Rapamune

1

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 
 
 
 

 



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1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg/mL oral solution 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
Each mL contains 1 mg sirolimus. 
Each 60 mL bottle contains 60 mg sirolimus. 
 
Excipients with known effect  
Each mL contains up to 25 mg of ethanol, approximately 350 mg of propylene glycol (E1520), and 
20 mg of soya oil. 
 
For the full list of excipients, see section 6.1. 
 
 
3. PHARMACEUTICAL FORM 
 
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). 
 
Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis with 
moderate lung disease or declining lung function (see sections 4.2 and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
Prophylaxis of organ rejection 
 
Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist 
in transplantation. 
 
Initial therapy (2 to 3 months post-transplantation) 
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as 
possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of 
the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose 
adjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of 
4 to 12 ng/mL (chromatographic assay). Rapamune therapy should be optimised with a tapering 
regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges 
for the first 2-3 months after transplantation are 150-400 ng/mL (monoclonal assay or equivalent 
technique) (see section 4.5). 
 



  3

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 



  4

sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by 
both chromatographic and immunoassay methodologies. The concentration values obtained by these 
different methodologies are not interchangeable. All sirolimus concentrations reported in this 
Summary of Product Characteristics were either measured using chromatographic methods or have 
been converted to chromatographic method equivalents. Adjustments to the targeted range should be 
made according to the assay being utilised to determine the sirolimus trough concentrations. Since 
results are assay and laboratory dependent, and the results may change over time, adjustment to the 
targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. 
Physicians should therefore remain continuously informed by responsible representatives for their 
local laboratory on the performance of the locally used method for concentration determination of 
sirolimus. 
 
Patients with sporadic lymphangioleiomyomatosis (S-LAM)  
 
Treatment should be initiated by and remain under the guidance of an appropriately qualified 
specialist. 
 
For patients with S-LAM, the initial Rapamune dose should be 2 mg/day. Sirolimus whole blood 
trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain 
concentrations between 5 to 15 ng/mL. 
 
In most patients, dose adjustments can be based on simple proportion: new Rapamune dose=current 
dose x (target concentration/current concentration). Frequent Rapamune dose adjustments based on 
non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has 
a long half-life. Once Rapamune maintenance dose is adjusted, patients should continue on the new 
maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration 
monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least 
every 3 months. 
 
Data from controlled studies for treatment of S-LAM longer than one year are currently not available, 
therefore the benefit of treatment should be reassessed when used long-term. 
 
Special populations 
 
Black population 
There is limited information indicating that Black renal transplant recipients (predominantly 
African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as 
observed in non-Black patients. The efficacy and safety data are too limited to allow specific 
recommendations for use of sirolimus in Black recipients.  
 
Elderly  
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above 
65 years of age to determine whether they will respond differently than younger patients (see 
section 5.2).  
 
Renal impairment  
No dose adjustment is required (see section 5.2). 
 
Hepatic impairment  
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2). 
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune 
be reduced by approximately one-half. 
 
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with 
impaired hepatic function (see Therapeutic monitoring of the medicinal product and dose adjustment). 
It is not necessary to modify the Rapamune loading dose. 
 



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



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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). Based on information from an open-label randomised study, 
conversion from the calcineurin inhibitor tacrolimus to Rapamune in maintenance renal transplant 
patients was associated with an unfavourable safety profile without efficacy benefit and can therefore 
not be recommended (see section 5.1). 
 
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin 
inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic 
microangiopathy (HUS/TTP/TMA). 
 
HMG-CoA reductase inhibitors 
In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors 
and/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should be 
monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or 
fibrate should be monitored for the possible development of rhabdomyolysis and other adverse 
reactions, as described in the respective Summary of Product Characteristics of these agents. 
 
Cytochrome P450 isozymes 
Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole, 
itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is 
not recommended (see section 4.5). 
 
Angioedema  
The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitors 
has resulted in angioneurotic oedema-type reactions. Elevated sirolimus levels, for example due to 
interaction with strong CYP3A4 inhibitors, (with/without concomitant ACE inhibitors) may also 
potentiate angioedema (see section 4.5). In some cases, the angioedema has resolved upon 
discontinuation or dose reduction of Rapamune. 
 
Increased rates of biopsy confirmed acute rejection (BCAR) in renal transplant patients have been 
observed with concomitant use of sirolimus with ACE inhibitors (see section 5.1). Patients receiving 
sirolimus should be monitored closely if taking ACE inhibitors concomitantly.  
 
Vaccination 
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, 
including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided 
during treatment with Rapamune. 
 
Malignancy 
 
Increased susceptibility to infection and the possible development of lymphoma and other 
malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual 
for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should 
be limited by wearing protective clothing and using a sunscreen with a high protection factor. 
 



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Infections 
 
Oversuppression of the immune system can also increase susceptibility to infection, including 
opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis. 
 
Among these conditions in renal transplant patients are BK virus-associated nephropathy and JC 
virus-associated progressive multifocal leukoencephalopathy (PML). These infections are often related 
to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians 
should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal 
function or neurological symptoms. 
 
Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receiving 
antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia 
should be administered for the first 12 months following transplantation. 
 
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, 
particularly for patients at increased risk for CMV disease. 
 
Hepatic impairment 
 
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely 
monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one half is 
recommended based on decreased clearance (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 in renal transplant patients and wound dehiscence. Patients with a body mass 
index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data 
from the medical literature. 
 



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There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, 
pleural effusion and pericardial effusions (including haemodynamically significant effusions in 
children and adults), in patients receiving Rapamune. 
 
The use of Rapamune was associated with increased serum cholesterol and triglycerides that may 
require treatment. Patients administered Rapamune should be monitored for hyperlipidaemia using 
laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and 
lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with 
established hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune. 
Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with 
severe refractory hyperlipidaemia. 
 
Ethanol 
 
Rapamune oral solution contains up to 3.17 vol % ethanol (alcohol). A 6 mg loading dose contains up 
to 150 mg of alcohol which is equivalent to 3.80 mL beer or 1.58 mL wine. This dose could 
potentially be harmful for those suffering from alcoholism and should be taken into account in 
pregnant or breast-feeding women, 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). 
 



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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 
 
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, telaprevir), nicardipine, bromocriptine, cimetidine, and danazol.  
 
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 



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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/sulfamethoxazole. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, 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 or limited amount of 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 unknown 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 treatment 
with Rapamune. 
 
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  
 
Undesirable effects observed with prophylaxis of organ rejection in renal transplantation 
 
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). 
 



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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 (≥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 with 
other immunosuppressive agents.  
 

System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
Infections and 
infestations 

Pneumonia; 
Fungal infection; 
Viral infection; 
Bacterial 
infection; 
Herpes simplex 
infection; 
Urinary tract 
infection 

Sepsis; 
Pyelonephritis; 
Cytomegalo-
virus infection; 
Herpes zoster 
caused by the 
varicella zoster 
virus 

Clostridium 
difficile colitis;  
Mycobacterial 
infection 
(including 
tuberculosis); 
Epstein-Barr 
virus infection 

  

Neoplasms 
benign, 
malignant and 
unspecified 
(including cysts 
and polyps) 

 Non-melanoma 
skin cancer* 

Lymphoma*; 
Malignant 
melanoma*; 
Post transplant 
lympho-
proliferative 
disorder 

 Neuroendoc
rine 
carcinoma 
of the skin* 

Blood and 
lymphatic 
system disorders 

Thrombo-
cytopaenia; 
Anaemia; 
Leucopenia 

Haemolytic 
uraemic 
syndrome; 
Neutropaenia  

Pancytopaenia; 
Thrombotic 
thrombo-
cytopaenic 
purpura 

  

Immune system 
disorders 

 Hyper-
sensitivity 
(including 
angioedema, 
anaphylactic 
reaction, and 
anaphylactoid 
reaction)

   



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System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
Metabolism and 
nutrition 
disorders 

Hypokalaemia; 
Hypophos-
phataemia; 
Hyperlipidaemia 
(including 
hypercholesterol-
aemia); 
Hyperglycaemia; 
Hyper-
triglyceridaemia; 
Diabetes mellitus 

    

Nervous system 
disorders 

Headache    Posterior 
reversible 
encephalo-
pathy 
syndrome 

Cardiac 
disorders  

Tachycardia Pericardial 
effusion

   

Vascular 
disorders  

Hypertension; 
Lymphocele 

Venous 
thrombosis 
(including deep 
vein 
thrombosis)

Lymphoedema   

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Pulmonary 
embolism; 
Pneumonitis*; 
Pleural 
effusion; 
Epistaxis 

Pulmonary 
haemorrhage 

Alveolar 
proteinosi
s 

 

Gastrointestinal 
disorders 

Abdominal pain; 
Constipation; 
Diarrhoea; 
Nausea 

Pancreatitis; 
Stomatitis; 
Ascites 

   

Hepatobiliary 
disorders 

Liver function 
test abnormal 
(including 
alanine 
aminotransferase 
increased and 
aspartate amino-
transferase 
increased) 

 Hepatic 
failure* 

  

Skin and 
subcutaneous 
tissue disorders  

Rash; 
Acne 

 Dermatitis 
exfoliative 

Hypersen-
sitivity 
vasculitis 

 



  13

System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
Musculoskeletal 
and connective 
tissue disorders 

Arthralgia Osteonecrosis    

Renal and 
urinary disorders 

Proteinuria  Nephrotic 
syndrome (see 
section 4.4); 
Focal 
segmental 
glomerulo-
sclerosis* 

  

Reproductive 
system and 
breast disorders 

Menstrual 
disorder 
(including 
amenorrhoea and 
menorrhagia) 

Ovarian cyst    

General 
disorders and 
administration 
site conditions  

Oedema; 
Oedema 
peripheral; 
Pyrexia; 
Pain; 
Impaired 
healing* 

    

Investigations Blood lactate 
dehydrogenase 
increased; 
Blood creatinine 
increased 

    

*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 
aetiology 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. 
 



  14

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). 
 
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 of 
ovarian cysts may be higher in premenopausal females compared to postmenopausal females. In some 
cases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of Rapamune. 
 
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 Epstein-Barr 
virus (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). 
 



  15

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 reactions 
observed in patients with S-LAM were consistent with the known safety profile of the product for the 
indication prophylaxis of organ rejection in renal transplantation with the addition of weight 
decreased, which was reported in the study at a greater incidence with Rapamune when compared to 
that observed with placebo (common, 9.5% vs. common, 2.6%). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
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. 
 
LAM involves lung tissue infiltration with smooth muscle-like cells that harbour inactivating 
mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function 
activates the mTOR signaling pathway, resulting in cellular proliferation and release of 
lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the 
proliferation of LAM cells. 
 
Clinical studies 
 
Prophylaxis of Organ Rejection 
 
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin 
elimination-Rapamune maintenance study, which included patients receiving a renal allograft from a 
cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at 
least 6 months after transplantation were included. Ciclosporin was not withdrawn in patients 



  16

experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum 
creatinine higher than 400 mol/L, or who had inadequate renal function to support ciclosporin 
withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in 
the ciclosporin elimination-Rapamune maintenance studies and are not recommended for this 
treatment regimen. 
 
At 12, 24 and 36 months, graft and patient survival were similar for both groups. At 48 months, there 
was a statistically significant difference in graft survival in favour of the Rapamune following 
ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including 
and excluding loss to follow-up). There was a significantly higher rate of first biopsy-proven rejection 
in the ciclosporin elimination group compared to the ciclosporin maintenance group during the period 
post-randomisation to 12 months (9.8% vs. 4.2%, respectively). Thereafter, the difference between the 
two groups was not significant.  
 
