sirolimus: prescribing information – dosing, contraindications, interactions, side effects

For healthcare professionals

Hyftor

4.1 Therapeutic indications

Hyftor is indicated for the treatment of facial angiofibroma associated with tuberous sclerosis complex in adults and paediatric patients aged 6 years and older.

4.2 Posology and method of administration

Posology

This medicinal product should be applied to the affected area twice daily (in the morning and at bedtime). The application should be limited to skin areas with angiofibroma.

A dose of 125 mg gel (or 0.5 cm gel, corresponding to 0.25 mg sirolimus) should be administered per 50 cm2 lesion in the face.

The maximum recommended daily dose in the face is:
- Patients aged 6-11 years should apply up to 600 mg gel (1.2 mg sirolimus), corresponding to approximately 2 cm gel strand per day.
- Patients aged ≥ 12 years should apply up to 800 mg gel (1.6 mg sirolimus), corresponding to approximately 2.5 cm gel strand per day.

The dose should be equally divided for two administrations.

Missed dose

If the first dose was missed in the morning, the application should be done immediately upon realisation of the fact provided this was before dinner of the same day. Otherwise only the application in the evening should be administered on that day. If the application in the evening was missed this should not be taken at a later point in time.

Special populations

Elderly
No dose adjustment is required in elderly patients (≥ 65 years) (see section 5.2).

Renal impairment
No formal studies have been performed in patients with renal impairment. However, no dose adjustment is required in this population since systemic exposure to sirolimus is low in individuals using Hyftor.

Hepatic impairment
No formal studies have been performed in patients with hepatic impairment. However, no dose adjustment is required in this population since systemic exposure to sirolimus is low in individuals using Hyftor (see section 4.4).

Paediatric population
The posology is the same in adults and children aged 12 years and older (up to a total of 800 mg gel per day).
The maximum dose for patients aged 6-11 years is a total of 600 mg gel per day.
The safety and efficacy of Hyftor in children less than 6 years has not been established. Currently available data are presented in section 5.2 but no recommendation on a posology can be made.

Method of administration

For cutaneous use only.

Application should be limited to areas of facial angiofibroma lesions (see section 4.4.).
A thin layer of gel should be administered to the affected skin and rubbed in gently.
The application site should not be occluded.

The gel should not be applied around the eyes and on the eyelids (see section 4.4).

In case no treatment effect appears, administration with Hyftor should be discontinued after 12 weeks.

Hands should be washed carefully before and after administration of the gel to ensure that no gel remains on the hands that may be accidentially ingested or trigger exposure to sirolimus of any other part of the body or other persons.

4.3 Contraindications

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

4.8 Undesirable effects

Summary of the safety profile

The most commonly reported adverse reactions were skin irritation events, including application site irritation (34.7%), dry skin (33.7%), acne (19.4%), and pruritus (11.2%). These events were generally mild or moderate in intensity, nonserious, and did not lead to treatment discontinuation.

Tabulated list of adverse reactions

Adverse reactions reported from the clinical studies are listed in table 1 by system organ class and frequency using the following convention: very common (≥1/10), common (≥ 1/100 to < 1/10), uncommon (≥ 1/1 000 to < 1/100), rare (≥ 1/10 000 to < 1/1 000), very rare (< 1/10 000), and not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 1: Adverse reactions
System Organ Class
Very common
Common
Infections and Infestations
Conjunctivitis;
Folliculitis
Furuncle;
Tinea versicolour
Eye disorders

Eye irritation;
Erythema of eyelid;
Ocular hyperaemia
Respiratory, thoracic and mediastinal disorders

Nasal discomfort
Gastrointestinal disorders

Stomatitis
Skin and subcutaneous tissue disorders
Dry skin;
Pruritus
Acne
Asteatosis;
Dermatitis;
Dermatitis contact;
Dermatitis acneiform;
Dermal cyst;
Eczema
Papule
Photosensitivity reaction;
Rash pruritic;
Seborrhoeic dermatitis
Solar dermatitis;
Urticaria;
Xeroderma
Erythema;
Rash;
Skin exfoliation;
Skin irritation;
Skin haemorrhage
General disorders and administration site conditions
Application site irritation
Application site haemorrhage;
Application site paraesthesia;
Application site swelling
Injury, poisoning and procedural complications

Skin abrasion

Description of selected adverse reactions

Application site irritation

Application site irritation of mild or moderate intensity occurred in 34.7% of patients treated with sirolimus gel in clinical studies. Application site irritation did not require discontinuation of treatment with the medicinal product.

Dry skin

Dry skin of mild or moderate intensity occurred in 33.7% of patients treated with sirolimus gel in clinical studies. Dry skin did not require discontinuation of treatment with the medicinal product.

Acne

Acne was reported in 19.4% of patients overall treated with sirolimus gel in clinical studies. Acne was of mild or moderate intensity; no severe acne was reported. Acne/dermatitis acneiform did not require discontinuation of treatment with the medicinal product.

Pruritus

Mild or moderate intensity pruritus occurred in 11.2% of patients treated with sirolimus gel in clinical studies. Pruritus did not require discontinuation of treatment with the medicinal product.

Paediatric population

In clinical development, no difference was seen in the safety between paediatric patients aged 6 years and older and adult patients included in a Phase III study including 27 patients ≤ 18 years (Hyftor: n=13) and a long-term study including 50 patients ≤ 18 years (Hyftor: all).

