100 tablets.

Not all pack sizes may be marketed.

Any unused medicinal product or waste material should be disposed of in accordance with local requirements.