RAPAMUNE 1mg dragees medication leaflet

Rapamune 0.5 mg coated tablets

Rapamune 1 mg coated tablets

Rapamune 2 mg coated tablets

Rapamune 0.5 mg coated tablets

Each coated tablet contains 0.5 mg sirolimus.

Rapamune 1 mg coated tablets

Each coated tablet contains 1 mg sirolimus.

Rapamune 2 mg coated tablets

Each coated tablet contains 2 mg sirolimus.

Rapamune 0.5 mg coated tablets

Each tablet contains 86.4 mg of lactose monohydrate and 215.7 mg of sucrose.

Rapamune 1 mg coated tablets

Each tablet contains 86.4 mg of lactose monohydrate and 215.8 mg of sucrose.

Rapamune 2 mg coated tablets

Each tablet contains 86.4 mg of lactose monohydrate and 214.4 mg of sucrose.

For the full list of excipients, see section 6.1.

Coated tablet (tablet).

Rapamune 0.5 mg coated tablets

Tan-coloured, triangular-shaped, coated tablet marked “RAPAMUNE 0.5 mg” on one side.

Rapamune 1 mg coated tablets

White-coloured, triangular-shaped, coated tablet marked “RAPAMUNE 1 mg” on one side.

Rapamune 2 mg coated tablets

Yellow to beige-coloured, triangular-shaped, coated tablet marked “RAPAMUNE 2 mg” on one side.

Rapamune is indicated for the prophylaxis of organ rejection in adult patients at low to moderateimmunological risk receiving a renal transplant. It is recommended that Rapamune be used initially incombination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Rapamune may becontinued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can beprogressively discontinued (see sections 4.2 and 5.1).

Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis withmoderate lung disease or declining lung function (see sections 4.2 and 5.1).

Prophylaxis of organ rejection

Treatment should be initiated by and remain under the guidance of an appropriately qualified specialistin 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 aspossible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring ofthe medicinal product are available (see Therapeutic monitoring of the medicinal product and doseadjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of4 to 12 ng/mL (chromatographic assay). Rapamune therapy should be optimised with a taperingregimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration rangesfor the first 2-3 months after transplantation are 150-400 ng/mL (monoclonal assay or equivalenttechnique) (see section 4.5).

To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hoursafter the ciclosporin dose, and consistently either with or without food (see section 5.2).

Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should beadjusted 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 givenwith corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot beattempted, the combination of ciclosporin and Rapamune should not be maintained for more than3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should bediscontinued 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 and/or P-glycoprotein (P-gp) are concurrentlyadministered 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 tohave special dosing requirements.

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

Most patients who received 2 mg of Rapamune 4 hours after ciclosporin had whole blood troughconcentrations of sirolimus within the 4 to 12 ng/mL target range (expressed as chromatographic assayvalues). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in allpatients.

Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtainedmore 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 ortablet 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, andconsequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimusdose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both theabsence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressiverequirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus isincreased should correspond to the rate of ciclosporin elimination.

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

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographicmethods. Several assay methodologies have been used to measure the whole blood concentrations ofsirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured byboth chromatographic and immunoassay methodologies. The concentration values obtained by thesedifferent methodologies are not interchangeable. All sirolimus concentrations reported in this

Summary of Product Characteristics were either measured using chromatographic methods or havebeen converted to chromatographic method equivalents. Adjustments to the targeted range should bemade according to the assay being utilised to determine the sirolimus trough concentrations. Sinceresults are assay and laboratory dependent, and the results may change over time, adjustment to thetargeted 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 theirlocal laboratory on the performance of the locally used method for concentration determination ofsirolimus.

Patients with sporadic lymphangioleiomyomatosis (S-LAM)

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

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

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

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 asobserved in non-Black patients. The efficacy and safety data are too limited to allow specificrecommendations for use of sirolimus in Black recipients.

Clinical studies with Rapamune oral solution did not include a sufficient number of patients above65 years of age to determine whether they will respond differently than younger patients (seesection 5.2).

No dose adjustment is required (see section 5.2).

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 Rapamunebe reduced by approximately one-half.

It is recommended that sirolimus whole blood trough levels be closely monitored in patients withimpaired 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 until3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment orafter loading dose due to the delay in reaching steady-state because of the prolonged half-life.

The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have notbeen established.

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

Rapamune is for oral use only.

Bioavailability has not been determined for tablets after they have been crushed, chewed or split, andtherefore 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).

Hypersensitivity to the active substance or to any of the excipients listed in section 6.1.

Rapamune has not been adequately studied in renal transplant patients at high immunological risk,therefore use is not recommended in this group of patients (see section 5.1).

In renal transplant patients with delayed graft function, sirolimus may delay recovery of renalfunction.

Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliativedermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus(see section 4.8).

Concomitant therapy

Immunosuppressive agents (Renal transplant patients only)

Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus,ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimusin 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 withelevated serum creatinine levels. Caution should be exercised when co-administering other agents thatare known to have a deleterious effect on renal function.

Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levelsand lower calculated glomerular filtration rates compared to patients treated with ciclosporin andplacebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin hadlower serum creatinine levels and higher calculated glomerular filtration rates, as well as lowerincidence of malignancy, compared to patients remaining on ciclosporin. The continuedco-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 notrecommended in the de novo renal transplant setting (see section 5.1).

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluatingconversion 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 thepatients in the study (see section 4.8). Based on information from an open-label randomised study,conversion from the calcineurin inhibitor tacrolimus to Rapamune in maintenance renal transplantpatients was associated with an unfavourable safety profile without efficacy benefit and can thereforenot be recommended (see section 5.1).

The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurininhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thromboticmicroangiopathy (HUS/TTP/TMA).

HMG-CoA reductase inhibitors

In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitorsand/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should bemonitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/orfibrate should be monitored for the possible development of rhabdomyolysis and other adversereactions, as described in the respective Summary of Product Characteristics of these agents.

Cytochrome P450 isozymes and P-glycoprotein

Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or the multidrug efflux pump

P-glycoprotein (P-gp) (such as ketoconazole, voriconazole, itraconazole, telithromycin orclarithromycin) may increase sirolimus blood levels and is not recommended.

Co-administration with strong inducers of CYP3A4 and/or P-gp (such as rifampin, rifabutin) is notrecommended.

If co-administration of inducers or inhibitors of CYP3A4 and/or P-gp cannot be avoided, it isrecommended that sirolimus whole blood trough concentrations and the clinical condition of thepatient be monitored while they are concurrently administered with sirolimus and after theirdiscontinuation. Dose adjustments of sirolimus may be required (see sections 4.2 and 4.5).

The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitorshas resulted in angioneurotic oedema-type reactions. Elevated sirolimus levels, for example due tointeraction with strong CYP3A4 inhibitors, (with/without concomitant ACE inhibitors) may alsopotentiate angioedema (see section 4.5). In some cases, the angioedema has resolved upondiscontinuation or dose reduction of Rapamune.

Increased rates of biopsy confirmed acute rejection (BCAR) in renal transplant patients have beenobserved with concomitant use of sirolimus with ACE inhibitors (see section 5.1). Patients receivingsirolimus should be monitored closely if taking ACE inhibitors concomitantly.

Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants,including Rapamune, vaccination may be less effective. The use of live vaccines should be avoidedduring treatment with Rapamune.

Increased susceptibility to infection and the possible development of lymphoma and othermalignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usualfor patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light shouldbe limited by wearing protective clothing and using a sunscreen with a high protection factor.

Oversuppression of the immune system can also increase susceptibility to infection, includingopportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.

Among these conditions in renal transplant patients are BK virus-associated nephropathy and JCvirus-associated progressive multifocal leukoencephalopathy (PML). These infections are often relatedto a high total immunosuppressive burden and may lead to serious or fatal conditions that physiciansshould consider in the differential diagnosis in immunosuppressed patients with deteriorating renalfunction or neurological symptoms.

Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receivingantimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumoniashould 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.

In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closelymonitored. In patients with severe hepatic impairment, reduction in maintenance dose by one-half isrecommended based on decreased clearance (see sections 4.2 and 5.2). Since half-life is prolonged inthese patients, therapeutic monitoring of the medicinal product after a loading dose or a change ofdose should be performed for a prolonged period of time until stable concentrations are reached (seesections 4.2 and 5.2).

Lung and liver transplant populations

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liveror 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 ortacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss ordeath.

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 regimen6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at12 months (-4.45 mL/min and -3.07 mL/min, respectively). The study also failed to demonstratenon-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimusconversion group compared to the CNI continuation group. The rate of death in the sirolimusconversion group was higher than the CNI continuation group, although the rates were notsignificantly different. The rates of premature study discontinuation, adverse events overall (andinfections, specifically), and biopsy-proven acute liver graft rejection at 12 months were allsignificantly 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 transplantpatients when sirolimus has been used as part of an immunosuppressive regimen.

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 massindex (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on datafrom the medical literature.

There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,pleural effusion and pericardial effusions (including haemodynamically significant effusions inchildren and adults), in patients receiving Rapamune.

The use of Rapamune was associated with increased serum cholesterol and triglycerides that mayrequire treatment. Patients administered Rapamune should be monitored for hyperlipidaemia usinglaboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, andlipid-lowering agents should be initiated. The risk/benefit should be considered in patients withestablished hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune.

Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients withsevere refractory hyperlipidaemia.