Reporting of suspected adverse reactions

Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

4.4 Special warnings and precautions for use

Immunosupressed patients

Although systemic exposure is much lower following topical treatment with Hyftor than after systemic treatment with sirolimus, the gel should not be used in immunocompromised adults and children as a precautionary measure.

Mucous membranes and damaged skin

Hyftor should not be used on wounds, irritated skin or skin with a clinically confirmed diagnosis of infection as well as in patients with known skin barrier defects.
Contact with eyes or mucous membranes (mouth, nose) should be avoided. Therefore, the gel should not be applied around the eyes and on the eyelids.

Photosensitivity

Photosensitivity reactions have been observed in patients treated with Hyftor (see sections 4.8 and 5.3). Therefore, patients should avoid exposure to natural or artificial sunlight during the treatment period. Physicians should advise patients on appropriate sun protection methods, such as minimisation of the time in the sun, use of a sunscreen product and covering of the skin with appropriate clothing and/or headgear.

Skin cancer

Skin cancer has been observed after long-term treatment with oral sirolimus in preclinical studies (see section 5.3) and in patients treated systemically for immunosuppression. Although systemic exposure is much lower during treatment with sirolimus gel than with systemically administered sirolimus, patients should minimise or avoid exposure to natural or artificial sunlight during therapy using the same measures as mentioned above, to prevent photosensitivity.

Lymphoproliferative disorders

Lymphoproliferative disorders secondary to chronic systemic use of immunosuppressive agents have been reported in patients.

Severe hepatic impairment

Sirolimus is metabolised in the liver and blood concentrations are low following topical administration. As a precautionary measure in patients with severe hepatic impairment, treatment should be discontinued in case any potential systemic side effects are observed.

Hyperlipidaemia

Increased serum levels of cholesterol or triglycerides have been observed during treatment with sirolimus, in particular after oral administration. Patients with established hyperlipidaemia should regularly monitor lipid blood levels during treatment with sirolimus gel.

Excipients with known effect

Ethanol

This medicinal product contains 458 mg ethanol in each gram. This may cause burning sensation on damaged skin.

4.5 Interaction with other medicinal products and other forms of interaction

No interaction studies have been performed.

Sirolimus is extensively metabolised by the CYP3A4 isoenzyme, and it is a substrate for the multidrug efflux pump P-glycoprotein (P-gp). In addition, sirolimus has been shown to inhibit human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro. In the light of the low systemic exposure after topical administration it is not expected that clinical relevant interactions will occur, but Hyftor should be used with caution in patients taking respective concomitant medicinal products. Potential adverse reactions should be monitored and in case observed, treatment should be interrupted.

Except for sunscreens, no other topical treatments should be used on the facial angiofibroma lesions while treatment is ongoing.

Vaccination

During treatment with Hyftor, vaccinations may be less effective. Vaccination with live vaccines should be avoided during treatment.

Oral contraceptives

No interactions studies with Hyftor and oral contraceptives have been performed. Low systemic exposure to sirolimus during topical treatment with Hyftor makes pharmacokinetic drug interactions unlikely. The possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Hyftor cannot be fully excluded. For this reason, patients should be advised to use non-hormonal contraceptive measures during treatment.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no or limited amount of data from the use of Hyftor in pregnant women. Studies in animals have shown reproductive toxicity following systemic administration (see section 5.3).
Hyftor should not be used during pregnancy, unless the clinical condition of the woman requires treatment with sirolimus.

Breast-feeding

Available pharmacokinetic data in rats have shown excretion of systemically administred sirolimus in milk. It is unknown whether sirolimus is excreted in human milk, although clinical data have shown that systemic exposure is low following administration of Hyftor.
A decision must be made whether to discontinue breast-feeding or to discontinue/abstain from Hyftor therapy, taking into account the benefit of breast feeding for the child and the benefit of therapy for the woman.

Fertility

Impairments of sperm parameters have been observed among some patients treated systemically with sirolimus. These effects were reversible upon discontinuation of systemic sirolimus treatment in most cases.

4.7 Effects on ability to drive and use machines

Hyftor has no or negligible influence on the ability to drive and use machines.

4.9 Overdose

If accidentally ingested, general supportive measures may be appropriate. Due to the poor aqueous solubility and high erythrocyte and plasma protein binding, sirolimus will not be dialysable to a significant extent.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: Protein kinase inhibitors, mammalian target of rapamycin (mTOR) kinase inhibitors, ATC code: L01EG04

Mechanism of action

The exact mechanism of action of sirolimus in the treatment of angiofibroma in the tuberous sclerosis complex is not exactly known.
In general, sirolimus inhibits activation of mTOR which is a serine/threonine protein kinase that belongs to the phosphatidylinositol-3-kinase (PI3K)-related kinase family and regulates cellular metabolism, growth and proliferation. In cells, sirolimus binds to the immunophilin, FK Binding Protein-12 (FKBP-12), to generate an immunosuppressive complex. This complex binds to and inhibits the activation of mTOR.

Clinical efficacy and safety

Sirolimus gel was evaluated in a Phase III, randomised, double-blind, placebo-controlled study (NPC- 12G-1).

In this study, patients enrolled were aged ≥ 6 years with a diagnosis of tuberous sclerosis complex with ≥ 3 facial, red angiofibroma (AF) lesions ≥ 2 mm in diameter, and who had not received prior laser therapy or surgery. Patients with clinical findings such as erosion, ulcer and eruption on or around the lesion of angiofibroma, which may affect assessment of safety or efficacy, were excluded.