The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly 
higher 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 and 
beyond, which showed a growing difference in graft survival and renal function, as well as 
significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue 
subjects from the Rapamune with ciclosporin group. By 60 months, the incidence of non-skin 
malignancies was significantly higher in the cohort who continued ciclosporin as compared with the 
cohort who had ciclosporin withdrawn (8.4% vs. 3.8%, respectively). For skin carcinoma, the median 
time to first occurrence was significantly delayed. 
 
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal 
transplant 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, and 
corticosteroids. Enrollment in the patient stratum with baseline calculated GFR below 40 mL/min was 
discontinued 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 not 
improved 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 and 
median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion 
group as compared to those of the calcineurin inhibitors continuation group at 24 months (see 
section 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 Rapamune 
conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%). In a 
subset of the study patients with a baseline GFR above 40 mL/min and normal urinary protein 
excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the 
corresponding subset of calcineurin inhibitor continuation patients. The rates of acute rejection, graft 
loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment 
arm of this subset. 
 
In an open-label, randomised, comparative, multi-centre study where renal transplant patients were 
either 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 sirolimus 
group (11, 8.4%) compared to the tacrolimus group (2, 1.6%) through 2 years; most rejections were 
mild in severity (8 of 9 [89%] T-cell BCAR, 2 of 4 [50%] antibody mediated BCAR) in the sirolimus 
group. Patients who had both antibody-mediated rejection and T-cell-mediated rejection on the same 
biopsy were counted once for each category. More patients converted to sirolimus developed new 



  17

onset 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 a 
non-fasting glucose ≥200 mg/dL after randomisation (18.3% vs. 5.6%, p=0.025*). A lower incidence 
of 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 significantly 
higher acute rejection rates and numerically higher death rates compared to patients treated with a 
calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4). Renal 
function 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 in 
kidney transplant patients converted from calcineurin inhibitors to sirolimus, a difference in the 
number 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 patients 
initiated on ramipril 5 mg (5%). Most rejections occurred within the first six months following 
conversion 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 to 
5-15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation 
period in patients with TSC-LAM or S-LAM. Eighty-nine (89) patients were enrolled at 13 study sites 
in 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 inclusion 
criteria was post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% of predicted 
during the baseline visit. In patients with S-LAM, enrolled patients had moderately advanced lung 
disease, with baseline FEV1 of 49.2±13.6% (mean ±SD) of the predicted value. The primary endpoint 
was the difference between the groups in the rate of change (slope) in FEV1. During the treatment 
period in patients with S-LAM, the mean ±SE FEV1 slope was -12±2 mL per month in the placebo 
group and 0.3±2 mL per month in the Rapamune group (p<0.001). The absolute between-group 
difference in the mean change in FEV1 during the treatment period was 152 mL, or approximately 
11% of the mean FEV1 at enrollment.  
 
As compared with the placebo group, the sirolimus group had improvement from baseline to 
12 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 was 
no 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-being 
score in patients with S-LAM.  
 
Paediatric population 
 
Rapamune was assessed in a 36-month controlled clinical study enrolling renal transplant patients 
below 18 years of age considered at high-immunologic risk, defined as having a history of one or more 
acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal 
biopsy. Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/mL) in 
combination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-based 
immunosuppression without Rapamune. The Rapamune group failed to demonstrate superiority to the 
control 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 inhibitors 



  18

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 total cholesterol), and 
urinary tract infections (see section 4.8). 
 
An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study when 
full-dose Rapamune was administered to children and adolescents in addition to full-dose calcineurin 
inhibitors with basiliximab and corticosteroids (see section 4.8). 
 
In a retrospective review of hepatic veno-occlusive disease (VOD) in patients who underwent 
myeloablative stem cell transplantation using cyclosphophamide and total body irradiation, an 
increased incidence of hepatic VOD was observed in patients treated with Rapamune, especially with 
concomitant use of methotrexate. 
 
5.2 Pharmacokinetic properties 
 
Oral solution 
 
Following administration of the Rapamune oral solution, sirolimus is rapidly absorbed, with a time to 
peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with 
stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination 
with simultaneously administered ciclosporin (Sandimune) is approximately 14%. Upon repeated 
administration, the average blood concentration of sirolimus is increased approximately 3-fold. The 
terminal half-life in stable renal transplant patients after multiple oral doses was 6216h. The effective 
half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days. 
The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed 
blood elements. 
 
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is 
extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, 
including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the 
major component in human whole blood and contributes to greater than 90% of the 
immunosuppressive activity. After a single dose of [14C] sirolimus in healthy volunteers, the majority 
(91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted 
in urine. 
 
Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age to 
determine whether they will respond differently than younger patients. Sirolimus trough concentration 
data 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 age 
ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger 
paediatric patients (580 mL/h/kg) than for older paediatric patients (450 mL/h/kg) as compared with 
adults (287 mL/h/kg). There was a large variability for individuals within the age groups. 
 
Sirolimus concentrations were measured in concentration-controlled studies of paediatric 
renal-transplant patients who were also receiving ciclosporin and corticosteroids. The target for trough 
concentrations was 10-20 ng/mL. At steady-state, 8 children aged 6-11 years received mean  SD 
doses of 1.75  0.71 mg/day (0.064  0.018 mg/kg, 1.65  0.43 mg/m2) while 14 adolescents aged 
12-18 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-normalized Cl/F (214 mL/h/kg) 
compared with the adolescents (136 mL/h/kg). These data indicate that younger children might require 
higher 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 to 
be definitely confirmed. 
 



  19

In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values 
for 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-Pugh 
classification 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 longer half-lives observed 
in hepatically impaired patients delay reaching steady state. 
 
Pharmacokinetic/pharmacodynamic relationship 
 
The pharmacokinetics of sirolimus were similar in various populations with renal function ranging 
from normal to absent (dialysis patients). 
 
Lymphangioleiomyomatosis (LAM) 
 
In a clinical trial of patients with LAM, the median whole blood sirolimus trough concentration after 
3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 
9.0 ng/mL; n=37). With concentration-control (target concentrations 5 to 15 ng/mL), the median 
sirolimus concentration at the end of 12 months of treatment was 6.8 ng/mL (interquartile range 5.9 to 
8.9 ng/mL; n=37). 
 
5.3 Preclinical safety data 
 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to 
clinical exposure levels and with possible relevance to clinical use were as follows: pancreatic islet 
cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and 
calluses, 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 the 
in vivo mouse micronucleus assay. 
 
Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male 
and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia 
(female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of 
immunosuppressive 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 chronic 
immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a 
species-dependent response to lutenising hormone levels and are usually considered of limited clinical 
relevance. 
 
In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible 
reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights 
and/or histological lesions (e.g. tubular atrophy and tubular giant cells) were observed in rats and in a 
monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and 
reduced foetal weights (with associated delays in skeletal ossification) (see section 4.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Polysorbate 80 (E433) 
 
Phosal 50 PG (phosphatidylcholine, propylene glycol [E1520], mono-and diglycerides, ethanol, 
soya fatty acids and ascorbyl palmitate). 
 



  20

6.2 Incompatibilities 
 
Rapamune must not be diluted in grapefruit juice or any other liquid other than water or orange juice 
(see section 6.6). 
 
Rapamune oral solution contains polysorbate-80, which is known to increase the rate of 
di-(2-ethylhexyl)phthalate (DEHP) extraction from polyvinyl chloride (PVC). It is important to follow 
the instructions to drink Rapamune oral solution at once when a plastic container is used for the 
dilution and/or administration (see section 6.6). 
 
6.3 Shelf life 
 
2 years. 
 
30 days for opened bottle. 
 
24 hours in the dosing syringe (at room temperature, but not to exceed 25C). 
 
After dilution (see section 6.6), the preparation should be used immediately. 
 
6.4 Special precautions for storage 
 
Store in a refrigerator (2C - 8C).  
 
Store in the original bottle in order to protect from light. 
 
If necessary, the patient may store the bottles at room temperatures up to 25C for a short period of 
time (24 hours). 
 
For storage conditions after dilution of the medicinal product, see section 6.3. 
 
6.5 Nature and contents of container 
 
Each pack contains: one bottle (amber glass) containing 60 mL of Rapamune solution, one syringe 
adapter, 30 dosing syringes (amber polypropylene) and one syringe carry case. 
 
6.6 Special precautions for disposal and other handling 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
Instructions for use and handling: 
 
The dosing syringe should be used to withdraw the prescribed amount of Rapamune from the bottle. 
Empty the correct amount of Rapamune from the syringe into only a glass or plastic container with at 
least 60 mL of water or orange juice. No other liquids, including grapefruit juice, should be used for 
dilution. Stir vigorously and drink at once. Refill the container with an additional volume (minimum 
of 120 mL) of water or orange juice, stir vigorously, and drink at once. 
 
 



  21

7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/171/001 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 March 2001 
Date of latest renewal: 13 March 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 
 
 
 



  22

 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 0.5 mg coated tablets 
Rapamune 1 mg coated tablets 
Rapamune 2 mg coated tablets 
 
 
2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 
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. 
 
Excipients with known effect  
 
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. 
 
 
3. PHARMACEUTICAL FORM 
 
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. 
 
 
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). 



  23

 
Rapamune is indicated for the treatment of patients with sporadic lymphangioleiomyomatosis with 
moderate lung disease or declining lung function (see sections 4.2 and 5.1). 
 
4.2 Posology and method of administration 
 
Posology 
 
Prophylaxis of organ rejection 
 
Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist 
in transplantation. 
 
Initial therapy (2 to 3 months post-transplantation) 
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as 
possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of 
the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose 
adjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of 
4 to 12 ng/mL (chromatographic assay). Rapamune therapy should be optimised with a tapering 
regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges 
for the first 2-3 months after transplantation are 150-400 ng/mL (monoclonal assay or equivalent 
technique) (see section 4.5). 
 
To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours 
after the ciclosporin dose, and consistently either with or without food (see section 5.2). 
 
Maintenance therapy 
Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be 
adjusted to obtain whole blood trough levels of 12 to 20 ng/mL (chromatographic assay; see 
Therapeutic monitoring of the medicinal product and dose adjustment). Rapamune should be given 
with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be 
attempted, the combination of ciclosporin and Rapamune should not be maintained for more than 
3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be 
discontinued and an alternative immunosuppressive regimen instituted. 
 
Therapeutic monitoring of the medicinal product and dose adjustment  
Whole blood sirolimus levels should be closely monitored in the following populations: 
  
(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. 
 



  24

Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis. 
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or 
tablet strength to confirm that the trough concentration is within the recommended target range. 
 
Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/mL 
(chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and 
consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus 
dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the 
absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive 
requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is 
increased should correspond to the rate of ciclosporin elimination. 
 
If further dose adjustment(s) are required during maintenance therapy (after discontinuation of 
ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune 
dose=current dose x (target concentration/current concentration). A loading dose should be considered 
in addition to a new maintenance dose when it is necessary to considerably increase sirolimus trough 
concentrations: Rapamune loading dose=3 x (new maintenance dose – current maintenance dose). The 
maximum Rapamune dose administered on any day should not exceed 40 mg. If an estimated daily 
dose exceeds 40 mg due to the addition of a loading dose, the loading dose should be administered 
over 2 days. Sirolimus trough concentrations should be monitored at least 3 to 4 days after a loading 
dose(s). 
 
The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic 
methods. Several assay methodologies have been used to measure the whole blood concentrations of 
sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by 
both chromatographic and immunoassay methodologies. The concentration values obtained by these 
different methodologies are not interchangeable. All sirolimus concentrations reported in this 
Summary of Product Characteristics were either measured using chromatographic methods or have 
been converted to chromatographic method equivalents. Adjustments to the targeted range should be 
made according to the assay being utilised to determine the sirolimus trough concentrations. Since 
results are assay and laboratory dependent, and the results may change over time, adjustment to the 
targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used. 
Physicians should therefore remain continuously informed by responsible representatives for their 
local laboratory on the performance of the locally used method for concentration determination of 
sirolimus. 
 
