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• Everolimus Novartis dispersible tablet ENG SmPC

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

Everolimus Novartis 0.1 mg dispersible tablets

Everolimus Novartis 0.25 mg dispersible tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

Each dispersible tablet contains 0.1/0.25 mg everolimus.

Excipient(s) with known effect:

Each dispersible tablet contains 1/2 mg lactose monohydrate and 72/179 mg anhydrous lactose.

For thefull list of excipients, see section 6.1.

3. PHARMACEUTICAL FORM

Dispersible tablet

Dispersible tablets are white to yellowish, marbled, round, flat with a bevelled edge.

0.1 mg (diameter of 7 mm): engraved with “I” on one side and “NVR” on the other.

0.25 mg (diameter of 9 mm): engraved with “JO” on one side and “NVR” on the other.

4. CLINICAL PARTICULARS

4.1 Therapeutic indications

Kidney and heart transplantation

Everolimus Novartis is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological riskreceiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, Everolimus Novartis should be used in combination with ciclosporin for microemulsion and corticosteroids.

Liver transplantation

Everolimus Novartis is indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver transplantation, Everolimus Novartis should be used in combination with tacrolimus and corticosteroids.

4.2 Posology and method of administration

Treatment with Everolimus Novartisshould only be initiated and maintained by physicians who are experienced in immunosuppressive therapy following organ transplantation and who have access to everolimus whole blood concentration monitoring.

Posology

Adults

An initial dose regimen of 0.75 mg twice daily in co-administration with ciclosporin is recommended for the general kidney and heart transplant population, administered as soon as possible after transplantation.

The dose of 1.0 mg twice daily in co-administration with tacrolimus is recommended for the hepatic transplant population with the initial dose approximately 4 weeks after transplantation.

Patients receiving Everolimus Novartismay require dose adjustments based on blood concentrations achieved, tolerability, individual response, change in co-medications and the clinical situation. Dose adjustments can be made at 4-5 day intervals (see Therapeutic drug monitoring).

Special population

Black patients

The incidence of biopsy-proven acute rejection episodes was significantly higher in black renal transplant patients compared with non-black patients. There is limited information indicating thatblack patients may require a higher Everolimus Novartis dose to achieve similar efficacy to non-black patients (see section 5.2). Currently, the efficacy and safety data are too limited to allow specific recommendations for use of everolimus in black patients.

Paediatric population

There is insufficient data in children and adolescents to recommend the use of Everolimus Novartis in renal transplantation (see section 5.1 and 5.2) and no recommendation on a posology can be made. In hepatic transplant paediatric patients, Everolimus Novartis should not be used (see section 5.1).

Elderly patients (≥ 65 years)

Clinicalexperience in patients >65 years of age is limited. Although data are limited, there are no apparent differences in the pharmacokinetics of everolimus in patients ≥ 65-70 years of age (see section 5.2).

Patients with renal impairment

No dosage adjustment is required (see section 5.2).

Patients with impaired hepatic function

Everolimus whole blood trough concentrations should be closely monitored in patients with impaired hepatic function. The dose should be reduced to approximately two thirds of the normal dose for patients with mild hepatic impairment (Child-Pugh Class A), to approximately one half of the normal dose for patients with moderate hepatic impairment (Child Pugh Class B),andtoapproximately one third of the normal dose for patients with severe hepatic impairment (Child Pugh Class C).Further dose titration should be based on therapeutic drug monitoring (see section 5.2). Reduced doses rounded to the nearest tablet strength are tabulated below:

Table 1 Everolimus Novartisdose reduction in patients with hepatic impairment

	Normal hepatic function	Mild hepatic impairment (Child-Pugh A)	Moderate hepatic impairment (Child-Pugh B)	Severe hepatic impairment (Child-Pugh C)
Renal and cardiac transplantation	0.75 mg b.i.d.	0.5 mg b.i.d.	0.5 mg b.i.d.	0.25 mg b.i.d.
Hepatic transplantation	1 mg b.i.d.	0.75 mg b.i.d.	0.5 mg b.i.d.	0.5 mg b.i.d.

Therapeutic drug monitoring

The use of drug assays with adequate performance characteristics when targeting low concentrations of ciclosporin or tacrolimus is recommended.

Routine everolimus whole blood therapeutic drug concentration monitoring is recommended. Based on exposure-efficacy and exposure-safety analysis, patients achieving everolimus whole blood trough concentrations ³3.0 ng/ml have been found to have a lower incidence of biopsy-proven acute rejection in renal, cardiac and hepatic transplantation compared with patients whose trough concentrations are below 3.0 ng/ml. The recommended upper limit ofthe therapeutic range is 8 ng/ml. Exposure above 12 ng/ml has not been studied. These recommended ranges for everolimus are based on chromatographic methods.

It is especially important to monitor everolimus blood concentrations in patients with hepatic impairment during concomitant administration of strong CYP3A4 inducers and inhibitors, when switching formulation,and/or if ciclosporin dosing is markedly reduced (see section 4.5). Everolimus concentrations might be slightly lower following dispersible tablet administration.

Ideally, dose adjustments of Everolimus Novartisshould be based on trough concentrations obtained >4-5 days after the previous dosing change. There is an interaction betweenciclosporin andeverolimus, and everolimus concentrations may thereforedecrease if ciclosporin exposure is markedly reduced (i.e. trough concentration <50 ng/ml).