Sucrose and lactose

Sucrose

Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption orsucrase-isomaltase insufficiency should not take this medicine.

Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency orglucose-galactose malabsorption should not take this medicine.

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 smallintestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced bysubstances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole,itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increasesirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism ofsirolimus 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 concentrationsfollowing a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance ofsirolimus 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 andsirolimus 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 andketoconazole is not recommended (see section 4.4).

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oralvoriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthysubjects 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 diltiazemsignificantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of eitherdiltiazem 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 rateand extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC wereincreased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil Cmax and AUC wereboth increased 1.5-fold, and tmax was decreased 24%. Sirolimus levels should be monitored, andappropriate dose reductions of both medicinal products should be considered.

Erythromycin (CYP3A4 inhibitor)

Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased therate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUCwere increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The Cmax, tmax, and AUC of plasmaerythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levelsshould 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 hoursbefore CsA administration, sirolimus Cmax and AUC were not affected. Single-dose sirolimus did notaffect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administeredsimultaneously or 4 hours apart. It is recommended that Rapamune be administered 4 hours afterciclosporin (microemulsion).

There have been reports of increased blood levels of sirolimus during concomitant use withcannabidiol. Co-administration of cannabidiol with another orally administered mTOR inhibitor in ahealthy volunteer study led to an increase in exposure to the mTOR inhibitor of approximately2.5-fold for both Cmax and AUC, due to inhibition of intestinal P-gp efflux by cannabidiol. Cautionshould be used when cannabidiol and Rapamune are co-administered, closely monitoring for sideeffects. Monitor sirolimus blood levels and adjust the dose as needed (see sections 4.2 and 4.4).

No clinically significant pharmacokinetic interaction was observed between Rapamune oral solutionand 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction studywith an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot excludethe possibility of changes in the pharmacokinetics that might affect the efficacy of the oralcontraceptive during long-term treatment with Rapamune.

Other possible interactions

Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels.

Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole),certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g.ritonavir, indinavir, boceprevir, and telaprevir), nicardipine, bromocriptine, cimetidine, danazol andletermovir.

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 isozymesin vivo since the sirolimus concentrations necessary to produce inhibition are much higher than thoseobserved in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease theefflux 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 ascisapride and metoclopramide.

No clinically significant pharmacokinetic interaction was observed between sirolimus and any of thefollowing substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine,prednisolone, and trimethoprim/sulfamethoxazole.

Interaction studies have only been performed in adults.

Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune hasbeen stopped (see section 4.5).

There are no or limited amount of data from the use of sirolimus in pregnant women. Studies inanimals 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 mustbe used during Rapamune therapy and for 12 weeks after Rapamune has been stopped.

Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactatingrats. It is unknown whether sirolimus is excreted in human milk. Because of the potential for adversereactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during treatmentwith Rapamune.

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).

Rapamune has no known influence on the ability to drive and use machines. No studies on the effectson the ability to drive and use machines have been performed.

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation

The most commonly reported adverse reactions (occurring in 10% of patients) arethrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tractinfection, 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 onpostmarketing experience.

Within the system organ classes, adverse reactions are listed under headings of frequency (number ofpatients expected to experience the reaction), using the following categories: very common (≥1/10);common (≥1/100 to <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000); not known(cannot be estimated from the available data).

Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Most patients were on immunosuppressive regimens, which included Rapamune in combination withother immunosuppressive agents.

System organ Very common Common Uncommon Rare Frequencyclass (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 not known<1/10) <1/100) to (cannot be<1/1,000) estimatedfromavailabledata)

Infections and Pneumonia; Sepsis; Clostridiuminfestations Fungal infection; Pyelonephritis; difficile colitis;

Viral infection; Cytomegalo- Mycobacterial

Bacterial virus infection; infectioninfection; Herpes zoster (including

Herpes simplex caused by the tuberculosis);infection; varicella zoster Epstein-Barr

Urinary tract virus virus infectioninfection

Neoplasms Non-melanoma Lymphoma*; Neuroendobenign, skin cancer* Malignant crinemalignant and melanoma*; carcinomaunspecified Post transplant of the skin*(including cysts lympho-and polyps) proliferativedisorder

Blood and Thrombo- Haemolytic Pancytopaenia;lymphatic cytopaenia; uraemic Thromboticsystem disorders Anaemia; syndrome; thrombo-

Leucopenia Neutropaenia cytopaenicpurpura

Immune system Hyper-disorders sensitivity(includingangioedema,anaphylacticreaction, andanaphylactoidreaction)

Metabolism and Hypokalaemia;nutrition Hypophos-disorders phataemia;

Hyperlipidaemia(includinghypercholesterol-aemia);

Hyperglycaemia;

Hyper-triglyceridaemia;