Patients with sporadic lymphangioleiomyomatosis (S-LAM)  
 
Treatment should be initiated by and remain under the guidance of an appropriately qualified 
specialist. 
 
For patients with S-LAM, the initial Rapamune dose should be 2 mg/day. Sirolimus whole blood 
trough concentrations should be measured in 10 to 20 days, with dosage adjustment to maintain 
concentrations between 5 to 15 ng/mL. 
 
In most patients, dose adjustments can be based on simple proportion: new Rapamune dose=current 
dose x (target concentration/current concentration). Frequent Rapamune dose adjustments based on 
non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has 
a long half-life. Once Rapamune maintenance dose is adjusted, patients should continue on the new 
maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration 
monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least 
every 3 months. 
 
Data from controlled studies for treatment of S-LAM longer than one year are currently not available, 
therefore the benefit of treatment should be reassessed when used long-term. 
 



  25

Special populations 
 
Black population 
There is limited information indicating that Black renal transplant recipients (predominantly 
African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as 
observed in non-Black patients. The efficacy and safety data are too limited to allow specific 
recommendations for use of sirolimus in Black recipients.  
 
Elderly  
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above 
65 years of age to determine whether they will respond differently than younger patients (see 
section 5.2).  
 
Renal impairment  
No dose adjustment is required (see section 5.2). 
 
Hepatic impairment  
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2). 
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune 
be reduced by approximately one-half. 
 
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with 
impaired hepatic function (see Therapeutic monitoring of the medicinal product and dose adjustment). 
It is not necessary to modify the Rapamune loading dose. 
 
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until 
3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or 
after loading dose due to the delay in reaching steady-state because of the prolonged half-life. 
 
Paediatric population 
The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not 
been established.  
 
Currently available data are described in sections 4.8, 5.1 and 5.2, but no recommendation on a 
posology can be made. 
 
Method of administration 
 
Rapamune is for oral use only. 
 
Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and 
therefore this cannot be recommended. 
 
To minimise variability, Rapamune should consistently be taken either with or without food. 
 
Grapefruit juice should be avoided (see section 4.5). 
 
Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths 
(see section 5.2). 
 
4.3 Contraindications 
 
Hypersensitivity to the active substance or to any of the excipients listed in section 6.1. 
 



  26

4.4 Special warnings and precautions for use 
 
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 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 (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. 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). Based on information from an open-label randomised study, 
conversion from the calcineurin inhibitor tacrolimus to Rapamune in maintenance renal transplant 
patients was associated with an unfavourable safety profile without efficacy benefit and can therefore 
not be recommended (see section 5.1). 
 
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. 
 



  27

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). 
 
Angioedema  
The concomitant administration of Rapamune and angiotensin-converting enzyme (ACE) inhibitors 
has resulted in angioneurotic oedema-type reactions. Elevated sirolimus levels, for example due to 
interaction with strong CYP3A4 inhibitors, (with/without concomitant ACE inhibitors) may also 
potentiate angioedema (see section 4.5). In some cases, the angioedema has resolved upon 
discontinuation or dose reduction of Rapamune. 
 
Increased rates of biopsy confirmed acute rejection (BCAR) in renal transplant patients have been 
observed with concomitant use of sirolimus with ACE inhibitors (see section 5.1). Patients receiving 
sirolimus should be monitored closely if taking ACE inhibitors concomitantly.  
 
Vaccination 
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants, 
including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided 
during treatment with Rapamune. 
 
Malignancy 
 
Increased susceptibility to infection and the possible development of lymphoma and other 
malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual 
for patients with increased risk for skin cancer, exposure to sunlight and ultraviolet (UV) light should 
be limited by wearing protective clothing and using a sunscreen with a high protection factor. 
 
Infections 
 
Oversuppression of the immune system can also increase susceptibility to infection, including 
opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis. 
 
Among these conditions in renal transplant patients are BK virus-associated nephropathy and JC 
virus-associated progressive multifocal leukoencephalopathy (PML). These infections are often related 
to a high total immunosuppressive burden and may lead to serious or fatal conditions that physicians 
should consider in the differential diagnosis in immunosuppressed patients with deteriorating renal 
function or neurological symptoms. 
 
Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receiving 
antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia 
should be administered for the first 12 months following transplantation. 
 
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, 
particularly for patients at increased risk for CMV disease. 
 
Hepatic impairment 
 
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely 
monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one-half is 
recommended based on decreased clearance (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). 
 



  28

Lung and liver transplant populations 
 
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver 
or lung transplant patients, and therefore such use is not recommended. 
 
In two clinical studies in de novo liver transplant patients, the use of sirolimus plus ciclosporin or 
tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or 
death. 
 
A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor 
(CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen 
6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at 
12 months (-4.45 mL/min and -3.07 mL/min, respectively). The study also failed to demonstrate 
non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus 
conversion group compared to the CNI continuation group. The rate of death in the sirolimus 
conversion group was higher than the CNI continuation group, although the rates were not 
significantly different. The rates of premature study discontinuation, adverse events overall (and 
infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all 
significantly greater in the sirolimus conversion group compared to the CNI continuation group. 
 
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant 
patients when sirolimus has been used as part of an immunosuppressive regimen. 
 
Systemic effects 
 
There have been reports of impaired or delayed wound healing in patients receiving Rapamune, 
including lymphocele in renal transplant patients and wound dehiscence. Patients with a body mass 
index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data 
from the medical literature. 
 
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema, 
pleural effusion and pericardial effusions (including haemodynamically significant effusions in 
children and adults), in patients receiving Rapamune. 
 
The use of Rapamune was associated with increased serum cholesterol and triglycerides that may 
require treatment. Patients administered Rapamune should be monitored for hyperlipidaemia using 
laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and 
lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with 
established hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune. 
Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with 
severe refractory hyperlipidaemia. 
 
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. 
 
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 



  29

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 



  30

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 
 
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, and danazol.  
 
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/sulfamethoxazole. 
 
Paediatric population 
 
Interaction studies have only been performed in adults. 
 
4.6 Fertility, 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 or limited amount of 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. 
 



  31

Breast-feeding 
 
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating 
rats. It is unknown 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 treatment 
with Rapamune. 
 
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  
 
Undesirable effects observed with prophylaxis of organ rejection in renal transplantation 
 
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 (≥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 with 
other immunosuppressive agents.  
 



  32

System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
Infections and 
infestations 

Pneumonia; 
Fungal infection; 
Viral infection; 
Bacterial 
infection; 
Herpes simplex 
infection; 
Urinary tract 
infection 

Sepsis; 
Pyelonephritis; 
Cytomegalo-
virus infection; 
Herpes zoster 
caused by the 
varicella zoster 
virus 

Clostridium 
difficile colitis; 
Mycobacterial 
infection 
(including 
tuberculosis); 
Epstein-Barr 
virus infection 

  

Neoplasms 
benign, 
malignant and 
unspecified 
(including cysts 
and polyps) 

 Non-melanoma 
skin cancer* 

Lymphoma*; 
Malignant 
melanoma*; 
Post transplant 
lympho-
proliferative 
disorder 

 Neuroendoc
rine 
carcinoma 
of the skin* 

Blood and 
lymphatic 
system disorders 

Thrombo-
cytopaenia; 
Anaemia; 
Leucopenia 

Haemolytic 
uraemic 
syndrome; 
Neutropaenia  

Pancytopaenia; 
Thrombotic 
thrombo-
cytopaenic 
purpura 

  

Immune system 
disorders 

 Hyper-
sensitivity 
(including 
angioedema, 
anaphylactic 
reaction, and 
anaphylactoid 
reaction)

   

Metabolism and 
nutrition 
disorders 

Hypokalaemia; 
Hypophos-
phataemia; 
Hyperlipidaemia 
(including 
hypercholesterol-
aemia); 
Hyperglycaemia; 
Hyper-
triglyceridaemia; 
Diabetes mellitus

    

Nervous system 
disorders 

Headache    Posterior 
reversible 
encephalo-
pathy 
syndrome

Cardiac 
disorders  

Tachycardia Pericardial 
effusion 

   



  33

System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
Vascular 
disorders  

Hypertension; 
Lymphocele 

Venous 
thrombosis 
(including deep 
vein 
thrombosis) 

Lymphoedema   

Respiratory, 
thoracic and 
mediastinal 
disorders 

 Pulmonary 
embolism; 
Pneumonitis*; 
Pleural 
effusion; 
Epistaxis

Pulmonary 
haemorrhage 

Alveolar 
proteinosi
s 

 

Gastrointestinal 
disorders 

Abdominal pain; 
Constipation; 
Diarrhoea; 
Nausea 

Pancreatitis; 
Stomatitis; 
Ascites 

   

Hepatobiliary 
disorders 

Liver function 
test abnormal 
(including 
alanine 
aminotransferase 
increased and 
aspartate amino-
transferase 
increased) 

 Hepatic 
failure* 

  

Skin and 
subcutaneous 
tissue disorders  

Rash; 
Acne 

 Dermatitis 
exfoliative 

Hypersen-
sitivity 
vasculitis 

 

Musculoskeletal 
and connective 
tissue disorders 

Arthralgia Osteonecrosis    

Renal and 
urinary disorders 

Proteinuria  Nephrotic 
syndrome (see 
section 4.4); 
Focal 
segmental 
glomerulo-
sclerosis*

  

Reproductive 
system and 
breast disorders 

Menstrual 
disorder 
(including 
amenorrhoea and 
menorrhagia) 

Ovarian cyst    



  34

System organ 
class  

Very common 
(≥1/10) 

Common 
(≥1/100 to 

<1/10) 

Uncommon 
(≥1/1,000 to 

<1/100) 

Rare 
(≥1/10,00

0 to 
 <1/1,000) 

Frequency 
not known 
(cannot be 
estimated 

from 
available 

data) 
General 
disorders and 
administration 
site conditions  

Oedema; 
Oedema 
peripheral; 
Pyrexia; 
Pain; 
Impaired 
healing* 

    

Investigations Blood lactate 
dehydrogenase 
increased; 
Blood creatinine 
increased 

    

*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 
aetiology 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. 
 



  35

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). 
 
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 of 
ovarian cysts may be higher in premenopausal females compared to postmenopausal females. In some 
cases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of Rapamune. 
 
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 Epstein-Barr 
virus (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).  
 
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 reactions 
observed in patients with S-LAM were consistent with the known safety profile of the product for the 
indication prophylaxis of organ rejection in renal transplantation with the addition of weight 
decreased, which was reported in the study at a greater incidence with Rapamune when compared to 
that observed with placebo (common, 9.5% vs. common, 2.6%). 
 
Reporting of suspected adverse reactions 
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It 
allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare 
professionals are asked to report any suspected adverse reactions via the national reporting system 
listed in Appendix V. 
 
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 



  36

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.  
 
LAM involves lung tissue infiltration with smooth muscle-like cells that harbour inactivating 
mutations of the tuberous sclerosis complex (TSC) gene (LAM cells). Loss of TSC gene function 
activates the mTOR signaling pathway, resulting in cellular proliferation and release of 
lymphangiogenic growth factors. Sirolimus inhibits the activated mTOR pathway and thus the 
proliferation of LAM cells. 
 
Clinical studies 
 
Prophylaxis of Organ Rejection 
 
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin 
elimination-Rapamune maintenance study, which included patients receiving a renal allograft from a 
cadaveric or living donor. In addition, re-transplant recipients whose previous grafts survived for at 
least 6 months after transplantation were included. Ciclosporin was not withdrawn in patients 
experiencing Banff Grade 3 acute rejection episodes, who were dialysis-dependent, who had a serum 
creatinine higher than 400 mol/L, or who had inadequate renal function to support ciclosporin 
withdrawal. Patients at high immunological risk of graft loss were not studied in sufficient number in 
the ciclosporin elimination-Rapamune maintenance studies and are not recommended for this 
treatment regimen. 
 
