ANNEX I
SUMMARY OF PRODUCT CHARACTERISTICS
1.
Rapamune 1 mg/ml oral solution
2.
Each ml contains 1 mg sirolimus.
Each 60 ml bottle contains 60 mg sirolimus.
Excipients: Each ml contains 20 mg of ethanol and 20 mg of soya oil.
For a full list of excipients, see section 6.1.
3.
Oral solution.
Pale yellow to yellow solution
4.
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).
Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist
in transplantation.
Posology
Initial therapy (2 to 3 months post
-
transplantation)
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as
possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of
the medicinal product are available (see
Therapeutic monitoring of the medicinal product and dose
adjustment
). The Rapamune dose should then be individualised to obtain whole blood trough levels of
4 to 12 ng/ml (chromatographic assay). Rapamune therapy should be optimised with a tapering
regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges
for the first 2-3 months after transplantation are 150-400 ng/ml (monoclonal assay or equivalent
technique) (see section 4.5
)
.
To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours
after the ciclosporin dose, and consistently either with or without food (see section 5.2).
Maintenance therapy
Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be
adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see
Therapeutic monitoring of the medicinal product and dose adjustment
). Rapamune should be given
2
with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be
attempted, the combination of ciclosporin and Rapamune should not be maintained for more than
3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be
discontinued and an alternative immunosuppressive regimen instituted.
Therapeutic monitoring of the medicinal product and dose adjustment
Whole blood sirolimus levels should be closely monitored in the following populations
:
(1) in patients with hepatic impairment
(2) when inducers or inhibitors of CYP3A4 are concurrently administered and after their
discontinuation (see section 4.5) and/or
(3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to
have special dosing requirements.
Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus
therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory
parameters.
Most patients who received 2 mg of Rapamune 4 hours after ciclosporin had whole blood trough
concentrations of sirolimus within the 4 to 12 ng/ml target range (expressed as chromatographic assay
values). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all
patients.
Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained
more than 5 days after a previous dosing change.
Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis.
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or
tablet strength to confirm that the trough concentration is within the recommended target range.
Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/ml
(chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and
consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus
dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the
absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive
requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is
increased should correspond to the rate of ciclosporin elimination.
If further dose adjustment(s) are required during maintenance therapy (after discontinuation of
ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune
dose = current dose x (target concentration/current concentration). A loading dose should be
considered in addition to a new maintenance dose when it is necessary to considerably increase
sirolimus trough concentrations: Rapamune loading dose = 3 x (new maintenance dose – current
maintenance dose). The maximum Rapamune dose administered on any day should not exceed 40 mg.
If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose
should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to
4 days after a loading dose(s).
The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic
methods. Several assay methodologies have been used to measure the whole blood concentrations of
sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by
both chromatographic and immunoassay methodologies. The concentration values obtained by these
different methodologies are not interchangeable. All sirolimus concentrations reported in this
Summary of Product Characteristics were either measured using chromatographic methods or have
been converted to chromatographic method equivalents. Adjustments to the targeted range should be
made according to the assay being utilised to determine the sirolimus trough concentrations. Since
results are assay and laboratory dependent, and the results may change over time, adjustment to the
targeted therapeutic range must be made with a detailed knowledge of the site--specific assay used.
3
Physicians should therefore remain continuously informed by responsible representatives for their
local laboratory on the performance of the locally used method for concentration determination of
sirolimus.
Special populations
Black population
There is limited information indicating that Black renal transplant recipients (predominantly
African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as
observed in non-Black patients. Currently, the efficacy and safety data are too limited to allow specific
recommendations for use of sirolimus in Black recipients.
Elderly population (above 65 years)
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above
65 years of age to determine whether they will respond differently than younger patients (see
section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
Hepatic impairment
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2).
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune
be reduced by approximately one-half.
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with
impaired hepatic function (see
Therapeutic monitoring of the medicinal product and dose adjustment
).
It is not necessary to modify the Rapamune loading dose.
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until
3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or
after loading dose due to the delay in reaching steady-state because of the prolonged half-life.
Paediatric population
The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not
been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no
recommendation on a posology can be made.
Method of administration
Rapamune is for oral use only.
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
Hypersensitivity to the active substance or to any of the excipients.
Rapamune oral solution contains soya oil. Patients allergic to peanut or soya must not take this
medicine.
4
Rapamune has not been adequately studied in patients at high immunological risk, therefore use is not
recommended in this group of patients (see section 5.1).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
Hypersensitivity reactions
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative
dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus
(see section 4.8).
Concomitant therapy
Immunosuppressive agents
Sirolimus has been administered concurrently with the following agents in clinical studies:
tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies.
Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.
Renal function should be monitored during concomitant administration of Rapamune and ciclosporin.
Appropriate adjustment of the immunosuppression regimen should be considered in patients with
elevated serum creatinine levels. Caution should be exercised when co-administering other agents that
are known to have a deleterious effect on renal function.
Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels
and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and
placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had
lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower
incidence of malignancy, compared to patients remaining on ciclosporin. The continued
co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.
Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil,
and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not
recommended in the
de novo
renal transplant setting (see section 5.1).
Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating
conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients,
increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to
Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the
patients in the study (see section 4.8). The safety and efficacy of conversion from calcineurin
inhibitors to Rapamune in maintenance renal transplant patients have not been established.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced haemolytic uraemic syndrome/thrombotic 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.
5
Cytochrome P450 isozymes
Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole,
itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is
not recommended (see section 4.5).
Angiotensin-converting enzyme inhibitors (ACE)
The concomitant administration of sirolimus and angiotensin-converting enzyme inhibitors has
resulted in angioneurotic oedema-type reactions.
Vaccination
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants,
including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided
during treatment with Rapamune.
Malignancy
Increased susceptibility to infection and the possible development of lymphoma and other
malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual
for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by
wearing protective clothing and using a sunscreen with a high protection factor.
Infections
Oversuppression of the immune system can also increase susceptibility to infection, including
opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.
Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive
multifocal leukoencephalopathy (PML). These infections are often related to a high total
immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider
in the differential diagnosis in immunosuppressed patients with deteriorating renal function or
neurological symptoms.
Cases of
Pneumocystis carinii
pneumonia have been reported in patients not receiving antimicrobial
prophylaxis. Therefore, antimicrobial prophylaxis for
Pneumocystis carinii
pneumonia should be
administered for the first 12 months following transplantation.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly
for patients at increased risk for CMV disease.
Hepatic impairment
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely
monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one half is
recommended based on decreased clearance (see sections 4.2 and 5.2). Since half-life is prolonged in
these patients, therapeutic monitoring of the medicinal product after a loading dose or a change of
dose should be performed for a prolonged period of time until stable concentrations are reached (see
sections 4.2 and 5.2).
Lung and liver transplant populations
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver
or lung transplant patients, and therefore such use is not recommended.