Diabetes mellitus

Nervous system Headache Posteriordisorders reversibleencephalo-pathysyndrome

System organ Very common Common Uncommon Rare Frequencyclass (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 not known<1/10) <1/100) to (cannot be<1/1,000) estimatedfromavailabledata)

Cardiac Tachycardia Pericardialdisorders effusion

Vascular Hypertension; Venous Lymphoedemadisorders Lymphocele thrombosis(including deepveinthrombosis)

Respiratory, Pulmonary Pulmonary Alveolarthoracic and embolism; haemorrhage proteinosismediastinal Pneumonitis*;disorders Pleuraleffusion;

Epistaxis

Gastrointestinal Abdominal pain; Pancreatitis;disorders Constipation; Stomatitis;

Diarrhoea; Ascites

Nausea

Hepatobiliary Liver function Hepaticdisorders test abnormal failure*(includingalanineaminotransferaseincreased andaspartate amino-transferaseincreased)

Skin and Rash; Dermatitis Hypersen-subcutaneous Acne exfoliative sitivitytissue disorders vasculitis

Musculoskeletal Arthralgia Osteonecrosisand connectivetissue disorders

Renal and Proteinuria Nephroticurinary disorders syndrome (seesection 4.4);

Focalsegmentalglomerulo-sclerosis*

Reproductive Menstrual Ovarian cystsystem and disorderbreast disorders (includingamenorrhoea andmenorrhagia)

System organ Very common Common Uncommon Rare Frequencyclass (≥1/10) (≥1/100 to (≥1/1,000 to (≥1/10,000 not known<1/10) <1/100) to (cannot be<1/1,000) estimatedfromavailabledata)

General Oedema;disorders and Oedemaadministration peripheral;site conditions Pyrexia;

Pain;

Impairedhealing*

Investigations Blood lactatedehydrogenaseincreased;

Blood creatinineincreased

*See section below.

Immunosuppression increases the susceptibility to the development of lymphoma and othermalignancies, particularly of the skin (see section 4.4).

Cases of BK virus-associated nephropathy, as well as cases of JC virus-associated progressivemultifocal leukoencephalopathy (PML), have been reported in patients treated withimmunosuppressants, including Rapamune.

Hepatoxicity has been reported. The risk may increase as the trough sirolimus level increases. Rarereports of fatal hepatic necrosis have been reported with elevated trough sirolimus levels.

Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliteransorganising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectiousaetiology have occurred in patients receiving immunosuppressive regimens including Rapamune. Insome 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 calcineurininhibitor-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 inchildren 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 thesubset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/min (seesection 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).

Ovarian cysts and menstrual disorders (including amenorrhoea and menorrhagia) have been reported.

Patients with symptomatic ovarian cysts should be referred for further evaluation. The incidence ofovarian cysts may be higher in premenopausal females compared to postmenopausal females. In somecases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of Rapamune.

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 ofage considered of high immunologic risk, defined as a history of one or more acute allograft rejectionepisodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). Theuse of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated withan increased risk of deterioration of renal function, serum lipid abnormalities (including, but notlimited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatmentregimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is notindicated 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 toassess the safety of progressive corticosteroid withdrawal (beginning at six monthspost-transplantation) from an immunosuppressive regimen initiated at transplantation that includedfull-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination withbasiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developedpost-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be Epstein-Barrvirus (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 (seesection 4.2).

Undesirable effects observed with patients with S-LAM

Safety was assessed in a controlled study involving 89 patients with LAM, of which 81 patients had

S-LAM and 42 of whom were treated with Rapamune (see section 5.1). The adverse drug reactionsobserved in patients with S-LAM were consistent with the known safety profile of the product for theindication prophylaxis of organ rejection in renal transplantation with the addition of weightdecreased, which was reported in the study at a greater incidence with Rapamune when compared tothat observed with placebo (common, 9.5% vs. common, 2.6%).

Reporting suspected adverse reactions after authorisation of the medicinal product is important. Itallows continued monitoring of the benefit/risk balance of the medicinal product. Healthcareprofessionals are asked to report any suspected adverse reactions via the national reporting systemlisted in Appendix V.

At present, there is minimal experience with overdose. One patient experienced an episode of atrialfibrillation after ingestion of 150 mg of Rapamune. In general, the adverse effects of overdose areconsistent with those listed in section 4.8. General supportive measures should be initiated in all casesof 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.

Pharmacotherapeutic group: Immunosuppressants, ATC code: L04AH01.

Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent andcalcium-independent intracellular signal transduction. Studies demonstrated that its effects aremediated by a mechanism that is different from that of ciclosporin, tacrolimus, and otherimmunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specificcytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of themammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibitionof mTOR results in blockage of several specific signal transduction pathways. The net result is theinhibition of lymphocyte activation, which results in immunosuppression.