At 12, 24 and 36 months, graft and patient survival were similar for both groups. At 48 months, there 
was a statistically significant difference in graft survival in favour of the Rapamune following 
ciclosporin elimination group compared to the Rapamune with ciclosporin therapy group (including 
and excluding loss to follow-up). There was a significantly higher rate of first biopsy-proven rejection 
in the ciclosporin elimination group compared to the ciclosporin maintenance group during the period 
post-randomisation to 12 months (9.8% vs. 4.2%, respectively). Thereafter, the difference between the 
two groups was not significant.  
 
The mean calculated glomerular filtration rate (GFR) at 12, 24, 36, 48 and 60 months was significantly 
higher 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 and 
beyond, which showed a growing difference in graft survival and renal function, as well as 
significantly lower blood pressure in the ciclosporin elimination group, it was decided to discontinue 
subjects from the Rapamune with ciclosporin group. By 60 months, the incidence of non-skin 



  37

malignancies was significantly higher in the cohort who continued ciclosporin as compared with the 
cohort who had ciclosporin withdrawn (8.4% vs. 3.8%, respectively). For skin carcinoma, the median 
time to first occurrence was significantly delayed. 
 
The safety and efficacy of conversion from calcineurin inhibitors to Rapamune in maintenance renal 
transplant 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, and 
corticosteroids. Enrollment in the patient stratum with baseline calculated GFR below40 mL/min was 
discontinued 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 not 
improved 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 and 
median urinary protein to creatinine ratios were significantly higher in the Rapamune conversion 
group as compared to those of the calcineurin inhibitors continuation group at 24 months (see 
section 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 Rapamune 
conversion group as compared to the calcineurin inhibitors continuation group (1.8% and 6.9%). In a 
subset of the study patients with a baseline GFR above 40 mL/min and normal urinary protein 
excretion, calculated GFR was higher at 1 and 2 years in patients converted to Rapamune than for the 
corresponding subset of calcineurin inhibitor continuation patients. The rates of acute rejection, graft 
loss, and death were similar, but urinary protein excretion was increased in the Rapamune treatment 
arm of this subset. 
 
In an open-label, randomised, comparative, multi-centre study where renal transplant patients were 
either 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 sirolimus 
group (11, 8.4%) compared to the tacrolimus group (2, 1.6%) through 2 years; most rejections were 
mild in severity (8 of 9 [89%] T-cell BCAR, 2 of 4 [50%] antibody mediated BCAR) in the sirolimus 
group. Patients who had both antibody-mediated rejection and T-cell-mediated rejection on the same 
biopsy were counted once for each category. More patients converted to sirolimus developed new 
onset 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 a 
non-fasting glucose ≥200 mg/dL after randomisation (18.3% vs. 5.6%, p=0.025*). A lower incidence 
of 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 significantly 
higher acute rejection rates and numerically higher death rates compared to patients treated with a 
calcineurin inhibitor, MMF, corticosteroids, and an IL-2 receptor antagonist (see section 4.4). Renal 
function 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 in 
kidney transplant patients converted from calcineurin inhibitors to sirolimus, a difference in the 
number 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 patients 
initiated on ramipril 5 mg (5%). Most rejections occurred within the first six months following 
conversion and were mild in severity; no graft losses were reported during the study (see section 4.4). 
 



  38

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 to 
5-15 ng/mL) with placebo for a 12-month treatment period, followed by a 12-month observation 
period in patients with TSC-LAM or S-LAM. Eighty-nine (89) patients were enrolled at 13 study sites 
in 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 inclusion 
criteria was post-bronchodilator forced expiratory volume in 1 second (FEV1) ≤70% of predicted 
during the baseline visit. In patients with S-LAM, enrolled patients had moderately advanced lung 
disease, with baseline FEV1 of 49.2±13.6% (mean ±SD) of the predicted value. The primary endpoint 
was the difference between the groups in the rate of change (slope) in FEV1. During the treatment 
period in patients with S-LAM, the mean ±SE FEV1 slope was -12±2 mL per month in the placebo 
group and 0.3±2 mL per month in the Rapamune group (p<0.001). The absolute between-group 
difference in the mean change in FEV1 during the treatment period was 152 mL, or approximately 
11% of the mean FEV1 at enrollment.  
 
As compared with the placebo group, the sirolimus group had improvement from baseline to 
12 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 was 
no 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-being 
score in patients with S-LAM.  
 
Paediatric population 
 
Rapamune was assessed in a 36-month controlled clinical study enrolling renal transplant patients 
below 18 years of age considered at high-immunologic risk, defined as having a history of one or more 
acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal 
biopsy. Subjects were to receive Rapamune (sirolimus target concentrations of 5 to 15 ng/mL) in 
combination with a calcineurin inhibitor and corticosteroids or to receive calcineurin-inhibitor-based 
immunosuppression without Rapamune. The Rapamune group failed to demonstrate superiority to the 
control 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 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 total cholesterol), and 
urinary tract infections (see section 4.8). 
 
An unacceptably high frequency of PTLD was seen in a paediatric clinical transplant study when 
full-dose Rapamune was administered to children and adolescents in addition to full-dose calcineurin 
inhibitors with basiliximab and corticosteroids (see section 4.8). 
 
In a retrospective review of hepatic veno-occlusive disease (VOD) in patients who underwent 
myeloablative stem cell transplantation using cyclosphophamide and total body irradiation, an 
increased incidence of hepatic VOD was observed in patients treated with Rapamune, especially with 
concomitant use of methotrexate. 
 
5.2 Pharmacokinetic properties 
 
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 summarised 
specifically in the Oral tablet section. 
 



  39

Oral solution 
 
Following administration of the Rapamune oral solution, sirolimus is rapidly absorbed, with a time to 
peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with 
stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination 
with simultaneously administered ciclosporin (Sandimune) is approximately 14%. Upon repeated 
administration, the average blood concentration of sirolimus is increased approximately 3-fold. The 
terminal half-life in stable renal transplant patients after multiple oral doses was 62  16 hours. The 
effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 
7 days. The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into 
formed blood elements. 
 
Sirolimus is a substrate for both cytochrome P450 IIIA4 (CYP3A4) and P-glycoprotein. Sirolimus is 
extensively metabolised by O-demethylation and/or hydroxylation. Seven major metabolites, 
including hydroxyl, demethyl, and hydroxydemethyl, are identifiable in whole blood. Sirolimus is the 
major component in human whole blood and contributes to greater than 90% of the 
immunosuppressive activity. After a single dose of [14C] sirolimus in healthy volunteers, the 
majority (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was 
excreted in urine. 
 
Clinical studies of Rapamune did not include a sufficient number of patients above 65 years of age to 
determine whether they will respond differently than younger patients. Sirolimus trough concentration 
data 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 age 
ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger 
paediatric patients (580 mL/h/kg) than for older paediatric patients (450 mL/h/kg) as compared with 
adults (287 mL/h/kg). There was a large variability for individuals within the age groups. 
 
Sirolimus concentrations were measured in concentration-controlled studies of paediatric 
renal-transplant patients who were also receiving ciclosporin and corticosteroids. The target for trough 
concentrations was 10-20 ng/mL. At steady-state, 8 children aged 6-11 years received mean  SD 
doses of 1.75  0.71 mg/day (0.064  0.018 mg/kg, 1.65  0.43 mg/m2) while 14 adolescents aged 
12-18 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 require 
higher 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 to 
be definitely confirmed. 
 
In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values 
for 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-Pugh 
classification 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 longer 
half-lives observed in hepatically impaired patients delay reaching steady-state. 
 
Pharmacokinetic/pharmacodynamic relationship  
 
The pharmacokinetics of sirolimus were similar in various populations, with renal function ranging 
from 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. 



  40

 
In healthy subjects, the mean extent of bioavailability of sirolimus after single-dose administration of 
the tablet formulation is about 27% higher relative to the oral solution. The mean Cmax was decreased 
by 35%, and mean tmax increased by 82%. The difference in bioavailability was less marked upon 
steady-state administration to renal transplant recipients, and therapeutic equivalence has been 
demonstrated in a randomised study of 477 patients. When switching patients between oral solution 
and tablet formulations, it is recommended to give the same dose and to verify the sirolimus trough 
concentration 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 is 
recommended. 
 
In 24 healthy volunteers receiving Rapamune tablets with a high-fat meal, Cmax, tmax and AUC showed 
increases of 65%, 32%, and 23%, respectively. To minimise variability, Rapamune tablets should be 
taken consistently with or without food. Grapefruit juice affects CYP3A4-mediated metabolism and 
must, therefore, be avoided. 
 
Sirolimus concentrations, following the administration of Rapamune tablets (5 mg) to healthy subjects 
as 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 to 
determine whether they will respond differently than younger patients. Rapamune tablets administered 
to 12 renal transplant patients above 65 years of age gave similar results to adult patients (n=167) 18 to 
65 years of age. 
 
Initial Therapy (2 to 3 months post-transplant): In most patients receiving Rapamune tablets with a 
loading dose of 6 mg followed by an initial maintenance dose of 2 mg, whole blood sirolimus trough 
concentrations rapidly achieved steady-state concentrations within the recommended target range (4 to 
12 ng/mL, chromatographic assay). Sirolimus pharmacokinetic parameters following daily doses of 
2 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 at 
months 1 and 3 after transplantation, were: Cmin,ss 7.39  2.18 ng/mL; Cmax,ss 15.0  4.9 ng/mL; tmax,ss 
3.46  2.40 hours; AUC,ss 230  67 ng.h/mL; CL/F/WT, 139  63 mL/h/kg (parameters calculated 
from LC-MS/MS assay results). The corresponding results for the oral solution in the same clinical 
study 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,ss 
194  78 ng.h/mL, CL/F/W 173  50 mL/h/kg. Whole blood trough sirolimus concentrations, as 
measured 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 the 
pharmacokinetic interaction with ciclosporin (2-fold increase) and the augmented immunosuppressive 
requirement 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 after 
3 weeks of receiving sirolimus tablets at a dose of 2 mg/day was 6.8 ng/mL (interquartile range 4.6 to 
9.0 ng/mL; n=37). With concentration-control (target concentrations 5 to 15 ng/mL), the median 
sirolimus concentration at the end of 12 months of treatment was 6.8 ng/mL (interquartile range 5.9 to 
8.9 ng/mL; n=37). 
 



  41

5.3 Preclinical safety data 
 
Adverse reactions not observed in clinical studies, but seen in animals at exposure levels similar to 
clinical exposure levels and with possible relevance to clinical use, were as follows: pancreatic islet 
cell vacuolation, testicular tubular degeneration, gastrointestinal ulceration, bone fractures and 
calluses, 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 the 
in vivo mouse micronucleus assay. 
 
Carcinogenicity studies conducted in mouse and rat showed increased incidences of lymphomas (male 
and female mouse), hepatocellular adenoma and carcinoma (male mouse) and granulocytic leukaemia 
(female mouse). It is known that malignancies (lymphoma) secondary to the chronic use of 
immunosuppressive 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 chronic 
immunosuppression. In rat, testicular interstitial cell adenomas were likely indicative of a 
species-dependent response to lutenising hormone levels and are usually considered of limited clinical 
relevance. 
 
In reproduction toxicity studies decreased fertility in male rats was observed. Partly reversible 
reductions in sperm counts were reported in a 13-week rat study. Reductions in testicular weights 
and/or histological lesions (e.g., tubular atrophy and tubular giant cells) were observed in rats and in a 
monkey study. In rats, sirolimus caused embryo/foetotoxicity that was manifested as mortality and 
reduced foetal weights (with associated delays in skeletal ossification) (see section 4.6). 
 