In two clinical studies in
de novo
liver transplant patients, the use of sirolimus plus ciclosporin or
tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or
death.
6
A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor
(CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen
6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at
12 months (-4.45 ml/min and -3.07 ml/min, respectively). The study also failed to demonstrate
non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus
conversion group compared to the CNI continuation group. The rate of death in the sirolimus
conversion group was higher than the CNI continuation group, although the rates were not
significantly different. The rates of premature study discontinuation, adverse events overall (and
infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all
significantly greater in the sirolimus conversion group compared to the CNI continuation group.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in
de novo
lung transplant
patients when sirolimus has been used as part of an immunosuppressive regimen.
Systemic effects
There have been reports of impaired or delayed wound healing in patients receiving Rapamune,
including lymphocele and wound dehiscence. Patients with a body mass index (BMI) greater than
30 kg/m
2
may be at increased risk of abnormal wound healing based on data from the medical
literature.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults), in patients receiving Rapamune.
The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and
triglycerides that may require treatment. Patients administered Rapamune should be monitored for
hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions
such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be
considered in patients with established hyperlipidaemia before initiating an immunosuppressive
regimen, including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be
re-evaluated in patients with severe refractory hyperlipidaemia.
Ethanol
Rapamune oral solution contains up to 2.5 vol % ethanol (alcohol). A 6 mg loading dose contains up
to 150 mg of alcohol which is equivalent to 3 ml beer or 1.25 ml wine. This dose could potentially be
harmful for those suffering from alcoholism and should be taken into account in children and high-risk
groups such as patients with liver disease or epilepsy.
Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to
be too low to be harmful.
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).
7
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 C
max
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 C
max
, t
max
, 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 C
max
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 C
max
, t
max
, 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 C
max
, t
max
, and AUC were
increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C
max
and AUC were
both increased 1.5-fold, and t
max
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 C
max
, t
max
, and AUC
were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C
max
, t
max
, 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 C
max
and t
max
. When given 2 hours
before CsA administration, sirolimus C
max
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).
8
Oral contraceptives
No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution
and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study
with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude
the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral
contraceptive during long-term treatment with Rapamune.
Other possible interactions
Moderate and weak inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase
sirolimus blood levels (e.g., calcium channel blockers: nicardipine; antifungal agents: clotrimazole,
fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol,
protease inhibitors).
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels
(e.g., St. John's Wort (
Hypericum perforatum
),
anticonvulsants: carbamazepine, phenobarbital,
phenytoin).
Although sirolimus inhibits human liver microsomal cytochrome P
450
CYP2C9, CYP2C19, CYP2D6,
and CYP3A4/5
in vitro
, the active substance is not expected to inhibit the activity of these isozymes
in vivo
since the sirolimus concentrations necessary to produce inhibition are much higher than those
observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the
efflux of sirolimus from intestinal cells and increase sirolimus levels.
Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as
cisapride and metoclopramide.
No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the
following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine,
prednisolone, and trimethoprim/sulphamethoxazole.
Women of childbearing potential
Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has
been stopped (see section 4.5)
Pregnancy
There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune
should not be used during pregnancy unless clearly necessary. Effective contraception must be used
during Rapamune therapy and for 12 weeks after Rapamune has been stopped.
Breast-feeding
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating
rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse
reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during therapy.
Fertility
Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).
9
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.
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 (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); 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
Common
Uncommon
Rare
Not known
Infections and
infestations
Urinary tract
infection
Sepsis
Pneumonia
Pyelonephritis
Herpes simplex
Fungal, viral,
and bacterial
infections (such
as
mycobacterial
infections,
including
tuberculosis,
Epstein-Barr
virus, CMV,
and Herpes
zoster)
Clostridium
difficile
enterocolitis
Neoplasms
benign,
malignant and
unspecified
(including cysts
and polyps)
Skin cancer*
Lymphoma*/
post-
transplant
lymphoproli-
ferative
disorder
Blood and
lymphatic
system
Thrombocyto-
paenia
Anaemia
Thrombotic
Thrombo-
cytopaenic
Pancyto-
paenia
10
System Organ
Class
Very common
Common
Uncommon
Rare
Not known
disorders
purpura/hae-
molytic
uraemic
syndrome
Leukopaenia
Neutropaenia
Immune system
disorders
Hypersensitivi-
ty reactions,
including
anaphylactic/
anaphylactoid
reactions,
angioedema,
exfoliative
dermatitis, and
hypersensitivi-
ty vasculitis
(see section
4.4)
Metabolism
and nutrition
disorders
Hypokalaemia
Hypophospha-
taemia
Hypercholeste-
rolaemia
Hyperglycaemia
Hypertriglyceri-
daemia
Diabetes
mellitus
Nervous
system
disorders
Headache
Cardiac
disorders
Tachycardia
Pericardial
effusion
(including
haemody-
namically
significant
effusions in
children and
adults)
Vascular
disorders
Lymphocele
Hypertension
Deep vein
thrombosis
Pulmonary
embolism
Lymphoedema
Respiratory,
thoracic, and
mediastinal
disorders
Pneumonitis*
Pleural effusion
Epistaxis
Pulmonary
haemorrhage
Alveolar
proteinosis
Gastrointestinal
disorders
Abdominal pain
Diarrhoea
Constipation
Nausea
Stomatitis
Ascites
Pancreatitis
Hepatobiliary
disorders
Liver function
tests abnormal
Liver failure*
11
System Organ
Class
Very common
Common
Uncommon
Rare
Not known
Skin and
subcutaneous
tissue disorders
Acne
Rash
Musculoskele-
tal and
connective
tissue disorders
Arthralgia
Osteonecrosis
Renal and
urinary
disorders
Proteinuria
Nephrotic
syndrome
(see section
4.4)
Focal
segmental
glomerulo-
sclerosis*
General
disorders and
administration
site conditions
Oedema
peripheral
Pyrexia
Pain
Impaired
healing*
Oedema
Investigations Blood lactate
dehydrogenase
increased
Blood creatinine
increased
Aspartate
aminotransfer-
ase increased
Alanine
aminotransfer-
ase 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
etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In
some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of
Rapamune. The risk may be increased as the trough sirolimus level increases.
Impaired healing following transplant surgery has been reported, including fascial dehiscence,
incisional hernia, and anastomotic disruption (e.g. wound, vascular, airway, ureteral, biliary).
Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced HUS/TTP/TMA.
Focal segmental glomerulosclerosis has been reported.
12
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults) in patients receiving Rapamune.
In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus
(target levels of 12 - 20 ng/ml in maintenance renal transplant patients, enrollment was stopped in the
subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 ml/min (see section
5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft
loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Paediatric population
Controlled clinical studies with posology comparable to that currently indicated for the use of
Rapamune in adults have not been conducted in children or adolescents below 18 years of age.
Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of
age considered of high immunologic risk, defined as a history of one or more acute allograft rejection
episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The
use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with
an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not
limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment
regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not
indicated for adult or paediatric patients (see section 4.1).
In another study enrolling renal transplant patients 20 years of age and below that was intended to
assess the safety of progressive corticosteroid withdrawal (beginning at six months
post-transplantation) from an immunosuppressive regimen initiated at transplantation that included
full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with
basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed
post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be EBV
seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients
who developed PTLD were aged below 18 years.
There is insufficient experience to recommend the use of Rapamune in children and adolescents (see
section 4.2).
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.
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
13
cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the
mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition
of mTOR results in blockage of several specific signal transduction pathways. The net result is the
inhibition of lymphocyte activation, which results in immunosuppression.
In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated
reactions, such as allograft rejection.
Clinical studies
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin
elimination-Rapamune maintenance study, which 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
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
14
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 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.
Paediatic Ppopulation
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
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 6216h. 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 [
14
C] 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.
15
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/m
2
) 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/m
2
). 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.
In mild and moderate hepatically impaired patients (Child-Pugh classification A or B), mean values
for sirolimus AUC and t
1/2
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 t
1/2
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.
The pharmacokinetics of sirolimus were similar in various populations with renal function ranging
from normal to absent (dialysis patients).
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).
16
6.
6.1 List of excipients
Polysorbate 80 (E433)
Phosal 50 PG (phosphatidylcholine, propylene glycol, monodiglycerides, ethanol, soya fatty acids and
ascorbyl palmitate).
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 25C).
After dilution (see section 6.6), the preparation should be used immediately.
6.4 Special precautions for storage
Store in a refrigerator at 2C - 8C.
Store in the original bottle in order to protect from light.
If necessary, the patient may store the bottles at room temperatures up to 25C for a short period of
time (24 hours).
For storage conditions of the diluted 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 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.
17
7.
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
8.
EU/1/01/171/001
9.
Date of first authorisation: 14 March 2001
Date of latest renewal: 14 March 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
18
1.
Rapamune 0.5 mg coated tablets
2.
Each coated tablet contains 0.5 mg sirolimus.
Excipients: each tablet contains 86.4 mg of lactose monohydrate and 215.7 mg of sucrose.
For a full list of excipients, see section 6.1.
3.
Coated tablet (tablet).
Tan-coloured, triangular-shaped coated tablet marked “RAPAMUNE 0.5 mg” on one side.
4.
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).
Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist
in transplantation.
Posology
Initial therapy (2 to 3 months post-transplantation)
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as
possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of
the medicinal product are available (see
Therapeutic monitoring of the medicinal product and dose
adjustment
). The Rapamune dose should then be individualised to obtain whole blood trough levels of
4 to 12 ng/ml (chromatographic assay). Rapamune therapy should be optimised with a tapering
regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges
for the first 2-3 months after transplantation are 150-400 ng/ml (monoclonal assay or equivalent
technique) (see section 4.5
)
.
To minimise variability, Rapamune should be taken at the same time in relation to ciclosporin, 4 hours
after the ciclosporin dose, and consistently either with or without food (see section 5.2).
Maintenance therapy
Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be
adjusted to obtain whole blood trough levels of 12 to 20 ng/ml (chromatographic assay; see
Therapeutic monitoring of the medicinal product and dose adjustment
). Rapamune should be given
with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be
19
attempted, the combination of ciclosporin and Rapamune should not be maintained for more than
3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be
discontinued and an alternative immunosuppressive regimen instituted.
Therapeutic monitoring of the medicinal product and dose adjustment
Whole blood sirolimus levels should be closely monitored in the following populations
:
(1) in patients with hepatic impairment
(2) when inducers or inhibitors of CYP3A4 are concurrently administered and after their
discontinuation (see section 4.5) and/or
(3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to
have special dosing requirements.
Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus
therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory
parameters.
Most patients who received 2 mg of Rapamune 4 hours after ciclosporin had whole blood trough
concentrations of sirolimus within the 4 to 12 ng/ml target range (expressed as chromatographic assay
values). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all
patients.
Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained
more than 5 days after a previous dosing change.
Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis.
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or
tablet strength to confirm that the trough concentration is within the recommended target range.
Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/ml
(chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and
consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus
dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the
absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive
requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is
increased should correspond to the rate of ciclosporin elimination.
If further dose adjustment(s) are required during maintenance therapy (after discontinuation of
ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune
dose = current dose x (target concentration/current concentration). A loading dose should be
considered in addition to a new maintenance dose when it is necessary to considerably increase
sirolimus trough concentrations: Rapamune loading dose = 3 x (new maintenance dose – current
maintenance dose). The maximum Rapamune dose administered on any day should not exceed 40 mg.
If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose
should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to
4 days after a loading dose(s).
The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic
methods. Several assay methodologies have been used to measure the whole blood concentrations of
sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by
both chromatographic and immunoassay methodologies. The concentration values obtained by these
different methodologies are not interchangeable. All sirolimus concentrations reported in this
Summary of Product Characteristics were either measured using chromatographic methods or have
been converted to chromatographic method equivalents. Adjustments to the targeted range should be
made according to the assay being utilised to determine the sirolimus trough concentrations. Since
results are assay and laboratory dependent, and the results may change over time, adjustment to the
targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Physicians should therefore remain continuously informed by responsible representatives for their
20
local laboratory on the performance of the locally used method for concentration determination of
sirolimus.
Special populations
Black population
There is limited information indicating that Black renal transplant recipients (predominantly
African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as
observed in non-Black patients. Currently, the efficacy and safety data are too limited to allow specific
recommendations for use of sirolimus in Black recipients.
Elderly population (above 65 years)
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above
65 years of age to determine whether they will respond differently than younger patients (see
section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
Hepatic impairment
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2).
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune
be reduced by approximately one-half.
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with
impaired hepatic function (see
Therapeutic monitoring of the medicinal product and dose adjustment
).
It is not necessary to modify the Rapamune loading dose.
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until
3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or
after loading dose due to the delay in reaching steady-state because of the prolonged half-life.
Paediatric population
The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not
been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no
recommendation on a posology can be made.
Method of administration
Rapamune is for oral use only.
Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and
therefore this cannot be recommended.
To minimise variability, Rapamune should consistently be taken either with or without food.
Grapefruit juice should be avoided (see section 4.5).
Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths
(see section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
21
Rapamune has not been adequately studied in patients at high immunological risk, therefore use is not
recommended in this group of patients (see section 5.1).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
Hypersensitivity reactions
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative
dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus
(see section 4.8).
Concomitant therapy
Immunosuppressive agents
Sirolimus has been administered concurrently with the following agents in clinical studies:
tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies.
Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.
Renal function should be monitored during concomitant administration of Rapamune and ciclosporin.
Appropriate adjustment of the immunosuppression regimen should be considered in patients with
elevated serum creatinine levels. Caution should be exercised when co-administering other agents that
are known to have a deleterious effect on renal function.
Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels
and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and
placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had
lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower
incidence of malignancy, compared to patients remaining on ciclosporin. The continued
co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.
Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil,
and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not
recommended in the
de novo
renal transplant setting (see section 5.1).
Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating
conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients,
increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to
Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the
patients in the study (see section 4.8). The safety and efficacy of conversion from calcineurin
inhibitors to Rapamune in maintenance renal transplant patients have not been established.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thrombotic
microangiopathy (HUS/TTP/TMA).
HMG-CoA reductase inhibitors
In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors
and/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should be
monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or
fibrate should be monitored for the possible development of rhabdomyolysis and other adverse
reactions, as described in the respective Summary of Product Characteristics of these agents.
22
Cytochrome P450 isozymes
Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole,
itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is
not recommended (see section 4.5).
Angiotensin-converting enzyme inhibitors (ACE)
The concomitant administration of sirolimus and angiotensin-converting enzyme inhibitors has
resulted in angioneurotic oedema-type reactions.
Vaccination
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants,
including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided
during treatment with Rapamune.
Malignancy
Increased susceptibility to infection and the possible development of lymphoma and other
malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual
for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by
wearing protective clothing and using a sunscreen with a high protection factor.
Infections
Oversuppression of the immune system can also increase susceptibility to infection, including
opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.
Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive
multifocal leukoencephalopathy (PML). These infections are often related to a high total
immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider
in the differential diagnosis in immunosuppressed patients with deteriorating renal function or
neurological symptoms.
Cases of
Pneumocystis carinii
pneumonia have been reported in patients not receiving antimicrobial
prophylaxis. Therefore, antimicrobial prophylaxis for
Pneumocystis carinii
pneumonia should be
administered for the first 12 months following transplantation.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly
for patients at increased risk for CMV disease.
Hepatic impairment
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely
monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one-half is
recommended based on decreased clearance (see sections 4.2 and 5.2). Since half-life is prolonged in
these patients, therapeutic monitoring of the medicinal product after a loading dose or a change of
dose should be performed for a prolonged period of time until stable concentrations are reached (see
sections 4.2 and 5.2).
Lung and liver transplant populations
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver
or lung transplant patients, and therefore such use is not recommended.
In two clinical studies in
de novo
liver transplant patients, the use of sirolimus plus ciclosporin or
tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or
death.
23
A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor
(CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen
6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at
12 months (-4.45 ml/min and -3.07 ml/min, respectively). The study also failed to demonstrate
non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus
conversion group compared to the CNI continuation group. The rate of death in the sirolimus
conversion group was higher than the CNI continuation group, although the rates were not
significantly different. The rates of premature study discontinuation, adverse events overall (and
infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all
significantly greater in the sirolimus conversion group compared to the CNI continuation group.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in
de novo
lung transplant
patients when sirolimus has been used as part of an immunosuppressive regimen.
Systemic effects
There have been reports of impaired or delayed wound healing in patients receiving Rapamune,
including lymphocele and wound dehiscence. Patients with a body mass index (BMI) greater than
30 kg/m
2
may be at increased risk of abnormal wound healing based on data from the medical
literature.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults), in patients receiving Rapamune.
The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and
triglycerides that may require treatment. Patients administered Rapamune should be monitored for
hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions
such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be
considered in patients with established hyperlipidaemia before initiating an immunosuppressive
regimen, including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be
re-evaluated in patients with severe refractory hyperlipidaemia.
Sucrose and lactose
Sirolimus tablets contain 215.7 mg of sucrose and 86.4 mg of 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.
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).
24
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 C
max
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 C
max
, t
max
, 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 C
max
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 C
max
, t
max
, 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 C
max
, t
max
, and AUC were
increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C
max
and AUC were
both increased 1.5-fold, and t
max
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 C
max
, t
max
, and AUC
were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C
max
, t
max
, 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 C
max
and t
max
. When given 2 hours
before CsA administration, sirolimus C
max
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).
25
Oral contraceptives
No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution
and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study
with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude
the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral
contraceptive during long-term treatment with Rapamune.
Other possible interactions
Moderate and weak inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase
sirolimus blood levels (e.g., calcium channel blockers: nicardipine; antifungal agents: clotrimazole,
fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol,
protease inhibitors).
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels
(e.g., St. John's Wort (
Hypericum perforatum
),
anticonvulsants: carbamazepine, phenobarbital,
phenytoin).
Although sirolimus inhibits human liver microsomal cytochrome P
450
CYP2C9, CYP2C19, CYP2D6,
and CYP3A4/5
in vitro
, the active substance is not expected to inhibit the activity of these isozymes
in vivo
since the sirolimus concentrations necessary to produce inhibition are much higher than those
observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the
efflux of sirolimus from intestinal cells and increase sirolimus levels.
Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as
cisapride and metoclopramide.
No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the
following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine,
prednisolone, and trimethoprim/sulphamethoxazole.
Women of childbearing potential
Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has
been stopped (see section 4.5)
Pregnancy
There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune
should not be used during pregnancy unless clearly necessary. Effective contraception must be used
during Rapamune therapy and for 12 weeks after Rapamune has been stopped.
Breast-feeding
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating
rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse
reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during therapy.
26
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).
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.
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 (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); 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 Common
Uncommon Rare
Not known
Infections and
infestations
Urinary tract
infection
Sepsis
Pneumonia
Pyelonephritis
Herpes simplex
Fungal, viral,
and bacterial
infections (such
as
mycobacterial
infections,
including
tuberculosis,
Epstein-Barr
virus, CMV,
and Herpes
zoster)
Clostridium
difficile
enterocolitis
27
System Organ
Class
Very common Common
Uncommon Rare
Not known
Neoplasms
benign,
malignant and
unspecified
(including cysts
and polyps)
Skin cancer*
Lymphoma*/
post-
transplant
lymphoproli-
ferative
disorder
Blood and
lymphatic
system disorders
Thrombocyto-
paenia
Anaemia
Thrombotic
Thrombo-
cytopaenic
purpura/hae-
molytic
uraemic
syndrome
Leukopaenia
Neutropaenia
Pancyto-
paenia
Immune system
disorders
Hypersensitivi-
ty reactions,
including
anaphylactic/
anaphylactoid
reactions,
angioedema,
exfoliative
dermatitis, and
hypersensitivi-
ty vasculitis
(see section
4.4)
Metabolism and
nutrition
disorders
Hypokalaemia
Hypophospha-
taemia
Hypercholeste-
rolaemia
Hyperglycaemia
Hypertriglyceri-
daemia
Diabetes
mellitus
Nervous system
disorders
Headache
Cardiac
disorders
Tachycardia
Pericardial
effusion
(including
haemody-
namically
significant
effusions in
children and
adults)
Vascular
disorders
Lymphocele
Hypertension
Deep vein
thrombosis
Pulmonary
embolism
Lymphoedema
Respiratory,
thoracic, and
mediastinal
disorders
Pneumonitis*
Pleural effusion
Epistaxis
Pulmonary
haemorrhage
Alveolar
proteinosis
28
System Organ
Class
Very common Common
Uncommon Rare
Not known
Gastrointestinal
disorders
Abdominal pain
Diarrhoea
Constipation
Nausea
Stomatitis
Ascites
Pancreatitis
Hepatobiliary
disorders
Liver function
tests abnormal
Liver failure*
Skin and
subcutaneous
tissue disorders
Acne
Rash
Musculoskeletal
and connective
tissue disorders
Arthralgia
Osteonecrosis
Renal and
urinary disorders
Proteinuria
Nephrotic
syndrome
(see section
4.4)
Focal
segmental
glomerulo-
sclerosis*
General
disorders and
administration
site conditions
Oedema
peripheral
Pyrexia
Pain
Impaired
healing*
Oedema
Investigations
Blood lactate
dehydrogenase
increased
Blood creatinine
increased
Aspartate
aminotransfe-
rase increased
Alanine
aminotransfe-
rase 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
etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In
some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of
Rapamune. The risk may be increased as the trough sirolimus level increases.