In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediatedreactions, such as allograft rejection.

LAM involves lung tissue infiltration with smooth muscle-like cells that harbour inactivatingmutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene functionactivates the mTOR signaling pathway, resulting in cellular proliferation and release oflymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus theproliferation of LAM cells.

Clinical studies

Prophylaxis of Organ Rejection

Patients at low to moderate immunological risk were studied in the phase 3 ciclosporinelimination-Rapamune maintenance study, which included patients receiving a renal allograft from acadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for atleast 6 months after transplantation were included. Ciclosporin was not withdrawn in patientsexperiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serumcreatinine higher than 400 mol/L, or who had inadequate renal function to support ciclosporinwithdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number inthe ciclosporin elimination-Rapamune maintenance studies and are not recommended for thistreatment regimen.

At 12, 24 and 36 months, graft and patient survival were similar for both groups. At 48 months, therewas a statistically significant difference in graft survival in favour of the Rapamune followingciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (includingand excluding loss to follow-up). There was a significantly higher rate of first biopsy-proven rejectionin the ciclosporin elimination group compared to the ciclosporin maintenance group during the periodpost-randomisation to 12 months (9.8% vs. 4.2%, respectively). Thereafter, the difference between thetwo groups was not significant.

The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantlyhigher for patients receiving Rapamune following ciclosporin elimination than for those in the

Rapamune with ciclosporin therapy group. Based upon the analysis of data from 36 months andbeyond, which showed a growing difference in graft survival and renal function, as well assignificantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinuesubjects from the Rapamune with ciclosporin group. By 60 months, the incidence of non-skinmalignancies was significantly higher in the cohort who continued ciclosporin as compared with thecohort who had ciclosporin withdrawn (8.4% vs. 3.8%, respectively). For skin carcinoma, the mediantime to first occurrence was significantly delayed.

The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renaltransplant patients (6-120 months after transplantation) was assessed in a randomised, multicentre,controlled trial, stratified by calculated GFR at baseline (20-40 mL/min vs. above 40 mL/min).

Concomitant immunosuppressive agents included mycophenolate mofetil, azathioprine, andcorticosteroids. Enrollment in the patient stratum with baseline calculated GFR below40 mL/min wasdiscontinued due to an imbalance in safety events (see section 4.8).

In the patient stratum with baseline calculated GFR above 40 mL/min, renal function was notimproved overall. The rates of acute rejection, graft loss, and death were similar at 1 and 2 years.

Treatment emergent adverse events occurred more frequently during the first 6 months after

Rapamune conversion. In the stratum with baseline calculated GFR above 40 mL/min, the mean andmedian urinary protein to creatinine ratios were significantly higher in the Rapamune conversiongroup as compared to those of the calcineurin inhibitors continuation group at 24 months (seesection 4.4). New onset nephrosis (nephrotic syndrome) was also reported (see section 4.8).

At 2 years, the rate of non-melanoma skin malignancies was significantly lower in the Rapamuneconversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%). In asubset of the study patients with a baseline GFR above 40 mL/min and normal urinary proteinexcretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for thecorresponding subset of calcineurin inhibitor continuation patients. The rates of acute rejection, graftloss, and death were similar, but urinary protein excretion was increased in the Rapamune treatmentarm of this subset.

In an open-label, randomised, comparative, multi-centre study where renal transplant patients wereeither converted from tacrolimus to sirolimus 3 to 5 months post-transplant or remained on tacrolimus,there was no significant difference in renal function at 2 years. There were more adverse events(99.2% vs. 91.1%, p=0.002*) and more discontinuations from the treatment due to adverse events(26.7% vs. 4.1%, p<0.001*) in the group converted to sirolimus compared to the tacrolimus group.

The incidence of biopsy confirmed acute rejection was higher (p=0.020*) for patients in the sirolimusgroup (11, 8.4%) compared to the tacrolimus group (2, 1.6%) through 2 years; most rejections weremild in severity (8 of 9 [89%] T-cell BCAR, 2 of 4 [50%] antibody mediated BCAR) in the sirolimusgroup. Patients who had both antibody-mediated rejection and T-cell-mediated rejection on the samebiopsy were counted once for each category. More patients converted to sirolimus developed newonset diabetes mellitus defined as 30 days or longer of continuous or at least 25 days non-stop(without gap) use of any diabetic treatment after randomisation, a fasting glucose ≥126 mg/dL or anon-fasting glucose ≥200 mg/dL after randomisation (18.3% vs. 5.6%, p=0.025*). A lower incidenceof squamous cell carcinoma of the skin was observed in the sirolimus group (0% vs. 4.9%). *Note:p-values not controlled for multiple testing.