 
6. PHARMACEUTICAL PARTICULARS 
 
6.1 List of excipients 
 
Tablet core: 
 
Lactose monohydrate 
Macrogol 
Magnesium stearate 
Talc 
 
Tablet coating: 
 
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) 
 



  42

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) 
 
6.2 Incompatibilities 
 
Not applicable. 
 
6.3 Shelf life 
 
Rapamune 0.5 mg coated tablets 
2 years. 
 
Rapamune 1 mg coated tablets 
3 years. 
 
Rapamune 2 mg coated tablets 
3 years. 
 
6.4 Special precautions for storage 
 
Do not store above 25ºC. 
 
Keep the blister in the outer carton in order to protect from light. 
 



  43

6.5 Nature and contents of container 
 
Clear polyvinyl chloride (PVC)/polyethylene (PE)/polychlorotrifluoroethylene (Aclar) aluminium 
blister packages of 30 and 100 tablets.  
 
Not all pack sizes may be marketed. 
 
6.6 Special precautions for disposal 
 
Any unused medicinal product or waste material should be disposed of in accordance with local 
requirements. 
 
 
7. MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
8. MARKETING AUTHORISATION NUMBER(S) 
 
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 
 
 
9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 
Date of first authorisation: 13 March 2001 
Date of latest renewal: 13 March 2011 
 
 
10. DATE OF REVISION OF THE TEXT 
 
Detailed information on this medicinal product is available on the website of the European Medicines 
Agency http://www.ema.europa.eu. 



  44

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

ANNEX II 
 
A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY 

AND USE 
 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE 
MARKETING AUTHORISATION 
 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 
THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 
PRODUCT 

 



  45

A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE 
 
Name and address of the manufacturers responsible for batch release  
 
Rapamune 1 mg/mL oral solution: 
 
Wyeth Pharmaceuticals  
New Lane Havant  
Hants PO9 2NG 
United Kingdom 
 
Pfizer Service Company bvba 
Hoge Wei 10, B-1930 Zaventem 
Belgium 
 
Rapamune 0.5 mg coated tablets, Rapamune 1 mg coated tablets, Rapamune 2 mg coated 
tablets: 
 
Pfizer Ireland Pharmaceuticals 
Little Connell, Newbridge, Co. Kildare 
Ireland 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 
 
The printed package leaflet of the medicinal product must state the name and address of the 
manufacturer responsible for the release of the concerned batch. 
 
 
B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 
 
Medicinal product subject to restricted medical prescription (See Annex I: Summary of Product 
Characteristics, section 4.2). 
 
 
C. OTHER CONDITIONS AND REQUIREMENTS OF THE 

MARKETING AUTHORISATION  
 
 Periodic Safety Update Reports  

 
The requirements for submission of periodic safety update reports for this medicinal product are set 
out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 
2001/83/EC and any subsequent updates published on the European medicines web-portal. 
 
 
D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 
 
 Risk Management Plan (RMP)  
 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 
agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 
updates of the RMP.  
 



  46

An updated RMP should be submitted:  
 At the request of the European Medicines Agency;  
 Whenever the risk management system is modified, especially as the result of new 

information being received that may lead to a significant change to the benefit/risk profile or 
as the result of an important (pharmacovigilance or risk minimisation) milestone being 
reached.  

 



  47

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 

ANNEX III 
 

LABELLING AND PACKAGE LEAFLET 



  48

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

A. LABELLING 



  49

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
TEXT FOR 60 mL OUTER CARTON (CONTAINING SYRINGES/BOTTLE IN CARTON)
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg/mL oral solution 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of Rapamune contains 1 mg sirolimus. 
Each 60 mL bottle of Rapamune contains 60 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: ethanol, propylene glycol (E1520), soya fatty acids. See package leaflet for further 
information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS
 
Oral solution 
 
1 bottle 
30 dosing syringes 
1 syringe adapter 
1 carrying case 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
 



  50

9. SPECIAL STORAGE CONDITIONS
 
Store in a refrigerator.  
Store in the original bottle in order to protect from light. 
 
Use within 30 days after opening bottle. 
Use within 24 hours after filling the dosing syringe. 
After dilution, the preparation should be used immediately. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)
 
EU/1/01/171/001 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE
 
 
16. INFORMATION IN BRAILLE 
 
Rapamune 1 mg/mL 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 



  51

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
INTERMEDIATE CARTON: 60 mL BOTTLE
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg/mL oral solution 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of Rapamune contains 1 mg sirolimus. 
Each 60 mL bottle of Rapamune contains 60 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: ethanol, propylene glycol (E1520), soya fatty acids. See package leaflet for further 
information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS
 
Oral solution 
60 mL bottle 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP  
 
 



  52

9. SPECIAL STORAGE CONDITIONS
 
Store in a refrigerator. Store in the original bottle in order to protect from light. 
 
Use within 30 days after opening bottle.  
Use within 24 hours after filling the dosing syringe. 
 
After dilution, the preparation should be used immediately. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S)
 
EU/1/01/171/001 
 
 
13. BATCH NUMBER 
 
Lot  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE
 
 
16. INFORMATION IN BRAILLE 
 
 
 



  53

 
PARTICULARS TO APPEAR ON THE IMMEDIATE PACKAGING 
 
BOTTLE LABEL: 60 mL BOTTLE 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg/mL oral solution 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each mL of Rapamune contains 1 mg sirolimus. 
Each 60 mL bottle of Rapamune contains 60 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: ethanol, propylene glycol (E1520), soya fatty acids. See package leaflet for further 
information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS 
 
60 mL oral solution. 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY 
 
 
8. EXPIRY DATE 
 
EXP 
 
Date opened 
 
 



  54

9. SPECIAL STORAGE CONDITIONS
 
Store in a refrigerator. Store in the original bottle in order to protect from light. 
 
Use within 30 days after opening bottle.  
Use within 24 hours after filling the dosing syringe. 
After dilution, the preparation should be used immediately. 
 
 
10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/171/001 
 
 
13. BATCH NUMBER 
 
Lot:  
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE 
 
 
16. INFORMATION IN BRAILLE 
 
 
 



  55

PARTICULARS TO APPEAR ON THE OUTER PACKAGING  
 
CARTONS – PACK SIZES 30 AND 100 TABLETS
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 0.5 mg coated tablets 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each coated tablet contains 0.5 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: lactose monohydrate, sucrose. See package leaflet for further information. 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS
 
30 coated tablets 
100 coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION
 
Read the package leaflet before use. 
Do not crush, chew or split. 
Oral use. 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25ºC. 
Keep the blister in the outer carton in order to protect from light.  
 
 



  56

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/171/013 30 tablets 
EU/1/01/171/014 100 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE
 
 
16. INFORMATION IN BRAILLE 
 
Rapamune 0.5 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 



  57

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 0.5 mg tablets 
sirolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



  58

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTONS – PACK SIZES 30 AND 100 TABLETS
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg coated tablets 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each coated tablet contains 1 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: lactose monohydrate, sucrose. See package leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS
 
30 coated tablets 
100 coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use 
Do not crush, chew or split 
Oral use  
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25˚C. 
Keep the blister in the outer carton in order to protect from light.  
 
 



  59

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/171/007 30 tablets 
EU/1/01/171/008 100 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE
 
 
16. INFORMATION IN BRAILLE 
 
Rapamune 1 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 



  60

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 1 mg tablets 
sirolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



  61

 
PARTICULARS TO APPEAR ON THE OUTER PACKAGING AND THE IMMEDIATE 
PACKAGING 
 
CARTONS – PACK SIZES 30 AND 100 TABLETS
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 2 mg coated tablets 
sirolimus 
 
 
2. STATEMENT OF ACTIVE SUBSTANCE(S) 
 
Each coated tablet contains 2 mg sirolimus. 
 
 
3. LIST OF EXCIPIENTS 
 
Also contains: lactose monohydrate, sucrose. See package leaflet for further information 
 
 
4. PHARMACEUTICAL FORM AND CONTENTS
 
30 coated tablets 
100 coated tablets 
 
 
5. METHOD AND ROUTE(S) OF ADMINISTRATION 
 
Read the package leaflet before use. 
Do not crush, chew or split 
Oral use 
 
 
6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 
 
Keep out of the sight and reach of children. 
 
 
7. OTHER SPECIAL WARNING(S), IF NECESSARY
 
 
8. EXPIRY DATE 
 
EXP 
 
 
9. SPECIAL STORAGE CONDITIONS 
 
Do not store above 25˚C. 
Keep the blister in the outer carton in order to protect from light.  
 
 



  62

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 
OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 
APPROPRIATE 

 
 
11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 
 
12. MARKETING AUTHORISATION NUMBER(S) 
 
EU/1/01/171/009 30 tablets 
EU/1/01/171/010 100 tablets 
 
 
13. BATCH NUMBER 
 
Lot 
 
 
14. GENERAL CLASSIFICATION FOR SUPPLY 
 
 
15. INSTRUCTIONS ON USE
 
 
16. INFORMATION IN BRAILLE 
 
Rapamune 2 mg 
 
 
17. UNIQUE IDENTIFIER – 2D BARCODE 
 
2D barcode carrying the unique identifier included. 
 
 
18. UNIQUE IDENTIFIER – HUMAN READABLE DATA 
 
PC:  
SN:  
NN: 
 
 



  63

 
MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 
 
BLISTER 
 
 
1. NAME OF THE MEDICINAL PRODUCT 
 
Rapamune 2 mg tablets 
sirolimus 
 
 
2. NAME OF THE MARKETING AUTHORISATION HOLDER 
 
Pfizer Europe MA EEIG 
 
 
3. EXPIRY DATE 
 
EXP 
 
 
4. BATCH NUMBER 
 
Lot 
 
 
5. OTHER 
 
 
 



  64

 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

B. PACKAGE LEAFLET 
 



  65

 
Package leaflet: Information for the user 

 
Rapamune 1 mg/mL oral solution 

sirolimus 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
 If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 

effects not listed in this leaflet. See section 4. 
 
 
What is in this leaflet 
 
1. What Rapamune is and what it is used for 
2. What you need to know before you take Rapamune 
3. How to take Rapamune 
4. Possible side effects 
5. How to store Rapamune 
6. Contents of the pack and other information 
 
 
1. What Rapamune is and what it is used for 
 
Rapamune contains the active substance sirolimus, which belongs to a group of medicines called 
immunosuppressants. It helps to control your body’s immune system after you have received a kidney 
transplant. 
 
Rapamune is used in adults to prevent your body from rejecting transplanted kidneys and is normally 
used with other immunosuppressant medicines called corticosteroids and initially (the first 2 to 
3 months) with ciclosporin. 
 
Rapamune is also used for the treatment of patients with sporadic lymphangioleiomyomatosis 
(S-LAM) with moderate lung disease or declining lung function. S-LAM is a rare progressive lung 
disease that affects predominantly women of childbearing age. The most common symptom of S-LAM 
is shortness of breath.  
 
 
2. What you need to know before you take Rapamune  
 
Do not take Rapamune:  
 
 if you are allergic to sirolimus or any of the other ingredients of this medicine (listed in 

section 6).  
 if you are allergic to peanut or soya. 
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Rapamune 
 
 If you have any liver problems or have had a disease which may have affected your liver, please 

tell your doctor as this may affect the dose of Rapamune that you receive and may result in your 
having additional blood tests. 



  66

 Rapamune, like other immunosuppressive medicines, may decrease your body’s ability to fight 
infection, and may increase the risk of developing cancer of the lymphoid tissues and skin. 

 If you have a body mass index (BMI) greater than 30 kg/m2, you may be at increased risk of 
abnormal wound healing. 