Patients with hepatic impairment should preferably have trough concentrations in the upper part of the 3‑8 ng/ml exposure range.

After starting treatment or after a dose adjustment, monitoringshould be performed every 4 to 5 days until 2 consecutive trough concentrations showstable everolimus concentrations, asthe prolonged half-lives in hepaticallyimpaired patients delay the time to reach steady state (see sections 4.4 and 5.2). Dose adjustments should be based on stable everolimus trough concentrations.

Ciclosporin dose recommendation in renal transplantation

Everolimus Novartisshould not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Everolimus Novartis-treated renal transplant patients improves renal function. Based on experience gained from study A2309, ciclosporin exposure reduction should be started immediately after transplantation with the following recommended whole blood trough concentration windows:

Table 2 Renal transplantation: recommended target ciclosporin blood trough- concentration windows

Target ciclosporin C0 (ng/ml)	Month 1	Months 2‑3	Months 4‑5	Months 6‑12
Everolimus Novartis groups	100‑200	75‑150	50‑100	25‑50

(Measured C₀and C2 concentrations are shown in section 5.1).

Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 ng/ml.

There are limited data regarding dosing Everolimus Novartiswith ciclosporin trough concentrations below 50 ng/ml, or C2 concentrations below 350 ng/ml, in the maintenance phase. If the patient cannot tolerate reduction of ciclosporin exposure, the continued use of Everolimus Novartisshould be reconsidered.

Ciclosporin dose recommendation in cardiac transplantation

Cardiac transplant patients in the maintenance phase should havetheirciclosporin dose reduced as tolerated in order to improve kidney function. If impairment of renal function is progressive or if the calculated creatinine clearance is < 60 ml/min, the treatment regimen should be adjusted. In cardiac transplant patients, the ciclosporin dose may be based on ciclosporin blood trough concentrations. See Section 5.1 for experience with reduced ciclosporin blood concentrations.

In cardiac transplantation, there are limited data regarding dosing Everolimus Novartiswith ciclosporin trough concentrations of 50-100 ng/mlafter 12 months.

Prior to dose reduction of ciclosporin it should be ascertained that steady-state everolimus whole blood trough concentrations are equal to or above 3 ng/ml.

Tacrolimus dose recommendation in hepatic transplantation

Hepatic transplant patients should have their tacrolimus exposure reduced to minimisecalcineurin-related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiatingco-administrationwith Everolimus Novartis,based on targeted tacrolimus blood trough concentrations (C₀) of3‑5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections.

Everolimus Novartishas not been evaluated with full-dose tacrolimus in controlled clinical trials.

Method of administration

Everolimus Novartis is for oral use only.

The daily dose of Everolimus Novartis should always be given orally in two divided doses, consistently either with or without food (see section 5.2) and at the same time as ciclosporin for microemulsion or tacrolimus (see Therapeutic drug monitoring).

For further instructions see section 6.6.

4.3 Contraindications

Everolimus Novartisis contraindicated in patients with a known hypersensitivity to everolimus, sirolimus, or to any of the excipients.

4.4 Special warnings and precautions for use

Management of immunosuppression

In clinical trials, Everolimus Novartishas been administered concurrently with ciclosporin for microemulsion, basiliximab, or with tacrolimus, and corticosteroids. Everolimus Novartisin combination with immunosuppressive agents other than these has not been adequately investigated.

Everolimus Novartishas not been adequately studied in patients at high immunological risk.

Combination with thymoglobulin induction

Strict caution is advised with the use of thymoglobulin (rabbit anti-thymocyte globulin) induction and the Everolimus Novartis/ciclosporin/steroid regimen. In a clinical study in heart transplant recipients (Study A2310, see section 5.1), an increased incidence of serious infections including fatal infections was observed within the first three months after transplantation in the subgroup of patients who had received induction with rabbit anti-thymocyte globulin.

Serious and opportunistic infections

Patients treated with immunosuppressants, including Everolimus Novartis, are at increased risk for opportunistic infections (bacterial, fungal, viral and protozoal). Among these conditions are BK virus-associated nephropathy and JC virus-associated progressive multiple 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. Fatal infections and sepsis have been reported in patients treated with Everolimus Novartis(see section 4.8).

In clinical trials with Everolimus Novartis, antimicrobial prophylaxis for Pneumocystis jiroveci (carinii)pneumonia and Cytomegalovirus(CMV) was recommended following transplantation, particularly for patients at increased risk for opportunistic infections.

Liver function impairment

Close monitoring of everolimus whole blood trough concentrations (C₀) and everolimus dose adjustment is recommended in patients with impaired hepatic function (see section 4.2).

Because of longer everolimus half-lives in patients with hepatic impairment (see section 5.2), everolimus therapeutic monitoring after starting treatment or after a dose adjustment should be performed until stable concentrations are reached.

Interaction with oral CYP3A4 substrates

Caution should be exercised when Everolimus Novartisis taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Everolimus Novartisis taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate (see section 4.5).

Interaction with strong inhibitorsorinducers of CYP3A4

Co-administration with strong CYP3A4-inhibitors (e.g. ketoconazole, itraconazole, voriconazole, clarithromycin, telithromycin, ritonavir) and inducers (e.g. rifampicin, rifabutin, carbamazepine, phenytoin) is not recommended unless the benefit outweighs the risk. It is recommended that everolimus whole blood trough concentrations be monitored whenever inducers or inhibitors of CYP3A4 are concurrently administered and after their discontinuation (see section 4.5).