Impaired healing following transplant surgery has been reported, including fascial dehiscence,
incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary).
Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
29
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced HUS/TTP/TMA.
Focal segmental glomerulosclerosis has been reported.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults) in patients receiving Rapamune.
In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus
(target levels of 12-20 ng/ml in maintenance renal transplant patients, enrollment was stopped in the
subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 ml/min (see section
5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft
loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Paediatric population
Controlled clinical studies with posology comparable to that currently indicated for the use of
Rapamune in adults have not been conducted in children or adolescents below 18 years of age).
Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of
age considered of high immunologic risk, defined as a history of one or more acute allograft rejection
episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The
use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with
an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not
limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment
regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not
indicated for adult or paediatric patients (see section 4.1).
In another study enrolling renal transplant patients 20 years of age and below that was intended to
assess the safety of progressive corticosteroid withdrawal (beginning at six months
post-transplantation) from an immunosuppressive regimen initiated at transplantation that included
full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with
basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed
post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be EBV
seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients
who developed PTLD were aged below 18 years.
There is insufficient experience to recommend the use of Rapamune in children and adolescents (see
section 4.2).
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.
30
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:
L04AA10.
Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and
calcium-independent intracellular signal transduction. Studies demonstrated that its effects are
mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other
immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific
cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the
mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition
of mTOR results in blockage of several specific signal transduction pathways. The net result is the
inhibition of lymphocyte activation, which results in immunosuppression.
In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated
reactions, such as allograft rejection.
Clinical studies
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin
elimination-Rapamune maintenance study, which 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
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).
31
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 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.
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.
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
32
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 [
14
C] 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/m
2
) 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/m
2
). 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 t
1/2
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 t
1/2
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.
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 C
max
.
Multiples of the 0.5 mg tablets should therefore not be used as a substitute for other tablet strengths.
33
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 C
max
was decreased
by 35%, and mean t
max
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, C
max
, t
max
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: C
min,ss
7.39 2.18 ng/ml; C
max,ss
15.0 4.9 ng/ml; t
max,ss
3.46 2.40 hours; AUC
,ss
230 67 ngh/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 C
min,ss
5.40 2.50 ng/ml, C
max,ss
14.4 5.3 ng/ml, t
max,ss
2.12 0.84 hours, AUC
,ss
194
78 ngh/ml, CL/F/W 173 50 ml/h/kg. Whole blood trough sirolimus concentrations, as measured by
LC/MS/MS, were significantly correlated (r
2
=0.85) with AUC
,ss
.
Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean
(10
th
, 90
th
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
(10
th
, 90
th
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).
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.
34
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.
6.1 List of excipients
Tablet core:
Lactose monohydrate
Macrogol
Magnesium stearate
Talc
Tablet coating:
Macrogol
Glycerol
monooleate
Pharmaceutical glaze (shellac)
Calcium sulphate
Microcrystalline cellulose
Sucrose
Titanium dioxide
Yellow iron oxide (E172)
Brown iron oxide (E172)
Poloxamer 188
-tocopherol
Povidone
Carnauba wax
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 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.
35
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
No special requirements.
7.
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
8.
EU/1/01/171/013-14
9.
Date of first authorisation: 14 March 2001
Date of latest renewal: 14 March 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
36
1.
Rapamune 1 mg coated tablets.
2.
Each coated tablet contains 1 mg sirolimus.
Excipients: each tablet contains 86.4 mg of lactose monohydrate and 215.8 mg of sucrose.
For a full list of excipients, see section 6.1.
3.
Coated tablet (tablet).
White-coloured, triangular-shaped coated tablet marked “RAPAMUNE 1 mg” on one side.
4.
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).
Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist
in transplantation.
Posology
Initial therapy (2 to 3 months post-transplantation)
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as
possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of
the medicinal product are available (see
Therapeutic monitoring of the medicinal product and dose
adjustment
). The Rapamune dose should then be individualised to obtain whole blood trough levels of
4 to 12 ng/ml (chromatographic assay). Rapamune therapy should be optimised with a tapering
regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges
for the first 2-3 months after transplantation are 150-400 ng/ml (monoclonal assay or equivalent
technique) (see section 4.5
)
.
To minimize 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
37
attempted, the combination of ciclosporin and Rapamune should not be maintained for more than
3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be
discontinued and an alternative immunosuppressive regimen instituted.
Therapeutic monitoring of the medicinal product and dose adjustment
Whole blood sirolimus levels should be closely monitored in the following populations
:
(1) in patients with hepatic impairment
(2) when inducers or inhibitors of CYP3A4 are concurrently administered and after their
discontinuation (see section 4.5) and/or
(3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to
have special dosing requirements.
Therapeutic monitoring of the medicinal product should not be the sole basis for adjusting sirolimus
therapy. Careful attention should be made to clinical signs/symptoms, tissue biopsies, and laboratory
parameters.
Most patients who received 2 mg of Rapamune 4 hours after ciclosporin had whole blood trough
concentrations of sirolimus within the 4 to 12 ng/ml target range (expressed as chromatographic assay
values). Optimal therapy requires therapeutic concentration monitoring of the medicinal product in all
patients.
Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained
more than 5 days after a previous dosing change.
Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis.
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or
tablet strength to confirm that the trough concentration is within the recommended target range.
Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/ml
(chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and
consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus
dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the
absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive
requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is
increased should correspond to the rate of ciclosporin elimination.
If further dose adjustment(s) are required during maintenance therapy (after discontinuation of
ciclosporin), in most patients these adjustments can be based on simple proportion: new Rapamune
dose = current dose x (target concentration/current concentration). A loading dose should be
considered in addition to a new maintenance dose when it is necessary to considerably increase
sirolimus trough concentrations: Rapamune loading dose = 3 x (new maintenance dose – current
maintenance dose). The maximum Rapamune dose administered on any day should not exceed 40 mg.