Sirolimus gel (or matching placebo) was applied to facial AF lesions twice daily for 12 weeks, with a Hyftor gel amount of 125 mg (corresponding to 0.25 mg sirolimus) per 50 cm2 affected skin area. No other medicinal products with an anticipated treatment effect on AF associated with tuberous sclerosis complex were allowed.

A total of 62 patients were enrolled (30 in the sirolimus gel group and 32 in the placebo group). The mean age was 21.6 years in the sirolimus gel group and 23.3 years in the placebo group and paediatric patients accounted for 44% overall trial population.

The results of the study showed a statistically significant increase in composite AF improvement (defined as concomitant improvement in AF size and AF redness) at 12 weeks with sirolimus gel treatment, compared with placebo treatment, based on independent review committee (IRC) assessment. The responder rate, defined as patients with improvement or markedly improvement, was 60% with sirolimus gel versus 0% with placebo (see Table 2).

Table 2: Efficacy results in study NPC-12G-1: composite AF improvement by IRC at week 12

Sirolimus gel
Placebo
Patients, n (%)
30 (100.0)
32 (100.0)
Markedly improved
5 (16.7)
Improved
13 (43.3)
Slightly improved
11 (36.7)
5 (15.6)
Unchanged
1 (3.3)
26 (81.3)
Slightly exacerbated
Exacerbated
Not evaluated
1 (3.1) p-value (Wilcoxon rank sum test)
<0.001

Excerpt – full text in the original document. Original document (PDF, EMA)

5.2 Pharmacokinetic properties

Absorption

In the phase III study in patients treated for angiofibroma, 70% of patients had measurable sirolimus plasma concentrations after 12 weeks of treatment (range 0.11-0.50 ng/ml). Blood samples were obtained in the 52-week long-term -study at pre-defined time points and the maximum sirolimus concentration measured at any time in adult patients was 3.27 ng/ml and the maximum sirolimus concentration measured at any time in paediatric patients was 1.80 ng/ml.

Distribution

For systemically administered sirolimus, terminal half-life in stable renal transplant patients after multiple oral doses was 62±16 hours.
The blood to plasma ratio of 36 indicates that sirolimus is extensively partitioned into formed blood elements.

Biotransformation

Sirolimus is a substrate for both, cytochrome CYP3A4 and P-gp. 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.

Elimination

Excretion of sirolimus is mainly via the hepatic/faecal route. After a single oral dose of [14C]-sirolimus in healthy volunteers, the greatest amount (91.1%) of radioactivity was recovered from the faeces, and only a minor amount (2.2%) was excreted in urine.

Special populations

Elderly

There are no pharmacokinetic data available after administration of sirolimus gel to patients aged 65 years and older since studies performed with sirolimus gel did not include patients of this age (see sections 4.2).

Renal impairment

Pharmacokinetic data from patients with renal impairment are not available.

Hepatic impairment

Pharmacokinetic data from patients with hepatic impairment are not available.

Paediatric population

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Rapamune

4.1 Therapeutic indications

Applies to: Rapamune 1 mg/mL oral solution · Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

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

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

4.2 Posology and method of administration

Applies to: Rapamune 1 mg/mL oral solution

Posology

Prophylaxis of organ rejection

Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation.

Initial therapy (2 to 3 months post-transplantation)
The usual dose regimen for Rapamune is a 6 mg single oral loading dose, administered as soon as possible after transplantation, followed by 2 mg once daily until results of therapeutic monitoring of the medicinal product are available (see Therapeutic monitoring of the medicinal product and dose adjustment). The Rapamune dose should then be individualised to obtain whole blood trough levels of 4 to 12 ng/mL (chromatographic assay). Rapamune therapy should be optimised with a tapering regimen of steroids and ciclosporin microemulsion. Suggested ciclosporin trough concentration ranges for the first 2-3 months after transplantation are 150-400 ng/mL (monoclonal assay or equivalent technique) (see section 4.5).

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

Maintenance therapy
Ciclosporin should be progressively discontinued over 4 to 8 weeks, and the Rapamune dose should be adjusted to obtain whole blood trough levels of 12 to 20 ng/mL (chromatographic assay; see Therapeutic monitoring of the medicinal product and dose adjustment). Rapamune should be given with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and Rapamune should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, Rapamune should be discontinued and an alternative immunosuppressive regimen instituted.

Therapeutic monitoring of the medicinal product and dose adjustment
Whole blood sirolimus levels should be closely monitored in the following populations:

(1) in patients with hepatic impairment
(2) when inducers or inhibitors of CYP3A4 and/or P-glycoprotein (P-gp) are concurrently administered and after their discontinuation (see section 4.5) and/or (3) if ciclosporin dosing is markedly reduced or discontinued, as these populations are most likely to have special dosing requirements.

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

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

Optimally, adjustments in Rapamune dose should be based on more than a single trough level obtained more than 5 days after a previous dosing change.

Patients can be switched from Rapamune oral solution to the tablet formulation on a mg per mg basis.
It is recommended that a trough concentration be taken 1 or 2 weeks after switching formulations or tablet strength to confirm that the trough concentration is within the recommended target range.

Following the discontinuation of ciclosporin therapy, a target trough range of 12 to 20 ng/mL (chromatographic assay) is recommended. Ciclosporin inhibits the metabolism of sirolimus, and consequently sirolimus levels will decrease when ciclosporin is discontinued, unless the sirolimus dose is increased. On average, the sirolimus dose will need to be 4-fold higher to account for both the absence of the pharmacokinetic interaction (2-fold increase) and the augmented immunosuppressive requirement in the absence of ciclosporin (2-fold increase). The rate at which the dose of sirolimus is increased should correspond to the rate of ciclosporin elimination.