Lymphomas and other malignancies

Patients receiving a regimen of immunosuppressive medicinal products, including Everolimus Novartis, are at increased risk of developing lymphomas or other malignancies, particularly of the skin (see section 4.8). The absolute risk seems related to the duration and intensity of immunosuppression rather than to the use of a specific medicinal product. Patients should be monitored regularly for skin neoplasms and advised to minimise exposure to UV lightandsunlight,andtouse appropriate sunscreen.

Hyperlipidaemia

The use of Everolimus Novartiswith ciclosporin for microemulsion or tacrolimus in transplant patients has been associated with increased serum cholesterol and triglycerides that may require treatment. Patients receiving Everolimus Novartisshould be monitored for hyperlipidaemiaand, if necessary, treated with lipid-lowering medicinal products andhaveappropriate dietary adjustments made (see section 4.5). The risk/benefit should be considered in patients with established hyperlipidaemia before initiating an immunosuppressive regimen including Everolimus Novartis. Similarly,the risk/benefit of continued Everolimus Novartistherapy should be re-evaluated in patients with severe refractory hyperlipidaemia.Patients administered aHMG-CoA reductase inhibitor and/or fibrate should be monitored for the possible development of rhabdomyolysis and other adverse effects as described in the Summary of Product Characteristics for the medicinal product(s)concerned (see section 4.5).

Angioedema

Everolimus Novartishas been associated with the development of angioedema. In the majority of cases reported,patients were receiving ACE inhibitors as co-medication.

Everolimus and calcineurin inhibitor-induced renal dysfunction

Inrenal and cardiac transplantation, Everolimus Novartiswith full-dose ciclosporin increases the risk of renal dysfunction. Reduced doses of ciclosporin are required for use in combination with Everolimus Novartisin order to avoid renal dysfunction. Appropriate adjustment of the immunosuppressive regimen, in particular reduction of the ciclosporin dose,should be considered in patients with elevated serum creatinine levels.

In a liver transplant study, Everolimus Novartiswith reduced tacrolimus exposure has not been found to worsen renal function in comparison to standard exposure tacrolimus without Everolimus Novartis. Regular monitoring of renal function is recommended in all patients. Caution should be exercised when co-administering other medicinal products that are known to have a negativeeffect on renal function.

Proteinuria

The use of Everolimus Novartiswith calcineurin inhibitors in transplant recipients has been associated with increased proteinuria. The risk increases with higher everolimus blood concentrations. In renal transplant patients with mild proteinuria while on maintenance immunosuppressive therapy including a calcineurin inhibitor (CNI),there have been reports of worsening proteinuria when the CNI is replaced by Everolimus Novartis. Reversibility has been observed with interruption of Everolimus Novartisand reintroduction of the CNI. The safety and efficacy of switchingfrom a CNI to Everolimus Novartisin such patients have not been established. Patients receiving Everolimus Novartis should be monitored for proteinuria.

Renal graft thrombosis

An increased risk of kidney arterial and venous thrombosis, resulting in graft loss, has been reported, mostly within the first 30 days post-transplantation.

Wound-healing complications

Everolimus Novartis, like other mTOR inhibitors, can impair healing,increasing the occurrence of post-transplant complications such as wound dehiscence, fluid accumulationand wound infection,which may require further surgical attention. Lymphocele is the most frequently reported such event in renal transplant recipients and tends to be more frequent in patients with a higher body mass index. The frequency of pericardial and pleural effusion is increased in cardiac transplant recipients and the frequency of incisional hernias is increased in liver transplant recipients.

Thrombotic microangiopathy/Thrombotic thrombocytopenic purpura/Haemolytic uraemic syndrome

The concomitant administration of Everolimus Novartiswith a calcineurin inhibitor (CNI) may increase the risk of CNI-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.

Vaccinations

Immunosuppressants may affecttheresponse to vaccination. During treatment with immunosuppressants, including everolimus, vaccination may be less effective. The use of live vaccines should be avoided.

Interstitiallung disease/non-infectious pneumonitis

A diagnosis of interstitial lung disease (ILD) should be considered in patients presenting with symptoms consistent with infectious pneumonia but not responding to antibiotic therapy and in whom infectious, neoplastic and other non-drug causes have been ruled outthrough appropriate investigations. Cases of ILD have been reported with Everolimus Novartis,which generally resolve on drug interruption with or without glucocorticoid therapy. However, fatal cases have also occurred (see section 4.8).

New onset diabetes mellitus

Everolimus Novartishas been shown to increase the risk of new onset diabetes mellitus after transplantation.Blood glucose concentrations should be monitored closely in patients treated with Everolimus Novartis.

Male infertility

There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. As preclinicaltoxicology studies haveshown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Everolimus Novartistherapy.

Risk of intolerance ofexcipients

Everolimus Novartis dispersible tablets contain lactose. Patients with rare hereditary problems of galactose intolerance, severe lactase deficiency or glucose-galactose malabsorption should not take this medicine.

4.5 Interaction with other medicinal products and other forms of interaction

Everolimus is mainly metabolised by CYP3A4 in the liver and to some extent in the intestinal wall and is a substrate for the multidrug efflux pump, P-glycoprotein(PgP).Therefore, absorption and subsequent elimination of systemically absorbed everolimus may be influenced by medicinal products that affect CYP3A4 and/or P-glycoprotein. Concurrent treatment with strong 3A4 inhibitors and inducers is not recommended. Inhibitors of P-glycoprotein may decrease the efflux of everolimus from intestinal cells and increase everolimus blood concentrations. In vitro, everolimus was a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6. All in vivointeraction studies were conducted without concomitant ciclosporin.