 If you are considered to be at high risk for kidney rejection, such as if you had a previous 
transplant that was lost to rejection. 

 
Your doctor will perform tests to monitor the levels of Rapamune in your blood. Your doctor will also 
perform tests to monitor your kidney function, your blood fat (cholesterol and/or triglycerides) levels 
and possibly your liver function, during treatment with Rapamune. 
 
Exposure to sunlight and UV light should be limited by covering your skin with clothing and using a 
sunscreen with a high protection factor because of the increased risk for skin cancer. 
 
Children and adolescents  
 
There is limited experience on the use of Rapamune in children and adolescents less than 18 years of 
age. The use of Rapamune is not recommended in this population. 
 
Other medicines and Rapamune 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines. 
 
Some medicines can interfere with the action of Rapamune and, therefore, dose adjustment of 
Rapamune may be required. In particular, you should inform your doctor or pharmacist if you are 
taking any of the following: 
 
 any other immunosuppressant medicines.  
 antibiotics or antifungal medicines used to treat infection e.g. clarithromycin, erythromycin, 

telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole. It is not 
recommended that Rapamune be taken with rifampicin, ketoconazole or voriconazole.  

 any high blood pressure medicines or medicines for heart problems including nicardipine, 
verapamil and diltiazem. 

 anti-epileptic medicines including carbamazepine, phenobarbital, phenytoin. 
 medicines used to treat ulcers or other gastrointestinal disorders such as cisapride, cimetidine, 

metoclopramide.  
 bromocriptine (used in the treatment of Parkinson’s disease and various hormonal disorders), 

danazol (used in the treatment of gynaecological disorders), or protease inhibitors (e.g. for HIV 
and hepatitis C such as ritonavir, indinavir, boceprevir, and telaprevir). 

 St. John’s Wort (Hypericum perforatum). 
 
The use of live vaccines should be avoided with the use of Rapamune. Before vaccinations, please 
inform your doctor or pharmacist that you are receiving Rapamune.  
 
The use of Rapamune may lead to increased levels of cholesterol and triglycerides (blood fats) in your 
blood that may require treatment. Medicines known as “statins” and “fibrates” used to treat elevated 
cholesterol and triglycerides have been associated with an increased risk of muscle breakdown 
(rhabdomyolysis). Please inform your doctor if you are taking medicines to lower your blood fats. 
 
The combined use of Rapamune with angiotensin-converting enzyme (ACE) inhibitors (a type of 
medicine used to lower blood pressure) may result in allergic reactions. Please inform your doctor if 
you are taking any of these medicines. 
 



  67

Rapamune with food and drink 
 
Rapamune should be taken consistently, either with or without food. If you prefer to take Rapamune 
with food, then you should always take it with food. If you prefer to take Rapamune without food, 
then you should always take it without food. Food can affect the amount of medicine that gets into 
your bloodstream, and taking your medicine in a consistent way means that the blood levels of 
Rapamune remain more stable. 
 
Rapamune should not be taken with grapefruit juice. 
 
Pregnancy, breast-feeding and fertility 
 
Rapamune should not be used during pregnancy unless clearly necessary. You must use an effective 
method of contraception during treatment with Rapamune and for 12 weeks after treatment has 
stopped. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a 
baby, ask your doctor or pharmacist for advice before taking this medicine. 
 
It is not known whether Rapamune passes into breast milk. Patients taking Rapamune should 
discontinue breast-feeding. 
 
Decreased sperm count has been associated with the use of Rapamune and usually returns to normal 
once treatment is stopped. 
 
Driving and using machines 
 
Although Rapamune treatment is not expected to affect your ability to drive, if you have any concerns 
please consult your doctor.  
 
Rapamune contains ethanol (alcohol) 
 
Rapamune contains up to 3.17 vol % ethanol (alcohol). An initial dose of 6 mg contains up to 150 mg 
of alcohol which is equivalent to 3.80 mL beer or 1.58 mL wine. This amount of alcohol may be 
harmful for those suffering from alcoholism as well as for pregnant or breast-feeding women, children 
and high-risk groups such as patients with liver disease, or epilepsy. Alcohol may modify or increase 
the effect of other medicines. 
 
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. 
 
 
3. How to take Rapamune 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Your doctor will decide exactly what dose of Rapamune you must take and how often to take it. 
Follow your doctor’s instructions exactly, and never change the dose yourself. 
 
Rapamune is for oral use only. Inform your doctor if you have difficulty taking the oral solution. 
 
Rapamune should be taken consistently, either with or without food. 
 
Kidney Transplant 
Your doctor will give you an initial dose of 6 mg as soon as possible after the kidney transplant 
operation. Then you will need to take 2 mg of Rapamune each day, until otherwise directed by your 
doctor. Your dose will be adjusted depending on the level of Rapamune in your blood. Your doctor 
will need to perform blood tests to measure Rapamune concentrations.  



  68

 
If you are also taking ciclosporin, then you must take the two medicines approximately 4 hours apart. 
 
It is recommended that Rapamune be used first in combination with ciclosporin and corticosteroids. 
After 3 months, your doctor may discontinue either Rapamune or ciclosporin, as it is not 
recommended that these medicines be taken together beyond this period.  
 
Sporadic Lymphangioleiomyomatosis (S-LAM) 
Your doctor will give you 2 mg of Rapamune each day, until otherwise directed by your doctor. Your 
dose will be adjusted depending on the level of Rapamune in your blood. Your doctor will need to 
perform blood tests to measure Rapamune concentrations. 
 
 
Instructions on how to dilute Rapamune 
 
1. Remove the safety cap from the bottle by squeezing the tabs on the cap and twisting. Insert the 

syringe adapter into the bottle until it is flush with the top of the bottle. Do not attempt to 
remove the syringe adapter from the bottle once inserted. 

 

 
 
2. With the plunger fully depressed, insert one of the dosing syringes into the opening in the 

adapter. 
 

 
 
3. Withdraw the exact amount of Rapamune oral solution as prescribed by your doctor by gently 

pulling out the plunger of the dosing syringe until the level of the oral solution is even with the 
appropriate mark on the dosing syringe. The bottle should remain in an upright position when 
withdrawing the solution. If bubbles form in the oral solution in the dosing syringe during 
withdrawal, empty the Rapamune solution back into the bottle and repeat the withdrawal 
procedure. You may need to repeat step 3 more than once to deliver your dose. 

 

 
 



  69

4. You may have been instructed to take your Rapamune oral solution at a particular time of day. If 
it is necessary to carry your medication with you, fill the dosing syringe to the appropriate mark 
and place a cap securely on it – the cap should snap into place. Then place the capped dosing 
syringe in the carrying case provided. Once in the syringe the medication may be kept at room 
temperature (not exceeding 25C) or refrigerated and should be used within 24 hours. 

 

         
 
5. Empty the contents of the dosing syringe into only a glass or plastic container holding at least 

60 mL of water or orange juice. Stir well for one minute and drink immediately at once. Refill the 
glass with at least 120 mL of water or orange juice, stir well, and drink immediately. No other 
liquids, including grapefruit juice, should be used for dilution. The dosing syringe and cap are to 
be used once and then discarded.  

 

 
 
When refrigerated the solution in the bottle may develop a slight haze. If this occurs, simply bring 
your Rapamune oral solution to room temperature and shake gently. The presence of this haze does 
not affect the quality of Rapamune. 
 
If you take more Rapamune than you should 
 
If you have taken more medicine than you were told contact a doctor or go to the nearest hospital 
emergency department straight away. Always take the labelled medicine bottle with you, even if it is 
empty. 
 
If you forget to take Rapamune 
 
If you forget to take Rapamune, take it as soon as you remember, but not within 4 hours of the next 
dose of ciclosporin. After that, continue to take your medicines as usual. Do not take a double dose to 
make up for a forgotten dose, and always take Rapamune and ciclosporin approximately 4 hours apart. 
If you miss a dose of Rapamune completely, you should inform your doctor. 
 
If you stop taking Rapamune 
  
Do not stop taking Rapamune unless your doctor tells you to, as you risk losing your transplant. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects 
 
Like all medicines, this medicine can cause side effects, although not everybody gets them.  
 
Allergic reactions 
 
You should see your doctor immediately if you experience symptoms, such as swollen face, tongue 
and/or back of the mouth (pharynx) and/or difficulties in breathing (angioedema), or a skin condition 



  70

whereby the skin can peel off (exfoliative dermatitis). These may be symptoms of a serious allergic 
reaction.  
 
Kidney damage with low blood cell counts (thrombocytopaenic purpura/haemolytic uraemic 
syndrome) 
 
When taken with medicines called calcineurin inhibitors (ciclosporin or tacrolimus), Rapamune may 
increase the risk of kidney damage with low blood platelets and low red blood cell counts, with or 
without rash (thrombocytopaenic purpura/haemolytic uraemic syndrome). If you experience 
symptoms, such as bruising or rash, changes in your urine, or changes in behaviour, or any others that 
are serious, unusual or prolonged, contact your doctor. 
 
Infections 
 
Rapamune reduces your body’s own defence mechanisms. Consequently your body will not be as 
good as normal at fighting infections. So if you are taking Rapamune, you may therefore catch more 
infections than usual, such as infections of the skin, mouth, stomach and intestines, lungs and urinary 
tract (see list below). You should contact your doctor if you experience symptoms that are serious, 
unusual, or prolonged. 
 
Side effect frequencies 
 
Very common: may affect more than 1 in 10 people 
 
 Fluid collection around the kidney  
 Swelling of the body including hands and feet 
 Pain 
 Fever 
 Headache 
 Increased blood pressure 
 Stomach pain, diarrhoea, constipation, nausea 
 Low red blood cells, low blood platelets 
 Increased fat in the blood (cholesterol and/or triglycerides), increased blood sugar, low blood 

potassium, low blood phosphorus, increased lactate dehydrogenase in the blood, increased 
creatinine in the blood 

 Joint pain 
 Acne 
 Urinary tract infection 
 Pneumonia and other bacterial, viral, and fungal infections 
 A reduced number of infection-fighting cells in the blood (white blood cells) 
 Diabetes 
 Abnormal tests of liver function, elevated AST and/or ALT liver enzymes 
 Rash 
 Elevated protein in the urine 
 Menstrual disorders (including absent, infrequent or heavy periods) 
 Slow healing (this may include separation of the layers of a surgical wound or stitch line) 
 Rapid heart rate 
 There is a general tendency for fluid to collect in various tissues. 
 
Common: may affect up to 1 in 10 people 
 
 Infections (including life-threatening infections) 
 Blood clots in the legs 
 Blood clots in the lung 
 Mouth sores 



  71

 Fluid collection in the abdomen 
 Kidney damage with low blood platelets and low red blood cell counts, with or without rash 

(haemolytic uraemic syndrome)  
 Low levels of a type of white blood cells called neutrophils 
 Deterioration of bone 
 Inflammation that may lead to lung damage, fluid around the lung 
 Nose bleeds 
 Skin cancer 
 Kidney infection  
 Ovarian cysts 
 Fluid collection in the sac around the heart, that in some cases may decrease the heart's ability to 

pump blood 
 Inflammation of the pancreas 
 Allergic reactions 
 Shingles 
 Cytomegalovirus infection 
 
Uncommon: may affect up to 1 in 100 people 
 
 Cancer of the lymph tissue (lymphoma/post-transplant lympho-proliferative disorder), combined 

lowering of red blood cells, white blood cells and blood platelets 
 Bleeding from the lung 
 Protein in the urine, occasionally severe and associated with side effects, such as swelling 
 Scarring in the kidney that may reduce kidney function 
 Too much fluid collecting in the tissues due to irregular lymph function 
 Low blood platelets, with or without rash (thrombocytopaenic purpura) 
 Serious allergic reactions that can cause peeling of the skin 
 Tuberculosis 
 Epstein-Barr virus infection  
 Infectious diarrhoea with Clostridium difficile 
 Serious liver damage 
 
Rare: may affect up to 1 in 1,000 people 
 
 Protein build-up in the air sacs of the lungs that may interfere with breathing 
 Serious allergic reactions that can affect blood vessels (see above paragraph on allergic reactions) 
 
Not known: frequency cannot be estimated from the available data 
 
 Posterior reversible encephalopathy syndrome (PRES), a serious nervous system syndrome that 

has the following symptoms: headache, nausea, vomiting, confusion, seizures, and visual loss. 
Should any of these occur together, please contact your physician. 