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

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of

sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents. Adjustments to the targeted range should be made according to the assay being utilised to determine the sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus.

Patients with sporadic lymphangioleiomyomatosis (S-LAM)

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

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

In most patients, dose adjustments can be based on simple proportion: new Rapamune dose=current dose x (target concentration/current concentration). Frequent Rapamune dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once Rapamune maintenance dose is adjusted, patients should continue on the new maintenance dose for at least 7 to 14 days before further dosage adjustment with concentration monitoring. Once a stable dose is achieved, therapeutic drug monitoring should be performed at least every 3 months.

Data from controlled studies for treatment of S-LAM longer than one year are currently not available, therefore the benefit of treatment should be reassessed when used long-term.

Special populations

Black population
There is limited information indicating that Black renal transplant recipients (predominantly African-American) require higher doses and trough levels of sirolimus to achieve the same efficacy as observed in non-Black patients. The efficacy and safety data are too limited to allow specific recommendations for use of sirolimus in Black recipients.

Elderly
Clinical studies with Rapamune oral solution did not include a sufficient number of patients above 65 years of age to determine whether they will respond differently than younger patients (see section 5.2).

Renal impairment
No dose adjustment is required (see section 5.2).

Hepatic impairment
The clearance of sirolimus may be reduced in patients with impaired hepatic function (see section 5.2).
In patients with severe hepatic impairment, it is recommended that the maintenance dose of Rapamune be reduced by approximately one-half.

It is recommended that sirolimus whole blood trough levels be closely monitored in patients with impaired hepatic function (see Therapeutic monitoring of the medicinal product and dose adjustment).
It is not necessary to modify the Rapamune loading dose.

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.

Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

Posology

Prophylaxis of organ rejection

Treatment should be initiated by and remain under the guidance of an appropriately qualified specialist in transplantation.

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).

Therapeutic monitoring of the medicinal product and dose adjustment
Whole blood sirolimus levels should be closely monitored in the following populations:

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.

The recommended 24-hour trough concentration ranges for sirolimus are based on chromatographic methods. Several assay methodologies have been used to measure the whole blood concentrations of sirolimus. Currently in clinical practice, sirolimus whole blood concentrations are being measured by both chromatographic and immunoassay methodologies. The concentration values obtained by these different methodologies are not interchangeable. All sirolimus concentrations reported in this Summary of Product Characteristics were either measured using chromatographic methods or have been converted to chromatographic method equivalents. Adjustments to the targeted range should be made according to the assay being utilised to determine the sirolimus trough concentrations. Since results are assay and laboratory dependent, and the results may change over time, adjustment to the targeted therapeutic range must be made with a detailed knowledge of the site-specific assay used.
Physicians should therefore remain continuously informed by responsible representatives for their local laboratory on the performance of the locally used method for concentration determination of sirolimus.

Patients with sporadic lymphangioleiomyomatosis (S-LAM)

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

Data from controlled studies for treatment of S-LAM longer than one year are currently not available, therefore the benefit of treatment should be reassessed when used long-term.

Special populations

Renal impairment
No dose adjustment is required (see section 5.2).

Paediatric population
The safety and efficacy of Rapamune in children and adolescents less than 18 years of age have not been established.

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

Method of administration

Rapamune is for oral use only.

Bioavailability has not been determined for tablets after they have been crushed, chewed or split, and therefore this cannot be recommended.

To minimise variability, Rapamune should consistently be taken either with or without food.

Grapefruit juice should be avoided (see section 4.5).

Multiples of 0.5 mg tablets should not be used as a substitute for the 1 mg tablet or for other strengths (see section 5.2).

4.3 Contraindications

Applies to: Rapamune 1 mg/mL oral solution

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

Rapamune oral solution contains soya oil. Patients allergic to peanut or soya must not take this medicine.

Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

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

4.8 Undesirable effects

Applies to: Rapamune 1 mg/mL oral solution

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation

The most commonly reported adverse reactions (occurring in 10% of patients) are thrombocytopaenia, anaemia, pyrexia, hypertension, hypokalaemia, hypophosphataemia, urinary tract infection, hypercholesterolaemia, hyperglycaemia, hypertriglyceridaemia, abdominal pain, lymphocoele, peripheral oedema, arthralgia, acne, diarrhoea, pain, constipation, nausea, headache, increased blood creatinine, and increased blood lactate dehydrogenase (LDH).

The incidence of any adverse reaction(s) may increase as the trough sirolimus level increases.

The following list of adverse reactions is based on experience from clinical studies and on postmarketing experience.