Table 3. Effects ofother active substanceson everolimus

Active substance by interaction	Interaction – Change in Everolimus AUC/Cmax Geometric mean ratio (observed range)	Recommendations concerning co- administration
Strong CYP3A4/PgP inhibitors
Ketoconazole	AUC ↑15.3-fold (range 11.2-22.5) Cmax ↑4.1-fold (range 2.6-7.0)	Co-administration with strong CYP3A4/PgP-inhibitors is not recommended unless the benefit outweighs the risk.
Itraconazole, posaconazole, voriconazole	Not studied. Large increase in everolimus concentration is expected.
Telithromycin, clarithromycin
Nefazodone
Ritonavir, atazanavir, saquinavir, darunavir, indinavir, nelfinavir
Moderate CYP3A4/PgP inhibitors
Erythromycin	AUC ↑4.4-fold (range 2.0-12.6) Cmax ↑2.0-fold (range 0.9-3.5)	Everolimus whole blood trough concentrations should be monitored whenever inhibitors of CYP3A4/PgP are concurrently administered and after their discontinuation. Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided.
Imatinib	AUC ↑3.7-fold Cmax ↑2.2-fold
Verapamil	AUC ↑3.5-fold (range 2.2-6.3) Cmax ↑2.3-fold (range1.3-3.8)
Ciclosporin oral	AUC ↑2.7-fold (range 1.5-4.7) Cmax ↑1.8-fold (range 1.3-2.6)
Fluconazole	Not studied. Increased exposure expected.
Diltiazem nicardipine
Dronedarone	Not studied. Increased exposure expected.
Amprenavir, fosamprenavir	Not studied. Increased exposure expected.
Grapefruit juice or other food affecting CYP3A4/PgP	Not studied. Increased exposure expected (the effect varies widely).	Combination should be avoided.
Strong and Moderate CYP3A4 inducers
Rifampicin	AUC ↓63% (range 0-80%) Cmax ↓58% (range 10-70%)	Co-administration with strong CYP3A4-inducers is not recommended unless the benefit outweighs the risk.
Rifabutin	Not studied. Decreased exposure expected.
Carbamazepine	Not studied. Decreased exposure expected.
Phenytoin	Not studied. Decreased exposure expected.
Phenobarbital	Not studied. Decreased exposure expected.	Everolimus whole blood trough concentrations should be monitored whenever inducers of CYP3A4 are concurrently administered and after their discontinuation.
Efavirenz, nevirapine	Not studied. Decreased exposure expected.
St John’s Wort (Hypericum perforatum)	Not studied. Large decrease in exposure expected.	Preparations containing St John’s Wort should not be used during treatment with everolimus

Agents whose plasma concentrations may be altered by everolimus:

Octreotide

Co-administration of everolimus (10 mg daily) with depot octreotide increased octreotide C_minwith a geometric mean ratio (everolimus/placebo) of 1.47-fold.

Ciclosporin

Everolimus Novartis had a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.

Atorvastatin (CYP3A4substrate) and pravastatin (PgPsubstrate)

Single-dose administration of Everolimus Novartis with either atorvastatin or pravastatin to healthy subjects did not influence the pharmacokinetics of atorvastatin, pravastatin and everolimus, as well as total HMG-CoA reductase bioreactivity in plasma to a clinically relevant extent. However,these results cannot be extrapolated to other HMG-CoA reductase inhibitors.Patients should be monitored for the development of rhabdomyolysis and other adverse events as described in the Summary of Product Characteristics of HMG-CoA reductase inhibitors.

Oral CYP3A4A substrates

Based on in vitro results, the systemic concentrations obtained after oral daily doses of 10 mg make inhibition of PgP, CYP3A4 and CYP2D6 unlikely. However, inhibition of CYP3A4 and PgP in the gut cannot be excluded. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A4 substrate probe, with everolimus resulted in a 25% increase in midazolam C_maxand a 30% increase in midazolam AUC. The effect is likely to be due to inhibition of intestinal CYP3A4 by everolimus. Hence,everolimus may affect the bioavailability of orally co‑administered CYP3A4 substrates. However,a clinically relevant effect on the exposure of systemically administered CYP3A4 substrates is not expected. If everolimus is taken with orally administered CYP3A4 substrates with a narrow therapeutic index (e.g. pimozide, terfenadine, astemizole, cisapride, quinidine or ergot alkaloid derivatives), the patient should be monitored for undesirable effects described in the product information of the orally administered CYP3A4 substrate.

Vaccinations

Immunosuppressants may affecttheresponse to vaccination and vaccination during treatment with Everolimus Novartis may be less effective. The use of live vaccines should be avoided.

Paediatric population

Interaction studies have only beenperformed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Everolimus Novartisin pregnant women. Studies in animals have shown reproductive toxicity effects including embryo/foetotoxicity (see section 5.3). The potential risk for humans is unknown. Everolimus Novartisshould not be given to pregnant women unless the potential benefit outweighs the potential risk for the foetus. Women of childbearing potential should be advised to use effective contraception methods while they are receiving Everolimus Novartisand up to 8 weeks after treatment has been stopped.

Breast-feeding

It is not known whether everolimus is excreted in human milk. In animal studies, everolimus and/or its metabolites were readily transferred into the milk of lactating rats. Therefore,women who are taking Everolimus Novartisshould not breast feed.

