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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. 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). 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.
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. 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. 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 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.
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. Currently, 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.
Renal impairment: No dose adjustment is required.
Hepatic impairment: The clearance of sirolimus may be reduced in patients with impaired hepatic function. 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. 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.
Method of administration: Rapamune is for oral use only. To minimise variability, Rapamune should consistently be taken either with or without food. Grapefruit juice should be avoided
For full details see prescribing information.
Prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that it be used initially in combination with cyclosporine micro-emulsion and corticosteroids for 2 to 3 months. May be continued as maintenance therapy with corticosteroids only if cyclosporine can be progressively discontinued.
Hypersensitivity to sirolimus or any of the excipients.
Rapamune has not been adequately studied in renal transplent patients at high immunological risk, therefore use is not recommended in this group of patients. In enal transplent patients with delayed graft function, sirolimus may delay recovery of renal function.
Hypersensitivity reactions: Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus.
Immunosuppressive agents (Renal transplent patients only): Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimus in combination with other immunosuppressive agents has not been extensively investigated. Renal function should be monitored during concomitant administration of Rapamune and ciclosporin. Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function. Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin. The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended. Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting. Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune. New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study.
Based on information from an open-label randomised study, conversion from the calcineurin inhibitor tacrolimus to Rapamune in maintenance renal transplant patients was associated with an unfavourable safety profile without efficacy benefit and can therefore not be recommended.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy (HUS/TTP/TMA).
HMG-CoA reductase inhibitors: In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors and/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should be monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse reactions, as described in the respective Summary of Product Characteristics of these agents.
Cytochrome P450 isozymes: Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is not recommended.
Angioedema: The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitors has resulted in angioneurotic oedema-type reactions. Elevated sirolimus levels, for example due to interaction with strong CYP3A4 inhibitors, (with/without concomitant ACE inhibitors) may also potentiate angioedema. In some cases, the angioedema has resolved upon discontinuation or dose reduction of Rapamune.
Increased rates of biopsy confirmed acute rejection (BCAR) in renal transplant patients have been observed with concomitant use of sirolimus with ACE inhibitors. Patients receiving sirolimus should be monitored closely if taking ACE inhibitors concomitantly.
Vaccination: Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided during treatment with Rapamune.
Malignancy: Increased susceptibility to infection and the possible development of lymphoma and other malignancies, particularly of the skin, may result from immunosuppression. As usual for patients with 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.
Infections: Oversuppression of the immune system can also increase susceptibility to infection, including opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis. Among these conditions in renal transplant patients are BK virus-associated nephropathy and JC virus-associated progressive multifocal leukoencephalopathy (PML). These infections are often related to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal function or neurological symptoms. Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation. Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, particularly for patients at increased risk for CMV disease.
Hepatic impairment: In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one half is recommended based on decreased clearance. Since half-life is prolonged in these patients, therapeutic monitoring of the medicinal product after a loading dose or a change of dose should be performed for a prolonged period of time until stable concentrations are reached.
Lung and liver transplant populations: The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore such use is not recommended. In two clinical studies in de novo liver transplant patients, the use of sirolimus plus ciclosporin or tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or death. A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor (CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen 6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at 12 months (-4.45 ml/min and -3.07 ml/min, respectively). The study also failed to demonstrate non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus conversion group compared to the CNI continuation group. The rate of death in the sirolimus conversion group was higher than the CNI continuation group, although the rates were not significantly different. The rates of premature study discontinuation, adverse events overall (and infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group. Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.
Systemic effects: There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele in renal transplant patients and wound dehiscence. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature. There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, pleural effusion and pericardial effusions (including haemodynamically significant effusions in children and adults), in patients receiving Rapamune.
The use of Rapamune was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune should be monitored for hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.
Ethanol: Rapamune oral solution contains up to 3.17 vol % ethanol (alcohol). A 6 mg loading dose contains up to 150 mg of alcohol which is equivalent to 3.80 ml beer or 1.58 ml wine. This dose could potentially be harmful for those suffering from alcoholism and should be taken into account in children and high-risk groups such as patients with liver disease or epilepsy. Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to be too low to be harmful.
Pregnancy and lactation: Should not be used during pregnancy unless clearly necessary. Effective contraception must be used during therapy and for 12 weeks after end of therapy. Nursing should be discontinued during therapy.
For full details see prescribing information.
The most commonly reported adverse reactions (occurring in > 10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).
The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases.
See prescribing information for full details.
Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin
or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Coadministration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended.
See prescribing information for full details.
Pregnancy and Lactation
Women of childbearing potential: Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped
Pregnancy: There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Rapamune should not be used during pregnancy unless clearly necessary. Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped.
Breast-feeding: Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during therapy.
Fertility: Impairments of sperm parameters have been observed among some patients treated with Rapamune. These effects have been reversible upon discontinuation of Rapamune in most cases.
For full details see prescribing information.
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 Side Effects. 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.
Storage: Store in a refrigerator (2ºC – 8ºC). Store in the original bottle in order to protect from light. If necessary, the patient may store the bottles at room temperatures up to 25ºC for a short period of time (24 hours).
Shelf-life: 30 days for opened bottle.
24 hours in the dosing syringe (at room temperature, but not to exceed 25ºC).
After dilution (see section 6.6), the preparation should be used immediately.