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

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

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

System organ class
Very common
(≥1/10)
Common
(≥1/100 to
<1/10)
Uncommon
(≥1/1,000 to
<1/100)
Rare
(≥1/10,000 to
<1/1,000)
Frequency not known
(cannot be estimated from available data)
Infections and infestations
Pneumonia;
Fungal infection;
Viral infection;
Bacterial infection;
Herpes simplex infection;
Urinary tract infection
Sepsis;
Pyelonephritis;
Cytomegalo- virus infection;
Herpes zoster caused by the varicella zoster virus
Clostridium difficile colitis;
Mycobacterial infection
(including tuberculosis);
Epstein-Barr virus infection

Non- melanoma skin cancer*
Lymphoma*;
Malignant melanoma*;
Post transplant lympho- proliferative disorder

Neuroendo crine carcinoma of the skin*
Blood and lymphatic system disorders
Thrombo- cytopaenia;
Anaemia;
Leucopenia
Haemolytic uraemic syndrome;
Neutropaenia
Pancytopaenia;
Thrombotic thrombo- cytopaenic purpura

Immune system disorders

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

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

Nervous system disorders
Headache

Posterior reversible encephalo- pathy syndrome
Cardiac disorders
Tachycardia
Pericardial effusion

Vascular disorders
Hypertension;
Lymphocele
Venous thrombosis
(including deep vein thrombosis)
Lymphoedema

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism;
Pneumonitis*;
Pleural effusion;
Epistaxis
Pulmonary haemorrhage
Alveolar proteinosis

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

Hepatic failure*

Skin and subcutaneous tissue disorders
Rash;
Acne

Dermatitis exfoliative
Hypersen- sitivity vasculitis

Musculoskeleta l and connective tissue disorders
Arthralgia
Osteonecrosis

Renal and urinary disorders
Proteinuria

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

Reproductive system and breast disorders
Menstrual disorder
(including amenorrhoea and menorrhagia)
Ovarian cyst

General disorders and administration site conditions
Oedema;
Oedema peripheral;
Pyrexia;
Pain;
Impaired healing*

Investigations
Blood lactate dehydrogenase increased;
Blood creatinine increased

*See section below.

Description of selected adverse reactions

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

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

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

Cases of interstitial lung disease (including pneumonitis and infrequently bronchiolitis obliterans organising pneumonia (BOOP) and pulmonary fibrosis), some fatal, with no identified infectious aetiology have occurred in patients receiving immunosuppressive regimens including Rapamune. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of Rapamune. The risk may be increased as the trough sirolimus level increases.

Impaired healing following transplant surgery has been reported, including fascial dehiscence, incisional hernia, and anastomotic disruption (e.g. wound, vascular, airway, ureteral, biliary).

Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

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

The concomitant use of sirolimus with a calcineurin inhibitor may increase the risk of calcineurin inhibitor-induced HUS/TTP/TMA.

Focal segmental glomerulosclerosis has been reported.

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

In a study evaluating the safety and efficacy of conversion from calcineurin inhibitors to sirolimus (target levels of 12 - 20 ng/mL in maintenance renal transplant patients, enrollment was stopped in the subset of patients (n=90) with a baseline glomerular filtration rate of less than 40 mL/min (see section 5.1). There was a higher rate of serious adverse events, including pneumonia, acute rejection, graft loss and death, in this sirolimus treatment arm (n=60, median time post-transplant 36 months).

Ovarian cysts and menstrual disorders (including amenorrhoea and menorrhagia) have been reported.
Patients with symptomatic ovarian cysts should be referred for further evaluation. The incidence of ovarian cysts may be higher in premenopausal females compared to postmenopausal females. In some cases, ovarian cysts and these menstrual disorders have resolved upon discontinuation of Rapamune.

Paediatric population

Controlled clinical studies with posology comparable to that currently indicated for the use of Rapamune in adults have not been conducted in children or adolescents below 18 years of age.

Safety was assessed in a controlled clinical study enrolling renal transplant patients below 18 years of age considered of high immunologic risk, defined as a history of one or more acute allograft rejection episodes and/or the presence of chronic allograft nephropathy on a renal biopsy (see section 5.1). The use of Rapamune in combination with calcineurin inhibitors and corticosteroids was associated with an increased risk of deterioration of renal function, serum lipid abnormalities (including, but not limited to, increased serum triglycerides and cholesterol), and urinary tract infections. The treatment

regimen studied (continuous use of Rapamune in combination with calcineurin inhibitor) is not indicated for adult or paediatric patients (see section 4.1).

In another study enrolling renal transplant patients 20 years of age and below that was intended to assess the safety of progressive corticosteroid withdrawal (beginning at six months post-transplantation) from an immunosuppressive regimen initiated at transplantation that included full-dose immunosuppression with both Rapamune and a calcineurin inhibitor in combination with basiliximab induction, of the 274 patients enrolled, 19 (6.9%) were reported to have developed post-transplant lymphoproliferative disorder (PTLD). Among 89 patients known to be Epstein-Barr virus (EBV) seronegative prior to transplantation, 13 (15.6%) were reported to have developed PTLD.
All patients who developed PTLD were aged below 18 years.

There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).

Undesirable effects observed with patients with S-LAM

Safety was assessed in a controlled study involving 89 patients with LAM, of which 81 patients had S-LAM and 42 of whom were treated with Rapamune (see section 5.1). The adverse drug reactions observed in patients with S-LAM were consistent with the known safety profile of the product for the indication prophylaxis of organ rejection in renal transplantation with the addition of weight decreased, which was reported in the study at a greater incidence with Rapamune when compared to that observed with placebo (common, 9.5% vs. common, 2.6%).

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important. It allows continued monitoring of the benefit/risk balance of the medicinal product. Healthcare professionals are asked to report any suspected adverse reactions via the national reporting system listed in Appendix V.

Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation

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 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.

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

Non- melanoma skin cancer*
Lymphoma*;
Malignant melanoma*;
Post transplant lympho- proliferative disorder

Immune system disorders

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

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

Nervous system disorders
Headache

Posterior reversible encephalo- pathy syndrome

Vascular disorders
Hypertension;
Lymphocele
Venous thrombosis
(including deep vein thrombosis)
Lymphoedema

Respiratory, thoracic and mediastinal disorders

Pulmonary embolism;
Pneumonitis*;
Pleural effusion;
Epistaxis
Pulmonary haemorrhage
Alveolar proteinosis

Gastrointestinal disorders
Abdominal pain;
Constipation;
Diarrhoea;
Nausea
Pancreatitis;
Stomatitis;
Ascites

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

Hepatic failure*

Skin and subcutaneous tissue disorders
Rash;
Acne

Dermatitis exfoliative
Hypersen- sitivity vasculitis

Musculoskeletal and connective tissue disorders
Arthralgia
Osteonecrosis

Renal and urinary disorders
Proteinuria

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

Reproductive system and breast disorders
Menstrual disorder
(including amenorrhoea and menorrhagia)
Ovarian cyst

Investigations
Blood lactate dehydrogenase increased;
Blood creatinine increased

*See section below.

Description of selected adverse reactions

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

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.

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.

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).

There is insufficient experience to recommend the use of Rapamune in children and adolescents (see section 4.2).

Undesirable effects observed with patients with S-LAM

4.4 Special warnings and precautions for use

Applies to: Rapamune 1 mg/mL oral solution

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

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

Hypersensitivity reactions

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

Concomitant therapy

Immunosuppressive agents (Renal transplant patients only)
Sirolimus has been administered concurrently with the following agents in clinical studies: tacrolimus, ciclosporin, azathioprine, mycophenolate mofetil, corticosteroids and cytotoxic antibodies. Sirolimus in combination with other immunosuppressive agents has not been extensively investigated.

Renal function should be monitored during concomitant administration of Rapamune and ciclosporin.
Appropriate adjustment of the immunosuppression regimen should be considered in patients with elevated serum creatinine levels. Caution should be exercised when co-administering other agents that are known to have a deleterious effect on renal function.

lower serum creatinine levels and higher calculated glomerular filtration rates, as well as lower incidence of malignancy, compared to patients remaining on ciclosporin. The continued co-administration of ciclosporin and Rapamune as maintenance therapy cannot be recommended.

Based on information from subsequent clinical studies, the use of Rapamune, mycophenolate mofetil, and corticosteroids, in combination with IL-2 receptor antibody (IL2R Ab) induction, is not recommended in the de novo renal transplant setting (see section 5.1).

Periodic quantitative monitoring of urinary protein excretion is recommended. In a study evaluating conversion from calcineurin inhibitors to Rapamune in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to Rapamune (see section 5.1). New onset nephrosis (nephrotic syndrome) was also reported in 2% of the patients in the study (see section 4.8). Based on information from an open-label randomised study, conversion from the calcineurin inhibitor tacrolimus to Rapamune in maintenance renal transplant patients was associated with an unfavourable safety profile without efficacy benefit and can therefore not be recommended (see section 5.1).

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

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

Cytochrome P450 isozymes and P-glycoprotein
Co-administration of sirolimus with strong inhibitors of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (P-gp) (such as ketoconazole, voriconazole, itraconazole, telithromycin or clarithromycin) may increase sirolimus blood levels and is not recommended.

Co-administration with strong inducers of CYP3A4 and/or P-gp (such as rifampin, rifabutin) is not recommended.

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

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

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

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

Malignancy

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

Infections

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

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

Cases of Pneumocystis carinii pneumonia have been reported in renal transplant patients not receiving antimicrobial prophylaxis. Therefore, antimicrobial prophylaxis for Pneumocystis carinii pneumonia should be administered for the first 12 months following transplantation.

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, particularly for patients at increased risk for CMV disease.

Hepatic impairment

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

Lung and liver transplant populations

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore such use is not recommended.

In two clinical studies in de novo liver transplant patients, the use of sirolimus plus ciclosporin or tacrolimus was associated with an increase in hepatic artery thrombosis, mostly leading to graft loss or death.

A clinical study in liver transplant patients randomised to conversion from a calcineurin inhibitor (CNI)-based regimen to a sirolimus-based regimen versus continuation of a CNI-based regimen 6-144 months post-liver transplantation failed to demonstrate superiority in baseline-adjusted GFR at 12 months (-4.45 mL/min and -3.07 mL/min, respectively). The study also failed to demonstrate non-inferiority of the rate of combined graft loss, missing survival data, or death for the sirolimus conversion group compared to the CNI continuation group. The rate of death in the sirolimus conversion group was higher than the CNI continuation group, although the rates were not significantly different. The rates of premature study discontinuation, adverse events overall (and infections, specifically), and biopsy-proven acute liver graft rejection at 12 months were all significantly greater in the sirolimus conversion group compared to the CNI continuation group.

Cases of bronchial anastomotic dehiscence, most fatal, have been reported in de novo lung transplant patients when sirolimus has been used as part of an immunosuppressive regimen.

Systemic effects

There have been reports of impaired or delayed wound healing in patients receiving Rapamune, including lymphocele in renal transplant patients and wound dehiscence. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

The use of Rapamune was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered Rapamune should be monitored for hyperlipidaemia using laboratory tests and if hyperlipidaemia is detected, subsequent interventions such as diet, exercise, and lipid-lowering agents should be initiated. The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen, including Rapamune.
Similarly the risk/benefit of continued Rapamune therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.

Ethanol

Rapamune oral solution contains up to 3.17 vol % ethanol (alcohol). A 6 mg loading dose contains up to 150 mg of alcohol which is equivalent to 3.80 mL beer or 1.58 mL wine. This dose could potentially be harmful for those suffering from alcoholism and should be taken into account in pregnant or breast-feeding women, children and high-risk groups such as patients with liver disease or epilepsy.

Maintenance doses of 4 mg or less contain small amounts of ethanol (100 mg or less) that are likely to be too low to be harmful.

Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

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

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

Hypersensitivity reactions

Concomitant therapy

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.

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).

Co-administration with strong inducers of CYP3A4 and/or P-gp (such as rifampin, rifabutin) is not recommended.

Malignancy

Infections

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

Cytomegalovirus (CMV) prophylaxis is recommended for 3 months after renal transplantation, particularly for patients at increased risk for CMV disease.

Hepatic impairment

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

Lung and liver transplant populations

The safety and efficacy of Rapamune as immunosuppressive therapy have not been established in liver or lung transplant patients, and therefore such use is not recommended.

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

Sucrose and lactose

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

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

4.5 Interaction with other medicinal products and other forms of interaction

Applies to: Rapamune 1 mg/mL oral solution

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver.
Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by substances that affect these proteins. Inhibitors of CYP3A4 (such as ketoconazole, voriconazole, itraconazole, telithromycin, or clarithromycin) decrease the metabolism of sirolimus and increase sirolimus levels. Inducers of CYP3A4 (such as rifampin or rifabutin) increase the metabolism of sirolimus and decrease sirolimus levels. Co-administration of sirolimus with strong inhibitors of CYP3A4 or inducers of CYP3A4 is not recommended (see section 4.4).

Rifampicin (CYP3A4 inducer)

Administration of multiple doses of rifampicin decreased sirolimus whole blood concentrations following a single 10 mg dose of Rapamune oral solution. Rifampicin increased the clearance of sirolimus by approximately 5.5-fold and decreased AUC and Cmax by approximately 82% and 71%, respectively. Co-administration of sirolimus and rifampicin is not recommended (see section 4.4).

Ketoconazole (CYP3A4 inhibitor)

Multiple-dose ketoconazole administration significantly affected the rate and extent of absorption and sirolimus exposure from Rapamune oral solution as reflected by increases in sirolimus Cmax, tmax, and AUC of 4.4-fold, 1.4-fold, and 10.9-fold, respectively. Co-administration of sirolimus and ketoconazole is not recommended (see section 4.4).

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).

Diltiazem (CYP3A4 inhibitor)

The simultaneous oral administration of 10 mg of Rapamune oral solution and 120 mg of diltiazem significantly affected the bioavailability of sirolimus. Sirolimus Cmax, tmax, and AUC were increased 1.4-fold, 1.3-fold, and 1.6-fold, respectively. Sirolimus did not affect the pharmacokinetics of either diltiazem or its metabolites desacetyldiltiazem and desmethyldiltiazem. If diltiazem is administered, sirolimus blood levels should be monitored and a dose adjustment may be necessary.

Verapamil (CYP3A4 inhibitor)

Multiple-dose administration of verapamil and sirolimus oral solution significantly affected the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 2.3-fold, 1.1-fold, and 2.2-fold, respectively. Plasma S-(-) verapamil Cmax and AUC were both increased 1.5-fold, and tmax was decreased 24%. Sirolimus levels should be monitored, and appropriate dose reductions of both medicinal products should be considered.

Erythromycin (CYP3A4 inhibitor)

Multiple-dose administration of erythromycin and sirolimus oral solution significantly increased the rate and extent of absorption of both medicinal products. Whole blood sirolimus Cmax, tmax, and AUC were increased 4.4-fold, 1.4-fold, and 4.2-fold, respectively. The Cmax, tmax, and AUC of plasma erythromycin base were increased 1.6-fold, 1.3-fold, and 1.7-fold, respectively. Sirolimus levels should be monitored and appropriate dose reductions of both medicinal products should be considered.

Ciclosporin (CYP3A4 substrate)

The rate and extent of sirolimus absorption was significantly increased by ciclosporin A (CsA).
Sirolimus administered concomitantly (5 mg), and at 2 hours (5 mg) and 4 hours (10 mg) after CsA (300 mg), resulted in increased sirolimus AUC by approximately 183%, 141% and 80%, respectively.
The effect of CsA was also reflected by increases in sirolimus Cmax and tmax. When given 2 hours before CsA administration, sirolimus Cmax and AUC were not affected. Single-dose sirolimus did not affect the pharmacokinetics of ciclosporin (microemulsion) in healthy volunteers when administered simultaneously or 4 hours apart. It is recommended that Rapamune be administered 4 hours after ciclosporin (microemulsion).

Cannabidiol (P-gp inhibitor)

There have been reports of increased blood levels of sirolimus during concomitant use with cannabidiol. Co-administration of cannabidiol with another orally administered mTOR inhibitor in a healthy volunteer study led to an increase in exposure to the mTOR inhibitor of approximately 2.5-fold for both Cmax and AUC, due to inhibition of intestinal P-gp efflux by cannabidiol. Caution should be used when cannabidiol and Rapamune are co-administered, closely monitoring for side effects. Monitor sirolimus blood levels and adjust the dose as needed (see sections 4.2 and 4.4).

Oral contraceptives

the possibility of changes in the pharmacokinetics that might affect the efficacy of the oral contraceptive during long-term treatment with Rapamune.

Other possible interactions

Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels.
Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole), certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g.
ritonavir, indinavir, boceprevir, telaprevir), nicardipine, bromocriptine, cimetidine, danazol and letermovir.

Inducers of CYP3A4 may increase the metabolism of sirolimus and decrease sirolimus blood levels (e.g. St. John's Wort (Hypericum perforatum), anticonvulsants: carbamazepine, phenobarbital, phenytoin).

Although sirolimus inhibits human liver microsomal cytochrome P450 CYP2C9, CYP2C19, CYP2D6, and CYP3A4/5 in vitro, the active substance is not expected to inhibit the activity of these isozymes in vivo since the sirolimus concentrations necessary to produce inhibition are much higher than those observed in patients receiving therapeutic doses of Rapamune. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.

Grapefruit juice affects CYP3A4-mediated metabolism, and should therefore be avoided.

Pharmacokinetic interactions may be observed with gastrointestinal prokinetic agents, such as cisapride and metoclopramide.

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

Paediatric population

Interaction studies have only been performed in adults.

Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

Rifampicin (CYP3A4 inducer)

Ketoconazole (CYP3A4 inhibitor)

Voriconazole (CYP3A4 inhibitor)

Co-administration of sirolimus (2 mg single dose) with multiple-dose administration of oral voriconazole (400 mg every 12 hours for 1 day, then 100 mg every 12 hours for 8 days) in healthy subjects has been reported to increase sirolimus Cmax and AUC by an average of 7-fold and 11-fold, respectively. Co-administration of sirolimus and voriconazole is not recommended (see section 4.4).

Diltiazem (CYP3A4 inhibitor)

Verapamil (CYP3A4 inhibitor)

Erythromycin (CYP3A4 inhibitor)

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)

Cannabidiol (P-gp inhibitor)

Oral contraceptives

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

Other possible interactions

Inhibitors of CYP3A4 may decrease the metabolism of sirolimus and increase sirolimus blood levels.
Such inhibitors include certain antifungals (e.g. clotrimazole, fluconazole, itraconazole, voriconazole), certain antibiotics (e.g. troleandomycin, telithromycin, clarithromycin), certain protease inhibitors (e.g.
ritonavir, indinavir, boceprevir, and telaprevir), nicardipine, bromocriptine, cimetidine, danazol and letermovir.

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).

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.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Applies to: Rapamune 1 mg/mL oral solution · Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

Women of childbearing potential

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

Pregnancy

There are no or limited amount of data from the use of sirolimus in pregnant women. Studies in animals have shown reproductive toxicity (see section 5.3). The potential risk for humans is unknown.
Rapamune should not be used during pregnancy unless clearly necessary. Effective contraception must be used during Rapamune therapy and for 12 weeks after Rapamune has been stopped.

Breast-feeding

Following administration of radiolabelled sirolimus, radioactivity is excreted in the milk of lactating rats. It is unknown whether sirolimus is excreted in human milk. Because of the potential for adverse reactions in breast-fed infants from sirolimus, breast-feeding should be discontinued during treatment with Rapamune.

Fertility

Impairments of sperm parameters have been observed among some patients treated with Rapamune.
These effects have been reversible upon discontinuation of Rapamune in most cases (see section 5.3).

4.7 Effects on ability to drive and use machines

Applies to: Rapamune 1 mg/mL oral solution · Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

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

4.9 Overdose

Applies to: Rapamune 1 mg/mL oral solution · Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of Rapamune. In general, the adverse effects of overdose are consistent with those listed in section 4.8. General supportive measures should be initiated in all cases of overdose. Based on the poor aqueous solubility and high erythrocyte and plasma protein binding of Rapamune, it is anticipated that Rapamune will not be dialysable to any significant extent.

5.
PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Applies to: Rapamune 1 mg/mL oral solution · Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

Pharmacotherapeutic group: Immunosuppressants, ATC code: L04AH01.

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

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

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

Clinical studies

Prophylaxis of Organ Rejection

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

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

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5.2 Pharmacokinetic properties

Applies to: Rapamune 1 mg/mL oral solution

Oral solution

Following administration of the Rapamune oral solution, sirolimus is rapidly absorbed, with a time to peak concentration of 1 hour in healthy subjects receiving single doses and 2 hours in patients with stable renal allografts receiving multiple doses. The systemic availability of sirolimus in combination with simultaneously administered ciclosporin (Sandimune) is approximately 14%. Upon repeated administration, the average blood concentration of sirolimus is increased approximately 3-fold. The terminal half-life in stable renal transplant patients after multiple oral doses was 6216h. The effective half-life, however, is shorter and mean steady-state concentrations were achieved after 5 to 7 days.
The blood to plasma ratio (B/P) of 36 indicates that sirolimus is extensively partitioned into formed blood elements.

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

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

In paediatric patients on dialysis (30% to 50% reduction in glomerular filtration rate) within age ranges of 5 to 11 years and 12 to 18 years, the mean weight-normalised CL/F was larger for younger

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Applies to: Rapamune 0.5 mg coated tablets / Rapamune 1 mg coated tablets / Rapamune 2 mg coated tablets

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 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.

Excerpt – full text in the original document. Original document (PDF, EMA)

Date of revision: OF THE TEXT Detailed information on this medicinal product is available on the website of the European Medicines Agency http://www.ema.europa.eu.

Source: European Medicines Agency (EMA), product information. Not advertising, not a treatment recommendation. For questions about your own treatment, ask your doctor or pharmacist.