In two multi-centre clinical studies, de novo renal transplant patients treated with sirolimus,mycophenolate mofetil (MMF), corticosteroids, and an IL-2 receptor antagonist had significantlyhigher acute rejection rates and numerically higher death rates compared to patients treated with acalcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4). Renalfunction was not better in the treatment arms with de novo sirolimus without a calcineurin inhibitor.

An abbreviated dosing schedule of daclizumab was used in one of the studies.

In a randomised, comparative evaluation of ramipril versus placebo for the prevention of proteinuria inkidney transplant patients converted from calcineurin inhibitors to sirolimus, a difference in thenumber of patients with BCAR through 52 weeks was observed [13 (9.5%) vs. 5 (3.2%), respectively;p=0.073]. Patients initiated on ramipril 10 mg had a higher rate of BCAR (15%) compared to patientsinitiated on ramipril 5 mg (5%). Most rejections occurred within the first six months followingconversion and were mild in severity; no graft losses were reported during the study (see section 4.4).

Sporadic Lymphangioleiomyomatosis (S-LAM) Patients

The safety and efficacy of Rapamune for treatment of S-LAM were assessed in a randomised,double-blind, multicentre, controlled trial. This study compared Rapamune (dose adjusted to5-15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observationperiod in patients with TSC-LAM or S-LAM. Eighty-nine (89) patients were enrolled at 13 study sitesin the United States, Canada, and Japan of which 81 patients had S-LAM; of these patients with

S-LAM, 39 were randomised to receive placebo and 42 to receive Rapamune. The key inclusioncriteria was post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% of predictedduring the baseline visit. In patients with S-LAM, enrolled patients had moderately advanced lungdisease, with baseline FEV1 of 49.2±13.6% (mean ±SD) of the predicted value. The primary endpointwas the difference between the groups in the rate of change (slope) in FEV1. During the treatmentperiod in patients with S-LAM, the mean ±SE FEV1 slope was -12±2 mL per month in the placebogroup and 0.3±2 mL per month in the Rapamune group (p<0.001). The absolute between-groupdifference in the mean change in FEV1 during the treatment period was 152 mL, or approximately11% of the mean FEV1 at enrollment.

As compared with the placebo group, the sirolimus group had improvement from baseline to12 months in measures of forced vital capacity (-12±3 vs. 7±3 mL per month, respectively, p<0.001),serum vascular endothelial growth factor D (VEGF-D; -8.6±15.2 vs. -85.3±14.2 pg/mL per month,respectively, p<0.001), and quality of life (Visual Analogue Scale - Quality of Life [VAS-QOL]score: -0.3±0.2 vs. 0.4±0.2 per month, respectively, p=0.022) and functional performance(-0.009±0.005 vs. 0.004±0.004 per month, respectively, p=0.044) in patients with S-LAM. There wasno significant between-group difference in this interval in the change in functional residual capacity,6-minute walk distance, diffusing capacity of the lung for carbon monoxide, or general well-beingscore in patients with S-LAM.

Rapamune was assessed in a 36-month controlled clinical study enrolling renal transplant patientsbelow 18 years of age considered at high-immunologic risk, defined as having a history of one or moreacute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renalbiopsy. Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/mL) incombination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-basedimmunosuppression without Rapamune. The Rapamune group failed to demonstrate superiority to thecontrol group in terms of the first occurrence of biopsy confirmed acute rejection, graft loss, or death.

One death occurred in each group. The use of Rapamune in combination with calcineurin inhibitorsand corticosteroids was associated with an increased risk of deterioration of renal function, serum lipidabnormalities (including, but not limited to, increased serum triglycerides and total cholesterol), andurinary tract infections (see section 4.8).

An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study whenfull-dose Rapamune was administered to children and adolescents in addition to full-dose calcineurininhibitors with basiliximab and corticosteroids (see section 4.8).

In a retrospective review of hepatic veno-occlusive disease (VOD) in patients who underwentmyeloablative stem cell transplantation using cyclosphophamide and total body irradiation, anincreased incidence of hepatic VOD was observed in patients treated with Rapamune, especially withconcomitant use of methotrexate.

Much of the general pharmacokinetic information was obtained using the Rapamune oral solution,which is summarised first. Information directly related to the tablet formulation is summarisedspecifically in the Oral tablet section.

Oral solution

Following administration of the Rapamune oral solution, sirolimus is rapidly absorbed, with a time topeak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients withstable renal allografts receiving multiple doses. The systemic availability of sirolimus in combinationwith simultaneously administered ciclosporin (Sandimune) is approximately 14%. Upon repeatedadministration, the average blood concentration of sirolimus is increased approximately 3-fold. Theterminal half-life in stable renal transplant patients after multiple oral doses was 62  16 hours. Theeffective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned intoformed blood elements.

Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus isextensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites,including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is themajor component in human whole blood and contributes to greater than 90% of theimmunosuppressive activity. After a single dose of [14C] sirolimus in healthy volunteers, themajority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) wasexcreted in urine.

Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age todetermine whether they will respond differently than younger patients. Sirolimus trough concentrationdata in 35 renal transplant patients above 65 years of age were similar to those in the adult population(n=822) from 18 to 65 years of age.

In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within ageranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for youngerpaediatric patients (580 mL/h/kg) than for older paediatric patients (450 mL/h/kg) as compared withadults (287 mL/h/kg). There was a large variability for individuals within the age groups.

Sirolimus concentrations were measured in concentration-controlled studies of paediatricrenal-transplant patients who were also receiving ciclosporin and corticosteroids. The target for troughconcentrations was 10-20 ng/mL. At steady-state, 8 children aged 6-11 years received mean  SDdoses of 1.75  0.71 mg/day (0.064  0.018 mg/kg, 1.65  0.43 mg/m2) while 14 adolescents aged12-18 years received mean  SD doses of 2.79  1.25 mg/day (0.053  0.0150 mg/kg,1.86  0.61 mg/m2). The younger children had a higher weight-normalised CL/F (214 mL/h/kg)compared with the adolescents (136 mL/h/kg). These data indicate that younger children might requirehigher bodyweight-adjusted doses than adolescents and adults to achieve similar target concentrations.

However, the development of such special dosing recommendations for children requires more data tobe definitely confirmed.

In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean valuesfor sirolimus AUC and t1/2 were increased 61% and 43%, respectively, and CL/F was decreased 33%compared to normal healthy subjects. In severe hepatically impaired patients (Child-Pughclassification C), mean values for sirolimus AUC and t1/2 were increased 210% and 170%,respectively, and CL/F was decreased by 67% compared to normal healthy subjects. The longerhalf-lives observed in hepatically impaired patients delay reaching steady-state.

The pharmacokinetics of sirolimus were similar in various populations, with renal function rangingfrom normal to absent (dialysis patients).

Oral tablet

The 0.5 mg tablet is not fully bioequivalent to the 1 mg, 2 mg and 5 mg tablets when comparing Cmax.

Multiples of the 0.5 mg tablets should therefore not be used as a substitute for other tablet strengths.

In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration ofthe tablet formulation is about 27% higher relative to the oral solution. The mean Cmax was decreasedby 35%, and mean tmax increased by 82%. The difference in bioavailability was less marked uponsteady-state administration to renal transplant recipients, and therapeutic equivalence has beendemonstrated in a randomised study of 477 patients. When switching patients between oral solutionand tablet formulations, it is recommended to give the same dose and to verify the sirolimus troughconcentration 1 to 2 weeks later to assure that it remains within recommended target ranges. Also,when switching between different tablet strengths, verification of trough concentrations isrecommended.

In 24 healthy volunteers receiving Rapamune tablets with a high-fat meal, Cmax, tmax and AUC showedincreases of 65%, 32%, and 23%, respectively. To minimise variability, Rapamune tablets should betaken consistently with or without food. Grapefruit juice affects CYP3A4-mediated metabolism andmust, therefore, be avoided.

Sirolimus concentrations, following the administration of Rapamune tablets (5 mg) to healthy subjectsas single doses are dose proportional between 5 and 40 mg.

Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age todetermine whether they will respond differently than younger patients. Rapamune tablets administeredto 12 renal transplant patients above 65 years of age gave similar results to adult patients (n=167) 18 to65 years of age.

Initial Therapy (2 to 3 months post-transplant): In most patients receiving Rapamune tablets with aloading dose of 6 mg followed by an initial maintenance dose of 2 mg, whole blood sirolimus troughconcentrations rapidly achieved steady-state concentrations within the recommended target range (4 to12 ng/mL, chromatographic assay). Sirolimus pharmacokinetic parameters following daily doses of2 mg Rapamune tablets administered in combination with ciclosporin microemulsion (4 hours prior to

Rapamune tablets) and corticosteroids in 13 renal transplant patients, based on data collected atmonths 1 and 3 after transplantation, were: Cmin,ss 7.39  2.18 ng/mL; Cmax,ss 15.0  4.9 ng/mL; tmax,ss3.46  2.40 hours; AUC,ss 230  67 ng.h/mL; CL/F/WT, 139  63 mL/h/kg (parameters calculatedfrom LC-MS/MS assay results). The corresponding results for the oral solution in the same clinicalstudy were Cmin,ss 5.40  2.50 ng/mL, Cmax,ss 14.4  5.3 ng/mL, tmax,ss 2.12  0.84 hours, AUC,ss194  78 ng.h/mL, CL/F/W 173  50 mL/h/kg. Whole blood trough sirolimus concentrations, asmeasured by LC/MS/MS, were significantly correlated (r2=0.85) with AUC,ss.

Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean(10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 8.6 3.0 ng/mL (5.0 to 13 ng/mL) and 2.1  0.70 mg (1.5 to 2.7 mg), respectively (see section 4.2).

Maintenance therapy: From month 3 to month 12, following discontinuation of ciclosporin, mean(10th, 90th percentiles) troughs (expressed as chromatographic assay values) and daily doses were 19 4.1 ng/mL (14 to 24 ng/mL) and 8.2  4.2 mg (3.6 to 13.6 mg), respectively (see section 4.2).

Therefore, the sirolimus dose was approximately 4-fold higher to account for both the absence of thepharmacokinetic interaction with ciclosporin (2-fold increase) and the augmented immunosuppressiverequirement in the absence of ciclosporin (2-fold increase).

Lymphangioleiomyomatosis (LAM)

In a clinical trial of patients with LAM, the median whole blood sirolimus trough concentration after3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to9.0 ng/mL; n=37). With concentration-control (target concentrations 5 to 15 ng/mL), the mediansirolimus concentration at the end of 12 months of treatment was 6.8 ng/mL (interquartile range 5.9 to8.9 ng/mL; n=37).

Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar toclinical exposure levels and with possible relevance to clinical use, were as follows: pancreatic isletcell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures andcalluses, hepatic haematopoiesis, and pulmonary phospholipidosis.

Sirolimus was not mutagenic in the in vitro bacterial reverse mutation assays, the Chinese Hamster

Ovary cell chromosomal aberration assay, the mouse lymphoma cell forward mutation assay, or thein vivo mouse micronucleus assay.

Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (maleand female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia(female mouse). It is known that malignancies (lymphoma) secondary to the chronic use ofimmunosuppressive agents can occur and have been reported in patients in rare instances. In mouse,chronic ulcerative skin lesions were increased. The changes may be related to chronicimmunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of aspecies-dependent response to lutenising hormone levels and are usually considered of limited clinicalrelevance.

In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversiblereductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weightsand/or histological lesions (e.g., tubular atrophy and tubular giant cells) were observed in rats and in amonkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality andreduced foetal weights (with associated delays in skeletal ossification) (see section 4.6).

Lactose monohydrate

Macrogol

Magnesium stearate

Talc

Rapamune 0.5 mg coated tablets

Macrogol

Glycerol monooleate

Pharmaceutical glaze (shellac)

Calcium sulfate

Microcrystalline cellulose

Sucrose

Titanium dioxide

Yellow iron oxide (E172)

Brown iron oxide (E172)

Poloxamer 188-tocopherol

Povidone

Carnauba wax

Printing ink (Shellac, Iron Oxide Red, Propylene Glycol [E1520], Concentrated Ammonia Solution,

Simethicone)

Rapamune 1 mg coated tablets

Macrogol

Glycerol monooleate

Pharmaceutical glaze (shellac)

Calcium sulfate

Microcrystalline cellulose

Sucrose

Titanium dioxide

Poloxamer 188-tocopherol

Povidone

Carnauba wax

Printing ink (Shellac, Iron Oxide Red, Propylene Glycol [E1520], Concentrated Ammonia Solution,

Simethicone)

Rapamune 2 mg coated tablets

Macrogol

Glycerol monooleate

Pharmaceutical glaze (shellac)

Calcium sulfate

Microcrystalline cellulose

Sucrose

Titanium dioxide

Yellow iron oxide (E172)

Brown iron oxide (E172)

Poloxamer 188-tocopherol

Povidone

Carnauba wax

Printing ink (Shellac, Iron Oxide Red, Propylene Glycol [E1520], Concentrated Ammonia Solution,

Simethicone)

Not applicable.

Rapamune 0.5 mg coated tablets3 years.

Rapamune 1 mg coated tablets3 years.

Rapamune 2 mg coated tablets3 years.

Do not store above 25ºC.

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

Clear polyvinyl chloride (PVC)/polyethylene (PE)/polychlorotrifluoroethylene (Aclar) aluminiumblister 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 localrequirements.

Pfizer Europe MA EEIG

Boulevard de la Plaine 171050 Bruxelles

Belgium

Rapamune 0.5 mg coated tablets

EU/1/01/171/013-14

Rapamune 1 mg coated tablets

EU/1/01/171/007-8

Rapamune 2 mg coated tablets

EU/1/01/171/009-010

Date of first authorisation: 13 March 2001

Date of latest renewal: 13 March 2011

Detailed information on this medicinal product is available on the website of the European Medicines

Agency http://www.ema.europa.eu.