If an estimated daily dose exceeds 40 mg due to the addition of a loading dose, the loading dose
should be administered over 2 days. Sirolimus trough concentrations should be monitored at least 3 to
4 days after a loading dose(s).
The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic
methods. Several assay methodologies have been used to measure the whole blood concentrations of
sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by
both chromatographic and immunoassay methodologies. The concentration values obtained by these
different methodologies are not interchangeable. All sirolimus concentrations reported in this
Summary of Product Characteristics were either measured using chromatographic methods or have
been converted to chromatographic method equivalents. Adjustments to the targeted range should be
made according to the assay being utilised to determine the sirolimus trough concentrations. Since
results are assay and laboratory dependent, and the results may change over time, adjustment to the
targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Physicians should therefore remain continuously informed by responsible representatives for their
38
local laboratory on the performance of the locally used method for concentration determination of
sirolimus.
Special populations
Black population
There is limited information indicating that Black renal transplant recipients (predominantly
African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as
observed in non-Black patients. Currently, the efficacy and safety data are too limited to allow specific
recommendations for use of sirolimus in Black recipients.
Elderly population (above 65 years)
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above
65 years of age to determine whether they will respond differently than younger patients (see
section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
Hepatic impairment
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2).
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune
be reduced by approximately one-half.
It is recommended that sirolimus whole blood trough levels be closely monitored in patients with
impaired hepatic function (see
Therapeutic monitoring of the medicinal product and dose adjustment
).
It is not necessary to modify the Rapamune loading dose.
In patients with severe hepatic impairment, monitoring should be performed every 5 to 7 days until
3 consecutive trough levels have shown stable concentrations of sirolimus after dose adjustment or
after loading dose due to the delay in reaching steady-state because of the prolonged half-life.
Paediatric population
The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not
been established. Currently available data are described in sections 4.8, 5.1 and 5.2, but no
recommendation on a posology can be made.
Method of administration
Rapamune is for oral use only.
Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and
therefore this cannot be recommended.
To minimise variability, Rapamune should consistently be taken either with or without food.
Grapefruit juice should be avoided (see section 4.5).
Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths
(see section 5.2).
Hypersensitivity to the active substance or to any of the excipients.
39
Rapamune has not been adequately studied in patients at high immunological risk, therefore use is not
recommended in this group of patients (see section 5.1).
In patients with delayed graft function, sirolimus may delay recovery of renal function.
Hypersensitivity reactions
Hypersensitivity reactions, including anaphylactic/anaphylactoid reactions, angioedema, exfoliative
dermatitis, and hypersensitivity vasculitis, have been associated with the administration of sirolimus
(see section 4.8).
Concomitant therapy
Immunosuppressive agents
Sirolimus has been administered concurrently with the following agents in clinical studies:
tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies.
Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.
Renal function should be monitored during concomitant administration of Rapamune and ciclosporin.
Appropriate adjustment of the immunosuppression regimen should be considered in patients with
elevated serum creatinine levels. Caution should be exercised when co-administering other agents that
are known to have a deleterious effect on renal function.
Patients treated with ciclosporin and Rapamune beyond 3 months had higher serum creatinine levels
and lower calculated glomerular filtration rates compared to patients treated with ciclosporin and
placebo or azathioprine controls. Patients who were successfully withdrawn from ciclosporin had
lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower
incidence of malignancy, compared to patients remaining on ciclosporin. The continued
co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.
Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil,
and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not
recommended in the
de novo
renal transplant setting (see section 5.1).
Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating
conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients,
increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to
Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the
patients in the study (see section 4.8). The safety and efficacy of conversion from calcineurin
inhibitors to Rapamune in maintenance renal transplant patients have not been established.
The concomitant use of Rapamune with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced haemolytic uraemic syndrome/thrombotic thrombocytopaenic purpura/thrombotic
microangiopathy (HUS/TTP/TMA).
HMG-CoA reductase inhibitors
In clinical studies, the concomitant administration of Rapamune and HMG-CoA reductase inhibitors
and/or fibrates was well-tolerated. During Rapamune therapy with or without CsA, patients should be
monitored for elevated lipids, and patients administered an HMG-CoA reductase inhibitor and/or
fibrate should be monitored for the possible development of rhabdomyolysis and other adverse
reactions, as described in the respective Summary of Product Characteristics of these agents.
40
Cytochrome P450 isozymes
Co-administration of sirolimus with strong inhibitors of CYP3A4 (such as ketoconazole, voriconazole,
itraconazole, telithromycin or clarithromycin) or inducers of CYP3A4 (such as rifampin, rifabutin) is
not recommended (see section 4.5).
Angiotensin-converting enzyme inhibitors (ACE)
The concomitant administration of sirolimus and angiotensin-converting enzyme inhibitors has
resulted in angioneurotic oedema-type reactions.
Vaccination
Immunosuppressants may affect response to vaccination. During treatment with immunosuppressants,
including Rapamune, vaccination may be less effective. The use of live vaccines should be avoided
during treatment with Rapamune.
Malignancy
Increased susceptibility to infection and the possible development of lymphoma and other
malignancies, particularly of the skin, may result from immunosuppression (see section 4.8). As usual
for patients with increased risk for skin cancer, exposure to sunlight and UV light should be limited by
wearing protective clothing and using a sunscreen with a high protection factor.
Infections
Oversuppression of the immune system can also increase susceptibility to infection, including
opportunistic infections (bacterial, fungal, viral and protozoal), fatal infections, and sepsis.
Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive
multifocal leukoencephalopathy (PML). These infections are often related to a high total
immunosuppressive burden and may lead to serious or fatal conditions that physicians should consider
in the differential diagnosis in immunosuppressed patients with deteriorating renal function or
neurological symptoms.
Cases of
Pneumocystis carinii
pneumonia have been reported in patients not receiving antimicrobial
prophylaxis. Therefore, antimicrobial prophylaxis for
Pneumocystis carinii
pneumonia should be
administered for the first 12 months following transplantation.
Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after transplantation, particularly
for patients at increased risk for CMV disease.
Hepatic impairment
In hepatically impaired patients, it is recommended that sirolimus whole blood trough levels be closely
monitored. In patients with severe hepatic impairment, reduction in maintenance dose by one half is
recommended based on decreased clearance (see sections 4.2 and 5.2). Since half-life is prolonged in
these patients, therapeutic monitoring of the medicinal product after a loading dose or a change of
dose should be performed for a prolonged period of time until stable concentrations are reached (see
sections 4.2 and 5.2).
Lung and liver transplant populations
The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver
or lung transplant patients, and therefore such use is not recommended.
In two clinical studies in
de novo
liver transplant patients, the use of sirolimus plus ciclosporin or
tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or
death.
41
A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor
(CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen
6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at
12 months (-4.45 ml/min and -3.07 ml/min, respectively). The study also failed to demonstrate
non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus
conversion group compared to the CNI continuation group. The rate of death in the sirolimus
conversion group was higher than the CNI continuation group, although the rates were not
significantly different. The rates of premature study discontinuation, adverse events overall (and
infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all
significantly greater in the sirolimus conversion group compared to the CNI continuation group.
Cases of bronchial anastomotic dehiscence, most fatal, have been reported in
de novo
lung transplant
patients when sirolimus has been used as part of an immunosuppressive regimen.
Systemic effects
There have been reports of impaired or delayed wound healing in patients receiving Rapamune,
including lymphocele and wound dehiscence. Patients with a body mass index (BMI) greater than
30 kg/m
2
may be at increased risk of abnormal wound healing based on data from the medical
literature.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults), in patients receiving Rapamune.
The use of Rapamune in renal transplant patients was associated with increased serum cholesterol and
triglycerides that may require treatment. Patients administered Rapamune should be monitored for
hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions
such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be
considered in patients with established hyperlipidaemia before initiating an immunosuppressive
regimen, including Rapamune. Similarly the risk/benefit of continued Rapamune therapy should be
re-evaluated in patients with severe refractory hyperlipidaemia.
Sucrose and lactose
Sirolimus tablets contain 215.8 mg of sucrose and 86.4 mg of 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.
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).
42
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 C
max
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 C
max
, t
max
, 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 C
max
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 C
max
, t
max
, 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 C
max
, t
max
, and AUC were
increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil C
max
and AUC were
both increased 1.5-fold, and t
max
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 C
max
, t
max
, and AUC
were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The C
max
, t
max
, 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 C
max
and t
max
. When given 2 hours
before CsA administration, sirolimus C
max
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).
43
Oral contraceptives
No clinically significant pharmacokinetic interaction was observed between Rapamune oral solution
and 0.3 mg norgestrel/0.03 mg ethinyl estradiol. Although the results of a single-dose interaction study
with an oral contraceptive suggest the lack of a pharmacokinetic interaction, the results cannot exclude
the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral
contraceptive during long-term treatment with Rapamune.
Other possible interactions
Moderate and weak inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase
sirolimus blood levels (e.g., calcium channel blockers: nicardipine; antifungal agents: clotrimazole,
fluconazole; antibiotics: troleandomycin; other substances: bromocriptine, cimetidine, danazol,
protease inhibitors).
Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels
(e.g., St. John's Wort (
Hypericum perforatum
),
anticonvulsants: carbamazepine, phenobarbital,
phenytoin).
Although sirolimus inhibits human liver microsomal cytochrome P
450
CYP2C9, CYP2C19, CYP2D6,
and CYP3A4/5
in vitro
, the active substance is not expected to inhibit the activity of these isozymes
in vivo
since the sirolimus concentrations necessary to produce inhibition are much higher than those
observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the
efflux of sirolimus from intestinal cells and increase sirolimus levels.
Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.
Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as
cisapride and metoclopramide.
No clinically significant pharmacokinetic interaction was observed between sirolimus and any of the
following substances: acyclovir, atorvastatin, digoxin, glibenclamide, methylprednisolone, nifedipine,
prednisolone, and trimethoprim/sulphamethoxazole.
Women of childbearing potential
Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has
been stopped (see section 4.5)
Pregnancy
There are no adequate data from the use of sirolimus in pregnant women. Studies in animals have
shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown. Rapamune
should not be used during pregnancy unless clearly necessary. Effective contraception must be used
during Rapamune therapy and for 12 weeks after Rapamune has been stopped.
Breast-feeding
Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating
rats. It is not known whether sirolimus is excreted in human milk. Because of the potential for adverse
reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during therapy.
44
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).
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.
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 (≥1/1000 to <1/100); rare (≥1/10,000 to <1/1000); 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.
Common
Uncommon
Rare
System Organ
Class
Very common
Not known
Infections and
infestations
Urinary tract
infection
Sepsis
Pneumonia
Pyelonephritis
Herpes simplex
Fungal, viral,
and bacterial
infections (such
as
mycobacterial
infections,
including
tuberculosis,
Epstein-Barr
virus, CMV,
and Herpes
zoster)
Clostridium
difficile
enterocolitis
Neoplasms
benign,
malignant and
unspecified
Skin cancer*
Lymphoma*/
post-
transplant
lymphoproli-
45
Common
Uncommon
Rare
System Organ
Class
Very common
Not known
(including cysts
and polyps)
ferative
disorder
Blood and
lymphatic
system
disorders
Thrombocyto-
paenia
Anaemia
Thrombotic
Thrombo-
cytopaenic
purpura/hae-
molytic
uraemic
syndrome
Leukopaenia
Neutropaenia
Pancyto-
paenia
Immune system
disorders
Hypersensitivi-
ty reactions,
including
anaphylactic/
anaphylactoid
reactions,
angioedema,
exfoliative
dermatitis, and
hypersensitivi-
ty vasculitis
(see section
4.4)
Metabolism
and nutrition
disorders
Hypokalaemia
Hypophospha-
taemia
Hypercholeste-
rolaemia
Hyperglycaemia
Hypertriglyceri-
daemia
Diabetes
mellitus
Nervous
system
disorders
Headache
Cardiac
disorders
Tachycardia
Pericardial
effusion
(including
haemody-
namically
significant
effusions in
children and
adults)
Vascular
disorders
Lymphocele
Hypertension
Deep vein
thrombosis
Pulmonary
embolism
Lymphoedema
Respiratory,
thoracic, and
mediastinal
disorders
Pneumonitis*
Pleural effusion
Epistaxis
Pulmonary
haemorrhage
Alveolar
proteinosis
Gastrointestinal Abdominalpain Stomatitis
Pancreatitis
46
Common
Uncommon
Rare
System Organ
Class
Very common
Not known
disorders
Diarrhoea
Constipation
Nausea
Ascites
Hepatobiliary
disorders
Liver function
tests abnormal
Liver failure*
Skin and
subcutaneous
tissue disorders
Acne
Rash
Musculoskeleta
l and
connective
tissue disorders
Arthralgia
Osteonecrosis
Renal and
urinary
disorders
Proteinuria
Nephrotic
syndrome
(see section
4.4)
Focal
segmental
glomerulo-
sclerosis*
General
disorders and
administration
site conditions
Oedema
peripheral
Pyrexia
Pain
Impaired
healing*
Oedema
Investigations Blood lactate
dehydrogenase
increased
Blood creatinine
increased
Aspartate
aminotransfer-
ase increased
Alanine
aminotransfer-
ase 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
etiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In
some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of
Rapamune. The risk may be increased as the trough sirolimus level increases.
Impaired healing following transplant surgery has been reported, including fascial dehiscence,
incisional hernia, and anastomotic disruption (e.g., wound, vascular, airway, ureteral, biliary).
Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).
47
In patients with delayed graft function, sirolimus may delay recovery of renal function.
The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin
inhibitor-induced HUS/TTP/TMA.
Focal segmental glomerulosclerosis has been reported.
There have also been reports of fluid accumulation, including peripheral oedema, lymphoedema,
pleural effusion and pericardial effusions (including haemodynamically significant effusions in
children and adults) in patients receiving Rapamune.
In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus
(target levels of 12-20 ng/ml in maintenance renal transplant patients, enrollment was stopped in the
subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 ml/min (see section
5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft
loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).
Paediatric population
Controlled clinical studies with posology comparable to that currently indicated for the use of
Rapamune in adults have not been conducted in children or adolescents below 18 years of age).
Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of
age considered of high immunologic risk, defined as a history of one or more acute allograft rejection
episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The
use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with
an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not
limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment
regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not
indicated for adult or paediatric patients (see section 4.1).
In another study enrolling renal transplant patients 20 years of age and below that was intended to
assess the safety of progressive corticosteroid withdrawal (beginning at six months
post-transplantation) from an immunosuppressive regimen initiated at transplantation that included
full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with
basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed
post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be EBV
seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD. All patients
who developed PTLD were aged below 18 years.
There is insufficient experience to recommend the use of Rapamune in children and adolescents (see
section 4.2).
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.
48
5.
5.1 Pharmacodynamic properties
Pharmacotherapeutic group: Immunosuppressants, selective immunosuppressants, ATC code:
L04AA10.
Sirolimus inhibits T-cell activation induced by most stimuli, by blocking calcium-dependent and
calcium-independent intracellular signal transduction. Studies demonstrated that its effects are
mediated by a mechanism that is different from that of ciclosporin, tacrolimus, and other
immunosuppressive agents. Experimental evidence suggests that sirolimus binds to the specific
cytosolic protein FKPB-12, and that the FKPB 12-sirolimus complex inhibits the activation of the
mammalian Target Of Rapamycin (mTOR), a critical kinase for cell cycle progression. The inhibition
of mTOR results in blockage of several specific signal transduction pathways. The net result is the
inhibition of lymphocyte activation, which results in immunosuppression.
In animals, sirolimus has a direct effect on T- and B-cell activation, suppressing immune-mediated
reactions, such as allograft rejection.
Clinical studies
Patients at low to moderate immunological risk were studied in the phase 3 ciclosporin
elimination-Rapamune maintenance study, which 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
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).
49
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 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.
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.
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
50
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 [
14
C] 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/m
2
) 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/m
2
). The younger children had a higher weight-normalised CL/F (214ml/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 t
1/2
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 t
1/2
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.
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 C
max
.
Multiples of the 0.5 mg tablets should therefore not be used as a substitute for other tablet strengths.
51
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 C
max
was decreased
by 35%, and mean t
max
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, C
max
, t
max
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: C
min,ss
7.39 2.18 ng/ml; C
max,ss
15.0 4.9 ng/ml; t
max,ss
3.46 2.40 hours; AUC
,ss
230 67 ngh/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 C
min,ss
5.40 2.50 ng/ml, C
max,ss
14.4 5.3 ng/ml, t
max,ss
2.12 0.84 hours, AUC
,ss
194
78 ngh/ml, CL/F/W 173 50 ml/h/kg. Whole blood trough sirolimus concentrations, as measured by
LC/MS/MS, were significantly correlated (r
2
=0.85) with AUC
,ss
.
Based on monitoring in all patients during the period of concomitant therapy with ciclosporin, mean
(10
th
, 90
th
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
(10
th
, 90
th
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).
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.
52
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.
6.1 List of excipients
Tablet core:
Lactose monohydrate
Macrogol
Magnesium stearate
Talc
Tablet coating:
Macrogol
Glycerol
monooleate
Pharmaceutical glaze (shellac)
Calcium sulphate
Microcrystalline cellulose
Sucrose
Titanium dioxide
Poloxamer 188
-tocopherol
Povidone
Carnauba wax
6.2 Incompatibilities
Not applicable.
6.3 Shelf life
2 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.
53
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
No special requirements.
7.
Wyeth Europa Ltd.
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
8.
EU/1/01/171/007-8
9.
Date of first authorisation: 14 March 2001
Date of latest renewal: 14 March 2006
Detailed information on this product is available on the website of the European Medicines Agency
http://www.ema.europa.eu
54
1.
FURTHER 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 sulphate,
microcrystalline cellulose, sucrose, titanium dioxide, poloxamer 188, -tocopherol, povidone,
carnauba wax. The 0.5 mg and 2 mg tablets also contain yellow iron oxide and brown iron oxide.
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:
Wyeth Europa Ltd
Huntercombe Lane South
Taplow, Maidenhead
Berkshire, SL6 0PH
United Kingdom
Manufacturer:
Wyeth Medica Ireland
Little Connell
Newbridge
Co. Kildare
Ireland
For any information about this medicinal product, 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
Magyarország
Pfizer Kft.
Tel: +36 1 488 3700
България/Eesti/Latvija/Lietuva/ Slovenija
Wyeth Whitehall Export GmbH
Teл/Tel/Tãlr:+43 1 89 1140
Malta
Vivian Corporation Ltd.
Tel: +35621 344610
Česká Republika
Pfizer s.r.o.
Tel: +420-283-004-111
Nederland
Wyeth Pharmaceuticals B.V.
Tel: +31 23 567 2567
Danmark
Pfizer ApS
Tlf: +45 44 201 100
Norge
Pfizer AS
Tlf: +47 67 526 100
107
Deutschland
Pfizer Pharma GmbH
Tel: +49 (0)30 550055-51000
Österreich
Pfizer Corporation Austria Ges.m.b.H.
Tel: +43 (0)1 521 15-0
Ελλάδα
Pfizer Hellas A.E.
Τηλ.: +30 210 6785 800
Polska
Pfizer Polska Sp. z o.o.,
Tel.: +48 22 335 61 00
España
Pfizer, S.A.
Télf:+34914909900
Portugal
Laboratórios Pfizer, Lda.
Tel: (+351) 21 423 55 00
France
Pfizer
Tél : +33 (0)1 58 07 34 40
România
Pfizer Romania S.R.L
Tel: +40 (0) 21 207 28 00
Ireland
Wyeth Pharmaceuticals
Tel: +353 1 449 3500
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
Wyeth Lederle S.p.A.
Tel: +39 06 927151
Sverige
Pfizer AB
Tel: +46 (0)8 550 520 00
Kύπρος
Wyeth Hellas (Cyprus Branch) AEBE
T: +357 22 817690
United Kingdom
Wyeth Pharmaceuticals
Tel: +44 1628 415330
This leaflet was last approved in:
Detailed information on this medicine is available on the European Medicines Agency website:
http://www.ema.europa.eu
108
Source: European Medicines Agency
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