Fertility

There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors (see section 4.4, 4.8, and 5.3). The potential for everolimus to cause infertility in male and female patients is unknown, however, male infertility and secondary amenorrhoea have been observed.

4.7 Effects on ability to drive and use machines

No studies of the effects on the ability to drive and use machines have been performed.

4.8 Undesirable effects

a) Summary of the safety profile

The frequencies of adverse reactions listed below are derived from analysis of the 12-month incidences of events reported in multicentre, randomised, controlled trials investigating Everolimus Novartis in combination with calcineurin inhibitors (CNI) and corticosteroids in adult transplant recipients. All but two of the trials (in renal transplantation) included non-Everolimus Novartis, CNI-based standard-therapy arms. Everolimus Novartis combined with ciclosporin was studied in five trials in renal transplant recipients totalling 2,497 patients (including two studies without a non-Everolimus Novartis control group), and three trials in heart transplant recipients totalling 1,531 patients (ITT populations, see section 5.1).

Everolimus Novartis combined with tacrolimus was studied in one trial, which included 719 liver transplant recipients (ITT population, see section 5.1).

The most common events are: infections, anaemia, hyperlipidaemia, new onset of diabetes mellitus, insomnia, headache, hypertension, cough, constipation, nausea, peripheral oedema, impaired healing (including pleural and pericardial effusion).

The occurrence of the adverse events may depend on the immunosuppressive regimen (i.e. degree and duration). In the studies combining Everolimus Novartis with ciclosporin,elevated serum creatinine was observed more frequently in patients administered Everolimus Novartis in combination with full-dose ciclosporin for microemulsion than in control patients. The overall incidence of adverse events was lower with reduced-dose ciclosporin for microemulsion (see section 5.1).

The safety profile of Everolimus Novartis administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studiesin which full-dose ciclosporin was administered, except that elevation of serum creatinine was less frequent, and mean and median serum creatinine values were lower, than in the Phase III studies.

b) Tabulated summary of adverse reactions

Table 4 contains adverse drug reactions possibly or probably related to Everolimus Novartis seen in Phase III clinical trials. Unless noted otherwise, these disorders have been identified by an increased incidence in the PhaseIII studies comparing Everolimus Novartis-treated patients with patients on a non-Everolimus Novartis, standard-therapy regimen, or the same incidence in case the event is a known ADR of the comparator MPA in renal and heart transplant studies (see section 5.1). Except where noted otherwise, the adverse reaction profile is relatively consistent across all transplant indications. It is compiled according to MedDRA standard organ classes:

Adverse reactions are listed according to their frequencies,which are defined as: 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).

Table 4: Adverse drug reactions possibly or probably related to Everolimus Novartis

Body system	Incidence	Adverse reaction
Infections and infestations	Very common	Infections (viral, bacterial, fungal), upper respiratory tract infection, lower respiratory tract and lung infections (including pneumonia)1, urinary tract infections2
	Common	Sepsis, wound infection
Neoplasms benign, malignant and unspecified	Common	Malignant or unspecified tumours, malignant and unspecified skin neoplasms
	Uncommon	Lymphomas/post-transplant lymphoproliferative disorders (PTDL)
Blood and lymphatic system disorders	Very common	Leukopaenia, anaemia/erythropenia, thrombocytopenia1
	Common	Pancytopenia, thrombotic microangiopathies (including thrombotic thrombocytopenic purpura/haemolytic uraemic syndrome)
Endocrine disorders	Uncommon	Hypogonadism male (testosterone decreased, FSH and LH increased)
Metabolism and nutrition disorders	Very common	Hyperlipidaemia (cholesterol and triglycerides), new onset diabetes mellitus, hypokalaemia
Psychiatric disorders	Very common	Insomnia, anxiety
Nervous system disorders	Very common	Headache
Cardiac disorders	Very common	Pericardial effusion3
	Common	Tachycardia
Vascular disorders	Very common	Hypertension, venous thromboembolic events
	Common	Lymphocoele4, epistaxis, renal graft thrombosis
Respiratory, thoracic and mediastinal disorders	Very common	Pleural effusion1, cough1, dyspnoea1
	Uncommon	Interstitial lung disease5
Gastrointestinal disorders	Very common	Abdominal pain, diarrhoea ,nausea, vomiting
	Common	Pancreatitis, stomatitis/mouth ulceration, oropharyngeal pain
Hepatobiliary disorders	Uncommon	Non infectious hepatitis, jaundice
Skin and subcutaneous tissue disorders	Common	Angiooedema6, acne, rash
Musculoskeletal and connective tissue disorders	Common	Myalgia, arthralgia
Renal and urinary disorders	Common	Proteinuria2, renal tubular necrosis7
Reproductive system and breast disorders	Common	Erectile dysfunction, menstrual disorder (including amenorrhoea and menorrhagia)
	Uncommon	Ovarian cyst
General disorders and administration site conditions	Very common	Peripheral oedema, pain, healing impaired, pyrexia
	Common	Incisional hernia
Investigations	Common	Hepatic enzyme abnormal8

¹common in renal and liver transplantation

²common in cardiac and liver transplantation

³in cardiac transplantation

⁴in renal and cardiac transplantation⁵the SMQ-based search for ILD showed the frequency of ILD in the clinical trials. This broad search also included cases caused by related events, e.g. by infections. The frequency category given here is derived from the medical review of the known cases.