 
S-LAM patients experienced similar side effects to those of kidney transplant patients, with the 
addition of weight loss, which may affect up to 1 in 10 people. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 



  72

5. How to store Rapamune 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date which is stated on the carton after “EXP”. The expiry 
date refers to the last day of that month. 
 
Store in a refrigerator (2C - 8C).  
 
Keep Rapamune oral solution in its original bottle in order to protect from light.  
 
Once the bottle has been opened, the contents should be kept refrigerated and used within 30 days. If 
necessary, you may store the bottle at room temperature up to 25C for a short period of time, but no 
longer than 24 hours. 
 
Once the dosing syringe has been filled with Rapamune oral solution, it should be kept at room 
temperature, but not above 25C, for maximum 24 hours. 
 
Once the contents of the dosing syringe have been diluted with water or orange juice, the preparation 
should be drunk immediately. 
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 
6. Contents of the pack and other information 
 
What Rapamune contains 
 
The active substance is sirolimus. Each mL of Rapamune oral solution contains 1 mg of sirolimus. 
 
The other ingredients are: 
 
Polysorbate 80 (E433) and phosal 50 PG (phosphatidylcholine, propylene glycol [E1520], mono-and 
diglycerides, ethanol, soya fatty acids, and ascorbyl palmitate). 
 
This medicine contains approximately 350 mg propylene glycol (E1520) in each mL. 
 
What Rapamune looks like and contents of the pack 
 
Rapamune oral solution is a pale yellow to yellow solution supplied in a 60 mL bottle. 
 
Each pack contains: one bottle (amber glass) containing 60 mL of Rapamune solution, one syringe 
adapter, 30 dosing syringes (amber plastic) and one syringe carry case. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 

Manufacturer: 
Wyeth Pharmaceuticals  
New Lane Havant  
Hants PO9 2NG 
United Kingdom 
 
Pfizer Service Company bvba 
Hoge Wei 10, B-1930 Zaventem 
Belgium

 



  73

For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Luxembourg/Luxemburg 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 
 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000 

България 
Пфайзер Люксембург САРЛ, Клон 
България  
Teл: +359 2 970 4333 
 

Magyarország 
Pfizer Kft. 
Tel: +36 1 488 3700 
 

Česká Republika 
Pfizer PFE, spol. s r.o.  
Tel: +420 283 004 111 

Malta 
Vivian Corporation Ltd. 
Tel: +35621 344610 
 

Danmark 
Pfizer ApS 
Tlf: +45 44 201 100 
 

Nederland 
Pfizer bv 
Tel: +31 (0)10 406 43 01 
 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055-51000 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 
 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

Ελλάδα  
PFIZER ΕΛΛΑΣ A.E. 
Τηλ.: +30 210 6785 800 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.: +48 22 335 61 00 

España 
Pfizer, S.L. 
Télf:+34914909900 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

France 
Pfizer 
Tél +33 (0)1 58 07 34 40 

România 
Pfizer Romania S.R.L 
Tel: +40 (0) 21 207 28 00 

Hrvatska  
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 
 

Slovenija 
Pfizer Luxembourg SARL, Pfizer, podružnica za 
svetovanje s področja farmacevtske dejavnosti, 
Ljubljana  
Tel: +386 (0)1 52 11 400 
 



  74

Ireland 
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
Tel: +44 (0)1304 616161 
 
 

Slovenská Republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel: + 421 2 3355 5500 

Ísland 
Icepharma hf 
Tel: +354 540 8000 
 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: +358 (0)9 430 040 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 
 

Sverige  
Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 
 

Kύπρος 
PFIZER ΕΛΛΑΣ Α.Ε. (Cyprus Branch)  
T: +357 22 817690 
 

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 
 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel. +371 67035775 
 

 

 
This leaflet was last revised in MM/YYYY 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu 
 



  75

 
Package leaflet: Information for the user 

 
Rapamune 0.5 mg coated tablets 
Rapamune 1 mg coated tablets 
Rapamune 2 mg coated tablets 

sirolimus 
 
Read all of this leaflet carefully before you start taking this medicine because it contains 
important information for you. 
 Keep this leaflet. You may need to read it again. 
 If you have any further questions, ask your doctor or pharmacist. 
 This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 
If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 
not listed in this leaflet. See section 4 
 
 
What is in this leaflet 
 
1. What Rapamune is and what it is used for 
2. What you need to know before you take Rapamune 
3. How to take Rapamune 
4. Possible side effects 
5. How to store Rapamune 
6. Contents of the pack and other information 
 
 
1. What Rapamune is and what it is used for 
 
Rapamune contains the active substance sirolimus, which belongs to a group of medicines called 
immunosuppressants. It helps to control your body’s immune system after you have received a kidney 
transplant.  
 
Rapamune is used in adults to prevent your body from rejecting transplanted kidneys and is normally 
used with other immunosuppressant medicines called corticosteroids and initially (the first 2 to 
3 months) with ciclosporin. 
 
Rapamune is also used for the treatment of patients with sporadic lymphangioleiomyomatosis 
(S-LAM) with moderate lung disease or declining lung function. S-LAM is a rare progressive lung 
disease that affects predominantly women of childbearing age. The most common symptom of S-LAM 
is shortness of breath.  
 
 
2. What you need to know before you take Rapamune 
 
Do not take Rapamune: 
 
 if you are allergic to sirolimus or any of the other ingredients of this medicine (listed in 

section 6).  
 
Warnings and precautions 
 
Talk to your doctor or pharmacist before taking Rapamune 
 



  76

 If you have any liver problems or have had a disease which may have affected your liver, please 
tell your doctor as this may affect the dose of Rapamune that you receive and may result in your 
having additional blood tests. 

 Rapamune, like other immunosuppressive medicines, may decrease your body’s ability to fight 
infection, and may increase the risk of developing cancer of the lymphoid tissues and skin. 

 If you have a body mass index (BMI) greater than 30 kg/m2, you may be at increased risk of 
abnormal wound healing. 

 If you are considered to be at high risk for kidney rejection, such as if you had a previous 
transplant that was lost to rejection. 

 
Your doctor will perform tests to monitor the levels of Rapamune in your blood. Your doctor will also 
perform tests to monitor your kidney function, your blood fat (cholesterol and/or triglycerides) levels 
and possibly your liver function, during treatment with Rapamune. 
 
Exposure to sunlight and UV light should be limited by covering your skin with clothing and using a 
sunscreen with a high protection factor because of the increased risk for skin cancer. 
 
Children and adolescents  
 
There is limited experience on the use of Rapamune in children and adolescents less than 18 years of 
age. The use of Rapamune is not recommended in this population. 
 
Other medicines and Rapamune 
 
Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 
medicines.  
 
Some medicines can interfere with the action of Rapamune and, therefore, dose adjustment of 
Rapamune may be required. In particular, you should inform your doctor or pharmacist if you are 
taking any of the following: 
 
 any other immunosuppressant medicines.  
 antibiotics or antifungal medicines used to treat infection e.g. clarithromycin, erythromycin, 

telithromycin, troleandomycin, rifabutin, clotrimazole, fluconazole, itraconazole. It is not 
recommended that Rapamune be taken with rifampicin, ketoconazole or voriconazole.  

 any high blood pressure medicines or medicines for heart problems including nicardipine, 
verapamil and diltiazem. 

 anti-epileptic medicines including carbamazepine, phenobarbital, phenytoin. 
 medicines used to treat ulcers or other gastrointestinal disorders such as cisapride, cimetidine, 

metoclopramide.  
 bromocriptine (used in the treatment of Parkinson’s disease and various hormonal disorders), 

danazol (used in the treatment of gynaecological disorders), or protease inhibitors (e.g., for HIV 
and hepatitis C such as ritonavir, indinavir, boceprevir, and telaprevir). 

 St. John’s Wort (Hypericum perforatum). 
 
The use of live vaccines should be avoided with the use of Rapamune. Before vaccinations, please 
inform your doctor or pharmacist that you are receiving Rapamune.  
 
The use of Rapamune may lead to increased levels of cholesterol and triglycerides (blood fats) in your 
blood that may require treatment. Medicines known as “statins” and “fibrates” used to treat elevated 
cholesterol and triglycerides have been associated with an increased risk of muscle breakdown 
(rhabdomyolysis). Please inform your doctor if you are taking medicines to lower your blood fats. 
 
The combined use of Rapamune with angiotensin-converting enzyme (ACE) inhibitors (a type of 
medicine used to lower blood pressure) may result in allergic reactions. Please inform your doctor if 
you are taking any of these medicines. 



  77

 
Rapamune with food and drink 
 
Rapamune should be taken consistently, either with or without food. If you prefer to take Rapamune 
with food, then you should always take it with food. If you prefer to take Rapamune without food, 
then you should always take it without food. Food can affect the amount of medicine that gets into 
your bloodstream, and taking your medicine in a consistent way means that the blood levels of 
Rapamune remain more stable. 
 
Rapamune should not be taken with grapefruit juice. 
 
Pregnancy, breast-feeding and fertility 
 
Rapamune should not be used during pregnancy unless clearly necessary. You must use an effective 
method of contraception during treatment with Rapamune and for 12 weeks after treatment has 
stopped. If you are pregnant or breast-feeding, think you may be pregnant or are planning to have a 
baby, ask your doctor or pharmacist for advice before taking this medicine. 
 
It is not known whether Rapamune passes into breast milk. Patients taking Rapamune should 
discontinue breast-feeding. 
 
Decreased sperm count has been associated with the use of Rapamune and usually returns to normal 
once treatment is stopped. 
 
Driving and using machines 
 
Although Rapamune treatment is not expected to affect your ability to drive, if you have any concerns 
please consult your doctor.  
 
Rapamune contains lactose and sucrose 
 
Rapamune contains 86.4 mg of lactose and up to 215.8 mg of sucrose. If you have been told by your 
doctor that you have an intolerance to some sugars, contact your doctor before taking this medicine. 
 
 
3. How to take Rapamune 
 
Always take this medicine exactly as your doctor has told you. Check with your doctor or pharmacist 
if you are not sure. 
 
Your doctor will decide exactly what dose of Rapamune you must take and how often to take it. 
Follow your doctor’s instructions exactly, and never change the dose yourself.  
 
Rapamune is for oral use only. Do not crush, chew, or split the tablets. Inform your doctor if you have 
difficulty taking the tablet. 
 
Multiples of 0.5 mg tablets should not be used as a substitute for 1 mg and 2 mg tablets, as the 
different strengths are not directly interchangeable. 
 
Rapamune should be taken consistently, either with or without food. 
 
Kidney Transplant 
Your doctor will give you an initial dose of 6 mg as soon as possible after the kidney transplant 
operation. Then you will need to take 2 mg of Rapamune each day, until otherwise directed by your 
doctor. Your dose will be adjusted depending on the level of Rapamune in your blood. Your doctor 
will need to perform blood tests to measure Rapamune concentrations.  
 



  78

If you are also taking ciclosporin, then you must take the two medicines approximately 4 hours apart. 
 
It is recommended that Rapamune be used first in combination with ciclosporin and corticosteroids. 
After 3 months, your doctor may discontinue either Rapamune or ciclosporin, as it is not 
recommended that these medicines be taken together beyond this period.  
 
