4.1. Therapeutic indications

This medicine 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 sirolimus be used initially in combination with ciclosporin microemulsion and corticosteroids for 2 to 3 months. Sirolimus may be continued as maintenance therapy with corticosteroids only if ciclosporin microemulsion can be progressively discontinued (see sections 4.2 and 5.1).

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

4.2. Posology and method of administration

Posology

Prophylaxis of organ rejection

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

Initial therapy (2 to 3 months post-transplantation)

The usual dose regimen 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 dose should then be individualised to obtain whole blood trough levels of 4 to 12 ng/mL (chromatographic assay). 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, sirolimus 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 sirolimus 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). Sirolimus should be given with corticosteroids. In patients for whom ciclosporin withdrawal is either unsuccessful or cannot be attempted, the combination of ciclosporin and sirolimus should not be maintained for more than 3 months post-transplantation. In such patients, when clinically appropriate, sirolimus 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 sirolimus 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 this medicine 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 this medicine 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 medicine 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: medicine loading dose = 3 x (new maintenance dose – current maintenance dose). The maximum 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 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 medicine dose = current dose x (target concentration/current concentration). Frequent medicine dose adjustments based on non-steady-state sirolimus concentrations can lead to overdosing or underdosing because sirolimus has a long half-life. Once 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 this medicine 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 this medicine 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 this medicine 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 this medicine 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

This medicine 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, this medicine should consistently be taken either with or without food.

Grapefruit juice should be avoided (see section 4.5).

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

4.3. Contraindications

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

4.4. Special warnings and precautions for use

This medicine 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 sirolimus 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 sirolimus 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 sirolimus as maintenance therapy cannot be recommended.

Based on information from subsequent clinical studies, the use of sirolimus, 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 this medicine in maintenance renal transplant patients, increased urinary protein excretion was commonly observed at 6 to 24 months after conversion to this medicine (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 sirolimus 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 sirolimus 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 sirolimus and HMG-CoA reductase inhibitors and/or fibrates was well-tolerated. During sirolimus 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 sirolimus 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 sirolimus.

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 sirolimus, vaccination may be less effective. The use of live vaccines should be avoided during treatment with sirolimus.

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 this medicine 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 this medicine, including lymphocele in renal transplant patients and wound dehiscence. Patients with a body mass index (BMI) greater than 30 kg/m2 may be at increased risk of abnormal wound healing based on data from the medical literature.

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

The use of this medicine was associated with increased serum cholesterol and triglycerides that may require treatment. Patients administered this medicine 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 this medicine. Similarly the risk/benefit of continued sirolimus therapy should be re-evaluated in patients with severe refractory hyperlipidaemia.

Sucrose and lactose

Sucrose

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

Lactose

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

4.5. Interaction with other medicinal products and other forms of interaction

Sirolimus is extensively metabolised by the CYP3A4 isozyme in the intestinal wall and liver. Sirolimus is also a substrate for the multidrug efflux pump, P-glycoprotein (P-gp) located in the small intestine. Therefore, absorption and the subsequent elimination of sirolimus may be influenced by 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 this medicine 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 this medicine 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 this medicine 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 sirolimus 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 sirolimus 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

No clinically significant pharmacokinetic interaction was observed between this medicine 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 sirolimus.

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).

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 this medicine. Inhibitors of P-gp may decrease the efflux of sirolimus from intestinal cells and increase sirolimus levels.

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

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

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

Paediatric population

Interaction studies have only been performed in adults.

4.6. Fertility, pregnancy and lactation

Women of childbearing potential

Effective contraception must be used during sirolimus therapy and for 12 weeks after this medicine 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. This medicine should not be used during pregnancy unless clearly necessary. Effective contraception must be used during sirolimus therapy and for 12 weeks after this medicine 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 this medicine.

Fertility

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

4.7. Effects on ability to drive and use machines

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

4.8. Undesirable effects

Undesirable effects observed with prophylaxis of organ rejection in renal transplantation

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

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

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

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

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

Most patients were on immunosuppressive regimens, which included sirolimus 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;

Cytomegalovirus infection;

Herpes zoster caused by the varicella zoster virus

Clostridium difficile colitis;

Mycobacterial infection (including tuberculosis);

Epstein-Barr virus infection

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

Non-melanoma skin cancer*

Lymphoma*; Malignant melanoma*;

Post-transplant lymphoproliferative disorder

Neuroendocrine carcinoma of the skin*

Blood and lymphatic system disorders

Thrombocytopaenia;

Anaemia;

Leucopenia

Haemolytic uraemic syndrome;

Neutropaenia

Pancytopaenia;

Thrombotic thrombocytopaenic purpura

Immune system disorders

Hypersensitivity (including angioedema, anaphylactic reaction, and anaphylactoid reaction)

Metabolism and nutrition disorders

Hypokalaemia;

Hypophosphataemia;

Hyperlipidaemia (including hypercholesterolaemia);

Hyperglycaemia;

Hypertriglyceridaemia;

Diabetes mellitus

Nervous system disorders

Headache

Posterior reversible encephalopathy 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

Gastrointestinal disorders

Abdominal pain;

Constipation;

Diarrhoea;

Nausea

Pancreatitis;

Stomatitis;

Ascites

Hepatobiliary disorders

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

Hepatic failure*

Skin and subcutaneous tissue disorders

Rash;

Acne

Dermatitis exfoliative

Hypersensitivity vasculitis

Musculoskeletal and connective tissue disorders

Arthralgia

Osteonecrosis

Renal and urinary disorders

Proteinuria

Nephrotic syndrome (see section 4.4); Focal segmental glomerulosclerosis*

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 sirolimus.

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 sirolimus. In some cases, the interstitial lung disease has resolved upon discontinuation or dose reduction of this medicine. 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 this medicine. These effects have been reversible upon discontinuation of this medicine 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 this medicine.

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, enrolment 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 this medicine.

Paediatric population

Controlled clinical studies with posology comparable to that currently indicated for the use of this medicine 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 this medicine 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 this medicine 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 this medicine 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 this medicine 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 this medicine (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 this medicine 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 Yellow Card Scheme at: www.mhra.gov.uk/yellowcard or search for MHRA Yellow Card in the Google Play or Apple App Store.

4.9. Overdose

At present, there is minimal experience with overdose. One patient experienced an episode of atrial fibrillation after ingestion of 150 mg of this medicine. 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 this medicine, it is anticipated that sirolimus will not be dialysable to any significant extent.