⁶predominantly in patients receiving concomitant ACE inhibitors

⁷in renal transplantation

⁸γ-GT, AST, ALT elevated

c) Description of selected adverse reactions

As preclinicaltoxicology studies haveshown that everolimus can reduce spermatogenesis,male infertility must be considered a potential risk of prolonged Everolimus Novartis therapy. There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors.

In controlled clinical trials in which a total of 3,256 patients receiving Everolimus Novartis in combination with other immunosuppressants were monitored for at least 1 year, a total of 3.1% developed malignancies, with 1.0% developing skin malignancies and 0.60% developing lymphomasor lymphoproliferative disorders.

Cases of interstitial lung disease, implying lung intraparenchymal inflammation (pneumonitis) and/or fibrosis of non-infectious aetiology, some fatal, have occurred in patients receiving rapamycin and derivatives, including Everolimus Novartis. Mostly, the condition resolves after discontinuation of Everolimus Novartis and/or addition of glucocorticoids. However, fatal cases have also occurred.

d) Adverse drug reactions from post-marketing spontaneous reports

The following adverse drug reactions have been derived from post-marketing experience with Everolimus Novartisvia spontaneous case reports and literature cases. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency,which is therefore categorised as not known. Adverse drug reactions are listed according to system organ classes in MedDRA. Within each system organ class, ADRs are presented in order of decreasing seriousness.

Table 5 Adverse drug reactions from spontaneous reports and literature (frequency not known)

Body system		Incidence	Adverse reaction
Vascular disorders		Not known	Leukocytoclastic vasculitis
Respiratory, thoracic and mediastinal disorders	Not known		Pulmonary alveolar proteinosis
Skin and subcutaneous tissue disorders	Not known		Erythroderma

Reporting of suspected adverse reactions

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

4.9 Overdose

In animal studies, everolimus showed low acute toxic potential. No lethality or severe toxicity was observed after single oral doses of 2000 mg/kg (limit test) in either mice or rats.

Reported experience with overdose in humans is very limited;there is a single case of accidental ingestion of 1.5 mg everolimus in a 2-year old child where no adverse events were observed. Single doses up to 25 mg have been administered to transplant patients with acceptable acute tolerability.

General supportive measures should be initiated in all cases of overdose.

5. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents. ATC code: LO4AA18.

Mechanism of action

Everolimus, a proliferation signal inhibitor, prevents allograft rejection in rodent and non-human primate models of allotransplantation. It exerts its immunosuppressive effect by inhibiting the proliferation, and thus clonal expansion, of antigen-activated T cells,which is driven by T cell-specific interleukins, e.g. interleukin-2 and interleukin-15. Everolimus inhibits an intracellular signalling pathway,which is triggered upon binding of these T cell growth factors to their respective receptors, and which normally leads to cell proliferation. The blockage of this signal by everolimus leads to an arrest of the cells at the G₁stage of the cell cycle.

At the molecular level, everolimus forms a complex with the cytoplasmic protein FKBP-12. In the presence of everolimus,the growth factor-stimulated phosphorylation of the p70 S6 kinase is inhibited. Since p70 S6 kinase phosphorylation is under the control of FRAP (also called mTOR), this finding suggests that the everolimus-FKBP-12 complex binds to and thus interferes with the function of FRAP. FRAP is a key regulatory protein thatgoverns cell metabolism, growth and proliferation; disabling FRAP function thus explains the cell cycle arrest caused by everolimus.

Everolimus thus has a different mode of action tociclosporin. In preclinical models of allotransplantation, the combination of everolimus and ciclosporin was more effective than either compound alone.

The effect of everolimus is not restricted to T cells. It inhibits growth factor-stimulated proliferation of hematopoietic as well as non-hematopoietic cellsin general, such asvascular smooth muscle cells. Growth factor-stimulated vascular smooth muscle cell proliferation, triggered by injury to endothelial cells and leading to neointima formation, plays a key role in the pathogenesis of chronic rejection. Preclinical studies with everolimus have shown inhibition of neointima formation in a rat aorta allotransplantation model.

Clinical efficacy and safety

Renal transplantation

Everolimus Novartis in fixed doses of 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids,was investigated in two PhaseIII de novoadult renal transplant trials (B201 and B251). Mycophenolate mofetil (MMF) 1 g b.i.dwas used as comparator. The co-primary composite endpoints were efficacy failure (biopsy-proven acute rejection, graft loss, death or loss to follow-up) at 6 months, and graft loss, death or loss to follow-up at 12 months. Everolimus Novartis was, overall, non-inferior to MMF in these trials. The incidence of biopsy-proven acute rejection at 6 months in the B201 study was 21.6%, 18.2%, and 23.5% for the Everolimus Novartis 1.5 mg/day, Everolimus Novartis 3 mg/day and MMF groups, respectively. In study B251, the incidences were 17.1%, 20.1%, and 23.5% for the Everolimus Novartis 1.5 mg/day, Everolimus Novartis 3 mg/day and MMF groups, respectively.