Sporadic Lymphangioleiomyomatosis (S-LAM) 
Your doctor will give you 2 mg of Rapamune each day, until otherwise directed by your doctor. Your 
dose will be adjusted depending on the level of Rapamune in your blood. Your doctor will need to 
perform blood tests to measure Rapamune concentrations. 
 
 
If you take more Rapamune than you should 
 
If you have taken more medicine than you were told to, contact a doctor or go to the nearest hospital 
emergency department as soon as possible. Always take the labelled blister with you, even if it is 
empty.  
 
If you forget to take Rapamune 
 
If you forget to take Rapamune, take it as soon as you remember, but not within 4 hours of the next 
dose of ciclosporin. After that, continue to take your medicines as usual. Do not take a double dose to 
make up for a forgotten dose, and always take Rapamune and ciclosporin approximately 4 hours apart. 
If you miss a dose of Rapamune completely, you should inform your doctor. 
 
If you stop taking Rapamune 
 
Do not stop taking Rapamune unless your doctor tells you to, as you risk losing your transplant. 
 
If you have any further questions on the use of this medicine, ask your doctor or pharmacist. 
 
 
4. Possible side effects  
 
Like all medicines, this medicine can cause side effects, although not everybody gets them. 
 
Allergic reactions 
 
You should see your doctor immediately if you experience symptoms, such as swollen face, tongue 
and/or back of the mouth (pharynx) and/or difficulties in breathing (angioedema), or a skin condition 
whereby the skin can peel off (exfoliative dermatitis). These may be symptoms of a serious allergic 
reaction.  
 
Kidney damage with low blood cell counts (thrombocytopaenic purpura/haemolytic uraemic 
syndrome) 
 
When taken with medicines called calcineurin inhibitors (ciclosporin or tacrolimus), Rapamune may 
increase the risk of kidney damage with low blood platelets and low red blood cell counts, with or 
without rash (thrombocytopaenic purpura/haemolytic uraemic syndrome). If you experience symptoms 
such as bruising or rash, changes in your urine, or changes in behaviour or any others that are serious, 
unusual or prolonged, contact your doctor. 
 
Infections 
 
Rapamune reduces your body’s own defence mechanisms. Consequently your body will not be as 
good as normal at fighting infections. So if you are taking Rapamune, you may therefore catch more 
infections than usual, such as infections of the skin, mouth, stomach and intestines, lungs and urinary 



  79

tract (see list below). You should contact your doctor if you experience symptoms that are serious, 
unusual, or prolonged. 
 
Side effect frequencies 
 
Very common: may affect more than 1 in 10 people 
 
 Fluid collection around the kidney 
 Swelling of the body including hands and feet 
 Pain 
 Fever 
 Headache 
 Increased blood pressure 
 Stomach pain, diarrhoea, constipation, nausea 
 Low red blood cells, low blood platelets 
 Increased fat in the blood (cholesterol and/or triglycerides), increased blood sugar, low blood 

potassium, low blood phosphorus, increased lactate dehydrogenase in the blood, increased 
creatinine in the blood 

 Joint pain 
 Acne 
 Urinary tract infection 
 Pneumonia and other bacterial, viral, and fungal infections 
 A reduced number of infection-fighting cells in the blood (white blood cells) 
 Diabetes 
 Abnormal tests of liver function, elevated AST and/or ALT liver enzymes 
 Rash 
 Elevated protein in the urine 
 Menstrual disorders (including absent, infrequent or heavy periods) 
 Slow healing (this may include separation of the layers of a surgical wound or stitch line) 
 Rapid heart rate 
 There is a general tendency for fluid to collect in various tissues. 
 
Common: may affect up to 1 in 10 people 
 
 Infections (including life-threatening infections) 
 Blood clots in the legs 
 Blood clots in the lung 
 Mouth sores 
 Fluid collection in the abdomen 
 Kidney damage with low blood platelets and low red blood cell counts, with or without rash 

(haemolytic uraemic syndrome) 
 Low levels of a type of white blood cells called neutrophils 
 Deterioration of bone 
 Inflammation that may lead to lung damage, fluid around the lung 
 Nose bleeds 
 Skin cancer 
 Kidney infection  
 Ovarian cysts 
 Fluid collection in the sac around the heart, that in some cases may decrease the heart's ability to 

pump blood 
 Inflammation of the pancreas 
 Allergic reactions 
 Shingles 
 Cytomegalovirus infection 
 



  80

Uncommon: may affect up to 1 in 100 people 
 
 Cancer of the lymph tissue (lymphoma/post-transplant lympho-proliferative disorder), combined 

lowering of red blood cells, white blood cells and blood platelets 
 Bleeding from the lung 
 Protein in the urine, occasionally severe and associated with side effects, such as swelling 
 Scarring in the kidney that may reduce kidney function 
 Too much fluid collecting in the tissues due to irregular lymph function 
 Low blood platelets, with or without rash (thrombocytopaenic purpura) 
 Serious allergic reactions that can cause peeling of the skin 
 Tuberculosis 
 Epstein-Barr virus infection  
 Infectious diarrhoea with Clostridium difficile 
 Serious liver damage 
 
Rare: may affect up to 1 in 1,000 people 
 
 Protein build-up in the air sacs of the lungs that may interfere with breathing 
 Serious allergic reactions that can affect blood vessels (see above paragraph on allergic reactions) 
 
Not known: frequency cannot be estimated from the available data 
 
 Posterior reversible encephalopathy syndrome (PRES), a serious nervous system syndrome that 

has the following symptoms: headache, nausea, vomiting, confusion, seizures, and visual loss. 
Should any of these occur together, please contact your physician. 

 
S-LAM patients experienced similar side effects to those of kidney transplant patients, with the 
addition of weight loss, which may affect up to 1 in 10 people. 
 
Reporting of side effects 
If you get any side effects, talk to your doctor, pharmacist or nurse. This includes any possible side 
effects not listed in this leaflet. You can also report side effects directly via the national reporting 
system listed in Appendix V. By reporting side effects you can help provide more information on the 
safety of this medicine. 
 
 
5. How to store Rapamune 
 
Keep this medicine out of the sight and reach of children. 
 
Do not use this medicine after the expiry date, which is stated on the blister and carton after “EXP”. 
The expiry date refers to the last day of that month. 
 
Do not store above 25˚C. 
 
Keep the blister in the outer carton in order to protect from light.  
 
Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 
throw away medicines you no longer use. These measures will help protect the environment. 
 
 



  81

6. Contents of the pack and other information 
 
What Rapamune contains 
 
The active substance is sirolimus. 
Each Rapamune 0.5 mg coated tablet contains 0.5 mg of sirolimus. 
Each Rapamune 1 mg coated tablet contains 1 mg of sirolimus. 
Each Rapamune 2 mg coated tablet contains 2 mg of sirolimus. 
 
The other ingredients are: 
 
Tablet core: lactose monohydrate, macrogol, magnesium stearate, talc 
Tablet coating: macrogol, glycerol monooleate, pharmaceutical glaze, 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). The 0.5 mg and 2 mg tablets also contain yellow iron oxide (E172) 
and brown iron oxide (E172). 
 
What Rapamune looks like and contents of the pack 
 
Rapamune 0.5 mg is supplied to you as tan-coloured, triangular-shaped, coated tablets marked 
“RAPAMUNE 0.5 mg” on one side. 
 
Rapamune 1 mg is supplied to you as white-coloured, triangular-shaped, coated tablets marked 
“RAPAMUNE 1 mg” on one side. 
 
Rapamune 2 mg is supplied to you as yellow to beige-coloured, triangular-shaped, coated tablets 
marked “RAPAMUNE 2 mg” on one side. 
 
The tablets are supplied in blister packs of 30 and 100 tablets. Not all pack sizes may be marketed. 
 
Marketing Authorisation Holder and Manufacturer 
 
Marketing Authorisation Holder: 
Pfizer Europe MA EEIG 
Boulevard de la Plaine 17 
1050 Bruxelles 
Belgium 
 

Manufacturer: 
Pfizer Ireland Pharmaceuticals 
Little Connell 
Newbridge 
Co. Kildare 
Ireland 
 
Pfizer Manufacturing Deutschland GmbH 
Betriebsstätte Freiburg 
Mooswaldallee 1 
79090 Freiburg 
Germany 

 
For any information about this medicine, please contact the local representative of the Marketing 
Authorisation Holder: 
 
België/Belgique/Belgien 
Luxembourg/Luxemburg 
Pfizer S.A. / N.V. 
Tél/Tel: +32 (0)2 554 62 11 

Lietuva 
Pfizer Luxembourg SARL filialas Lietuvoje 
Tel. +3705 2514000 



  82

България 
Пфайзер Люксембург САРЛ, Клон 
България  
Teл: +359 2 970 4333 
 

Magyarország 
Pfizer Kft. 
Tel: +36 1 488 3700 
 

Česká Republika 
Pfizer PFE, spol. s r.o.  
Tel: +420 283 004 111 

Malta 
Vivian Corporation Ltd. 
Tel: +35621 344610 
 

Danmark 
Pfizer ApS 
Tlf: +45 44 201 100 
 

Nederland 
Pfizer bvTel: +31(0)10 406 43 01 

Deutschland 
Pfizer Pharma GmbH 
Tel: +49 (0)30 550055-51000 

Norge 
Pfizer Norge AS 
Tlf: +47 67 52 61 00 

Eesti 
Pfizer Luxembourg SARL Eesti filiaal 
Tel: +372 666 7500 

Österreich 
Pfizer Corporation Austria Ges.m.b.H. 
Tel: +43 (0)1 521 15-0 

Ελλάδα  
PFIZER ΕΛΛΑΣ A.E. 
Τηλ.: +30 210 6785 800 

Polska 
Pfizer Polska Sp. z o.o. 
Tel.: +48 22 335 61 00 

España 
Pfizer, S.L. 
Télf:+34914909900 

Portugal 
Pfizer Biofarmacêutica, Sociedade Unipessoal Lda 
Tel: +351 21 423 5500 

France 
Pfizer 
Tél +33 (0)1 58 07 34 40 

România 
Pfizer Romania S.R.L 
Tel: +40 (0) 21 207 28 00 

Hrvatska  
Pfizer Croatia d.o.o. 
Tel: + 385 1 3908 777 
 

Slovenija 
Pfizer Luxembourg SARL, Pfizer, podružnica za 
svetovanje s področja farmacevtske dejavnosti, 
Ljubljana  
Tel: +386 (0)1 52 11 400 
 

Ireland 
Pfizer Healthcare Ireland 
Tel: +1800 633 363 (toll free) 
Tel: +44 (0)1304 616161 
 

Slovenská Republika 
Pfizer Luxembourg SARL, organizačná zložka  
Tel: + 421 2 3355 5500 

Ísland 
Icepharma hf 
Tel: +354 540 8000 
 

Suomi/Finland 
Pfizer Oy 
Puh/Tel: +358 (0)9 430 040 

Italia 
Pfizer S.r.l. 
Tel: +39 06 33 18 21 
 

Sverige  
Pfizer Innovations AB 
Tel: +46 (0)8 550 520 00 
 



  83

Kύπρος 
PFIZER ΕΛΛΑΣ Α.Ε. (Cyprus Branch)  
T: +357 22 817690 
 

United Kingdom 
Pfizer Limited 
Tel: +44 (0)1304 616161 
 

Latvija 
Pfizer Luxembourg SARL filiāle Latvijā 
Tel. +371 67035775 

 

 
This leaflet was last revised in MM/YYYY 
 
Detailed information on this medicine is available on the European Medicines Agency website: 
http://www.ema.europa.eu.  


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER(S) RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THEMARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE ANDEFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET