1. Name Of The Medicinal Product
Rapamune® 0.5 mg coated tablets
Rapamune® 1 mg coated tablets
Rapamune® 2 mg coated tablets
Rapamune® 1 mg/ml oral solution
2. Qualitative And Quantitative Composition
Each 0.5 mg coated tablet contains 0.5 mg sirolimus.
Each 1 mg coated tablet contains 1 mg sirolimus.
Each 2 mg coated tablet contains 2 mg sirolimus.
Each ml contains 1 mg sirolimus.
Each 60 ml bottle contains 60 mg sirolimus.
Excipients:
Rapamune Tablets:
Each 0.5 mg tablet contains 86.4 mg of lactose monohydrate and 215.7 mg of sucrose.
Each 1 mg tablet contains 86.4 mg of lactose monohydrate and 215.8 mg of sucrose.
Each 2 mg tablet contains 86.4 mg of lactose monohydrate and 214.4 mg of sucrose.
Rapamune Oral Solution:
Each ml contains 20 mg of ethanol and 20 mg of soya oil.
For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Coated tablet (tablet).
0.5 mg: Tan-coloured, triangular-shaped coated tablet marked "RAPAMUNE 0.5 mg" on one side.
1 mg: White-coloured, triangular-shaped coated tablet marked "RAPAMUNE 1 mg" on one side.
2 mg: Yellow to beige-coloured, triangular-shaped coated tablet marked "RAPAMUNE 2 mg" on one side.
or
Oral solution.
Pale yellow to yellow solution
4. Clinical Particulars
4.1 Therapeutic Indications
Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving a renal transplant. It is recommended that Rapamune be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued (see sections 4.2 and 5.1).
4.2 Posology And Method Of Administration
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 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.
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. Currently, the efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in Black recipients.
Elderly population (above 65 years)
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).
For instructions on dilution of the medicinal product before administration, see section 6.6
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).
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
Rapamune oral solution contains soya oil. Patients allergic to peanut or soya must not take this medicine.
4.4 Special Warnings And Precautions For Use
Rapamune has not been adequately studied in patients at high immunological risk, therefore use is not recommended in this group of patients (see section 5.1).
In 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 (see section 4.8).
Concomitant therapy
Immunosuppressive agents
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 (see section 5.1).
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 (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study (see section 4.8). The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients have not been established.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic 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 (see section 4.5).
Angiotensin-converting enzyme inhibitors (ACE)
The concomitant administration of sirolimus and angiotensin-converting enzyme inhibitors has resulted in angioneurotic oedema-type reactions.
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 (see section 4.8). 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 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 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 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 (see sections 4.2 and 5.2). 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 (see sections 4.2 and 5.2).
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 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 in renal transplant patients 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.
Sucrose and lactose
Sirolimus tablets contain sucrose and lactose.
Sucrose
Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.
Lactose
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine.
Ethanol
Rapamune oral solution contains up to 2.5 vol % ethanol (alcohol). A 6 mg loading dose contains up to 150 mg of alcohol which is equivalent to 3 ml beer or 1.25 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.
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
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. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4).
Rifampicin (CYP3A4 inducer)
Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4).
Ketoconazole (CYP3A4 inhibitor)
Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4).
Voriconazole (CYP3A4 inhibitor)
Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).
Diltiazem (CYP3A4 inhibitor)
The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.
Verapamil (CYP3A4 inhibitor)
Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil Cmax and AUC were both increased 1.5-fold, and tmax was decreased 24%. Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.
Erythromycin (CYP3A4 inhibitor)
Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The Cmax, tmax, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.
Ciclosporin (CYP3A4 substrate)
The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA). Sirolimus administered concomitantly (5 mg), and at 2 hours (5 mg) and 4 hours (10 mg) after CsA (300 mg), resulted in increased sirolimus AUC by approximately 183%, 141% and 80%, respectively. The effect of CsA was also reflected by increases in sirolimus Cmax and tmax. When given 2 hours before CsA administration, sirolimus Cmax and AUC were not affected. Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. It is recommended that Rapamune be administered 4 hours after ciclosporin (microemulsion).
Oral contraceptives
No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Rapamune.
Other possible interactions
Moderate and weak inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels (e.g., calcium channel blockers: nicardipine; antifungal agents: clotrimazole, fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol, protease inhibitors).
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g., St. John's Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).
Although sirolimus inhibits human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.
Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.
No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine, prednisolone, and trimethoprim/sulphamethoxazole.
4.6 Pregnancy And Lactation
Women of childbearing potential
Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped (see section 4.5)
Pregnancy
There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). 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 (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
Rapamune has no known influence on the ability to drive and use machines. No studies on the effects on the ability to drive and use machines have been performed.
4.8 Undesirable Effects
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.
The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience.
Within the system organ classes, adverse reactions are listed under headings of frequency (number of patients expected to experience the reaction), using the following categories: very common (
Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.
Most patients were on immunosuppressive regimens, which included Rapamune in combination with other immunosuppressive agents.
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*See section below.
Description of selected adverse reactions
Immunosuppression increases the susceptibility to the development of lymphoma and other malignancies, particularly of the skin (see section 4.4).
Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressive multifocal leukoencephalopathy (PML), have been reported in patients treated with immunosuppressants, including Rapamune.
Hepatoxicity has been reported. The risk may increase as the trough sirolimus level increases. Rare reports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.
Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus level increases.
Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary).
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 (see section 5.3).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.
Focal segmental glomerulosclerosis has been reported.
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.
In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12-20 ng/ml in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 ml/min (see section 5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Paediatric population
Controlled clinical studies with posology comparable to that currently indicated for the use of Rapamune in adults have not been conducted in children or adolescents below 18 years of age.
Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of age considered of high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients (see section 4.1).
In another study enrolling renal transplant patients 20 years of age and below that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be EBV seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients who developed PTLD were aged below 18 years.
There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).
4.9 Overdose
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code: L04AA10.
Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and calcium-independent intracellular signal transduction. Studies demonstrated that its effects are mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition of mTOR results in blockage of several specific signal transduction pathways. The net result is the inhibition of lymphocyte activation, which results in immunosuppression.
In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated reactions, such as allograft rejection.
Clinical studies
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin elimination-Rapamune maintenance study, which
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