Reduced allograft function with elevated serum creatinine was observed more frequently among subjects using Everolimus Novartis in combination with full-dose ciclosporin for microemulsion than in MMF patients. This effect suggests that Everolimus Novartis increases ciclosporin nephrotoxicity. Drug concentration-pharmacodynamic analysis showed that renal function was not impaired with reduced exposure to ciclosporin,while conserving efficacy for as long as the blood trough everolimus concentration was maintained above 3ng/ml. This concept was subsequently confirmed in two further Phase III studies (A2306 and A2307, including 237 and 256 patients,respectively),which evaluated the efficacy and safety of Everolimus Novartis 1.5 mg and 3 mg per day (initial dosing;subsequent dosing based on target trough concentration ≥3 ng/ml) in combination with reduced exposure to ciclosporin. In both studies, renal function was preserved without compromising efficacy. In these studies,however,there was no non-Everolimus Novartis comparative arm. A PhaseIII, multicentre, randomised, open-label, controlled trial (A2309)has been completed in which 833 denovorenal transplant recipients were randomised to one of two Everolimus Novartis regimens, differing by dosage, and combined with reduced-dose ciclosporin or a standard regimen of sodium mycophenolate (MPA) + ciclosporin,and treated for 12 months. All patients received induction therapy with basiliximab pre-transplant,and on Day 4 post-transplant. Steroids were given as required post-transplant.

Starting dosages in the two Everolimus Novartis groups were 1.5 mg/d and 3 mg, given b.i.d., subsequently modified from Day 5 onwards to maintain target blood trough everolimus concentrations of 3-8 ng/mland 6‑12 ng/ml,respectively. Sodium mycophenolate dosage was 1.44 g/d. Ciclosporin dosages were adapted to maintain target blood troughconcentration windows as shown in Table 6. The actual measured values for blood concentrations of everolimus and ciclosporin (C₀and C2) are shown in Table7.

Although the higher-dosage Everolimus Novartis regimen was as effective as the lower-dosage regimen, the overall safety was poorer,and so the higher-dosage regimen is not recommended.

The lower-dosage regimen for Everolimus Novartis is recommended (see section 4.2).

Table 6 Study A2309: Target ciclosporin blood troughconcentration windows

Target ciclosporin C0 (ng/ml)	Mo 1	Mo 2-3	Mo 4-5	Mo 6-12
Everolimus Novartis groups	100-200	75-150	50-100	25-50
MPA group	200-300	100-250	100-250	100-250

Table 7 Study A2309: Measured trough blood concentrations of ciclosporin and everolimus

Trough concentrations (ng/ml)	Everolimus Novartis groups (low-dose ciclosporin)				MPA (standard ciclosporin)
	Everolimus Novartis 1.5 mg		Everolimus Novartis 3.0 mg		Myfortic 1.44 g
Ciclosporin	Co	C2	Co	C2	Co	C2
Day 7	195 ± 106	847 ± 412	192 ± 104	718 ± 319	239 ± 130	934 ± 438
Month 1	173 ± 84	770 ± 364	177 ± 99	762 ± 378	250 ± 119	992 ± 482
Month 3	122 ± 53	580 ± 322	123 ± 75	548 ± 272	182 ± 65	821 ± 273
Month 6	88 ± 55	408 ± 226	80 ± 40	426 ± 225	163 ± 103	751 ± 269
Month 9	55± 24	319 ± 172	51 ± 30	296 ± 183	149 ± 69	648 ± 265
Month 12	55 ± 38	291 ± 155	49 ± 27	281 ± 198	137 ± 55	587± 241
Everolimus	(Target Co 3-8)		(Target Co 6-12)		-
Day 7	4.5 ± 2.3		8.3 ± 4.8		-
Month 1	5.3 ± 2.2		8.6 ± 3.9		-
Month 3	6.0 ± 2.7		8.8 ± 3.6		-
Month 6	5.3 ± 1.9		8.0 ± 3.1		-
Month 9	5.3 ± 1.9		7.7 ± 2.6		-
Month 12	5.3 ± 2.3		7.9 ± 3.5		-
Numbers are mean ± SD of measured values with C0 = trough concentration, C2 = value 2 hours post-dose.

The primary efficacy endpoint was a composite failure variable (biopsy-proven acute rejection, graft loss, death or loss to follow-up). The outcome is shown in Table8.

Table8 Study A2309: Composite and individual efficacy endpoints at 6 and 12 months (incidence in ITT population)

Changes in renal function, as shown by calculated glomerular filtration rate (GFR) using the MDRD formula,are shown in Table9.

Proteinuria was assessed at scheduled visits by spot analysis of urinary protein/creatinine (see Table10). A concentration effect was shown relating proteinuria levels to everolimus trough concentrations,particularly at C_minvalues above 8 ng/ml.

Adverse events reported more frequently in the recommended (lower-dosage) Everolimus Novartis regimen than in the MPA control group have been included in Table 4. A lower frequency ofviral infectionswas reported for Everolimus Novartis-treated patients,resulting principally from lower reporting rates for CMV infection (0.7% vs.5.95%) and BK virus infection (1.5% vs.4.8%).

Table 9 Study A2309: Renal function (MDRD-calculated GFR) at 12 months (ITT population)

	Everolimus Novartis 1.5 mg N=277	Everolimus Novartis 3.0 mg N=279	MPA 1.44 g N=277
12-month mean GFR (ml/min/1.73 m2)	54.6	51.3	52.2
Difference in mean (everolimus - MPA) 95% CI	2.37 (-1.7, 6.4)	-0.89 (-5.0, 3.2)	- -
12-month GFR missing value imputation: graft loss = 0; death or loss to follow-up for renal function = LOCF1 (last-observation-carried-forward approach 1: End of Treatment (up to Month 12)). MDRD: modification of diet in renal disease

Table 10 Study A2309: Urinary protein to creatinine ratio

Cardiac transplantation

In the PhaseIII cardiac study (B253), both Everolimus Novartis 1.5 mg/day and 3 mg/day, in combination with standard doses of ciclosporin for microemulsion and corticosteroids, was investigated vs. azathioprine (AZA) 1-3 mg/kg/day. The primary endpoint was a composite of theincidence of acute rejection ³ISHLT grade 3A, acute rejection associated with haemodynamic compromise, graft loss, patient death or loss to follow-up at 6, 12 and 24 months. Both doses of Everolimus Novartis were superior to AZA at 6, 12 and 24 months. The incidence of biopsy-proven acute rejection ³ISHLT grade 3A at month 6 was 27.8% for the 1.5 mg/day group, 19% for the 3 mg/day group and 41.6% for the AZA group, respectively (p = 0.003 for 1.5 mg vs.control, <0.001 for 3 mg vs.control).

Based on coronary artery intravascular ultrasound data obtained from a subset of the study population, both Everolimus Novartis doses were statistically significantly more effective than AZA in preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from baseline ³0.5mm in at least one matched slice of an automated pullback sequence), an important risk factor for long-term graft loss.

Elevated serum creatinine was observed more frequently among subjects using Everolimus Novartis in combination with full-dose ciclosporin for microemulsion than in AZA patients. These results indicated that Everolimus Novartis increases ciclosporin-induced nephrotoxicity.

Study A2411 was a randomised, 12-month, open-label study comparing Everolimus Novartis in combination with reduced doses of ciclosporin microemulsion and corticosteroids to mycophenolic mofetil (MMF) and standard doses of ciclosporin microemulsion and corticosteroids in denovocardiac transplant patients. Everolimus Novartis was initiated at 1.5 mg/day and the dose was adjusted to maintain target blood everolimus trough concentrations of3-8 ng/ml. MMF dosage was initiated at 1500 mg b.i.d.Ciclosporin microemulsion doses were adjusted to the following target trough concentrations (ng/ml):

Table 11 Target ciclosporin trough concentrations bymonth

Target ciclosporin C0	Mo 1	Mo 2	Mo 3-4	Mo 5-6	Mo 7-12
Everolimus Novartis group	200-350	150-250	100-200	75-150	50-100
MMF group	200-350	200-350	200-300	150-250	100-250

Actual blood concentrations measured are shown in Table 12.

Table 12 Study A2411: Summary statistics for CsA blood concentrations * (mean ± SD)

	Everolimus Novartis group (N=91)	MMF group (N=83)
Visit	C0	C0
Day 4	154 ± 71 n=79	155 ± 96 n=74
Mo 1	245 ± 99 n=76	308 ± 96 n=71
Mo 3	199 ± 96 n=70	256 ± 73 n=70
Mo 6	157 ± 61 n=73	219 ± 83 n=67
Mo 9	133 ± 67 n=72	187 ± 58 n=64
Mo 12	110 ± 50 n=68	180 ± 55 n=64
*:whole blood trough concentrations (C0)

Changes in renal function are shown in Table 13. Efficacy outcome is shown in Table 14.

Table 13 StudyA2411: Changes in creatinine clearance during study (patients with paired values)

		Estimated creatinine clearance (Cockcroft-Gault)* ml/mn
		Baseline Mean (± SD)	Value at timepoint Mean (± SD)	Difference between groups Mean (95% CI)
Month 1	Everolimus Novartis (n=87)	73.8 (± 27.8)	68.5 (± 31.5)	-7.3 (-18.1, 3.4)
	MMF (n=78)	77.4 (± 32.6)	79.4 (± 36.0)
Month 6	Everolimus Novartis (n=83)	74.4 (± 28.2)	65.4 (± 24.7)	-5.0 (-13.6, 2.9)
	MMF (n=72)	76.0 (± 31.8)	72.4 (± 26.4)
Month 12	Everolimus Novartis (n=71)	74.8 (± 28.3)	68.7 (± 27.7)	-1.8 (-11.2, 7.5)
	MMF (n=71)	76.2 (± 32.1)	71.9 (± 30.0)
* includes patients with value at both baseline and visit

Table 14 Study A2411: Efficacy event rates (incidence in ITT population)

Efficacy endpoint	Everolimus Novartis n=92	MMF n=84	Difference in event rates Mean (95% CI)
At 6 months
Biopsy-proven acute rejection ≥ ISHLT grade 3A	18 (19.6%)	23 (27.4%)	-7.8 (-20.3, 4.7)
Composite efficacy failure *	26 (28.3%)	31 (36.9%)	-8.6 (-22.5, 5.2)
At 12 months
Biopsy-proven acute rejection ≥ ISHLT grade 3A	21 (22.8%)	25 (29.8%)	-6.9 (-19.9, 6.1)
Composite efficacy failure*	30 (32.6%)	35 (41.7%)	-9.1 (-23.3, 5.2)
Death or graft loss/re-transplant	10 (10.9%)	10 (11.9%)	-
* Composite efficacy failure: any of the following – acute rejection ≥ grade 3A, acute rejection with haemodynamic compromise, graft loss, death or loss to follow-up.

Study A2310 is a PhaseIII, multicentre, randomised, open-label study comparing two Everolimus Novartis/reduced-dose ciclosporin regimens against a standard mycophenolate mofetil (MMF)/ciclosporin regimen over 24 months. The use of induction therapy was centre