Everolimus Tablets 5mg (EVEROTAJ) Taj Pharma

  1. NAME OF THE MEDICINAL PRODUCT

Everolimus Tablets 5mg (EVEROTAJ) Taj Pharma
Everolimus Tablets 10mg (EVEROTAJ) Taj Pharma

  1. QUALITATIVE AND QUANTITATIVE COMPOSITIONa) Each tablet contains:
    Everolimus………………………..5mg
    Excipients………………………….q.s.

    b) Each tablet contains:
    Everolimus………………………..10mg
    Excipients………………………….q.s.

  2. PHARMACEUTICAL FORM

Tablet

  1. CLINICAL PARTICULARS

4.1 Therapeutic indications

Kidney and heart transplantation

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is indicated for the prophylaxis of organ rejection in adult patients at low to moderate immunological risk receiving an allogeneic renal or cardiac transplant. In kidney and heart transplantation, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be used in combination with ciclosporin for microemulsion and corticosteroids.

Liver transplantation

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is indicated for the prophylaxis of organ rejection in adult patients receiving a hepatic transplant. In liver transplantation, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be used in combination with tacrolimus and corticosteroids.

4.2 Posology and method of administration

Treatment with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma may 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 that black patients may require a higher Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should not be used (see section 5.1).

Elderly patients (≥65 years)

Clinical experience 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), and to approximately 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dose 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.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has a narrow therapeutic index which may require adjustments in dosing to maintain therapeutic response. 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 ≥3.0 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 of the 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be based on trough concentrations obtained >4-5 days after the previous dosing change. There is an interaction between ciclosporin and everolimus, and everolimus concentrations may therefore decrease 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, monitoring should be performed every 4 to 5 days until 2 consecutive trough concentrations show stable everolimus concentrations, as the prolonged half-lives in hepatically impaired 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should not be used long-term together with full doses of ciclosporin. Reduced exposure to ciclosporin in Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma-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 C(ng/ml) Month 1 Months 2-3 Months 4-5 Months 6-12
Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma groups 100-200 75-150 50-100 25-50

(Measured Cand 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be reconsidered.

Ciclosporin dose recommendation in cardiac transplantation

Cardiac transplant patients in the maintenance phase should have their ciclosporin 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with ciclosporin trough concentrations of 50-100 ng/ml after 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 minimise calcineurin-related renal toxicity. The tacrolimus dose should be reduced starting approximately 3 weeks after initiating co-administration with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, based on targeted tacrolimus blood trough concentrations (C0) of 3-5 ng/ml. In a controlled clinical trial, complete withdrawal of tacrolimus has been associated with an increased risk of acute rejections.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has not been evaluated with full-dose tacrolimus in controlled clinical trials.

Method of administration

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is for oral use only.

The daily dose of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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).

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma tablets should be swallowed whole with a glass of water and not crushed before use. For patients unable to swallow whole tablets, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dispersible tablets are also available (see Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dispersible tablets Summary of Product Characteristics).

4.3 Contraindications

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has been administered concurrently with ciclosporin for microemulsion, basiliximab, or with tacrolimus, and corticosteroids. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with immunosuppressive agents other than these has not been adequately investigated.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma/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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma (see section 4.8).

In clinical trials with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 (see section 4.5).

Interaction with strong inhibitors or inducers 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, 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 light and sunlight, and to use appropriate sunscreen.

Hyperlipidaemia

The use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with ciclosporin for microemulsion or tacrolimus in transplant patients has been associated with increased serum cholesterol and triglycerides that may require treatment. Patients receiving Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be monitored for hyperlipidaemia and, if necessary, treated with lipid-lowering medicinal products and have appropriate 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma. Similarly, the risk/benefit of continued Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma therapy should be re-evaluated in patients with severe refractory hyperlipidaemia. Patients administered a HMG-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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has 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

In renal and cardiac transplantation, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with full-dose ciclosporin increases the risk of renal dysfunction. Reduced doses of ciclosporin are required for use in combination with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with reduced tacrolimus exposure has not been found to worsen renal function in comparison to standard exposure tacrolimus without Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma. 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 negative effect on renal function.

Proteinuria

The use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma. Reversibility has been observed with interruption of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and reintroduction of the CNI. The safety and efficacy of switching from a CNI to Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in such patients have not been established. Patients receiving Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, like other mTOR inhibitors, can impair healing, increasing the occurrence of post-transplant complications such as wound dehiscence, fluid accumulation and 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with a calcineurin inhibitor (CNI) may increase the risk of CNI-induced haemolytic uraemic syndrome/thrombotic thrombocytopenic purpura/thrombotic microangiopathy.

Vaccinations

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

Interstitial lung 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 out through appropriate investigations. Cases of ILD have been reported with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma has 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma.

Male infertility

There are literature reports of reversible azoospermia and oligospermia in patients treated with mTOR inhibitors. As preclinical toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma therapy.

Risk of intolerance of excipients

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 vivo interaction studies were conducted without concomitant ciclosporin.

Table 3 Effects of other active substances on 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 Cmin with a geometric mean ratio (everolimus/placebo) of 1.47-fold.

Ciclosporin

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma had a minor clinical influence on ciclosporin pharmacokinetics in renal and heart transplant patients receiving ciclosporin for microemulsion.

Atorvastatin (CYP3A4 substrate) and pravastatin (PgP substrate)

Single-dose administration of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Cmax and 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 affect the response to vaccination and vaccination during treatment with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma may be less effective. The use of live vaccines should be avoided.

Paediatric population

Interaction studies have only been performed in adults.

4.6 Fertility, pregnancy and lactation

Pregnancy

There are no adequate data from the use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should 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

  1. 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with calcineurin inhibitors (CNI) and corticosteroids in adult transplant recipients. All but two of the trials (in renal transplantation) included non-Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, CNI-based standard-therapy arms. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma combined with ciclosporin was studied in five trials in renal transplant recipients totalling 2,497 patients (including two studies without a non-Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma control group), and three trials in heart transplant recipients totalling 1,531 patients (ITT populations, see section 5.1).

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with ciclosporin, elevated serum creatinine was observed more frequently in patients administered Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma administered with reduced-dose ciclosporin was similar to that described in the 3 pivotal studies in 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.

  1. b) Tabulated summary of adverse reactions

Table 4 contains adverse drug reactions possibly or probably related to Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma seen in Phase III clinical trials. Unless noted otherwise, these disorders have been identified by an increased incidence in the Phase III studies comparing Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma-treated patients with patients on a non-Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

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

  1. c) Description of selected adverse reactions

As preclinical toxicology studies have shown that everolimus can reduce spermatogenesis, male infertility must be considered a potential risk of prolonged Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 lymphomas or 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma. Mostly, the condition resolves after discontinuation of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and/or addition of glucocorticoids. However, fatal cases have also occurred.

  1. d) Adverse drug reactions from post-marketing spontaneous reports

The following adverse drug reactions have been derived from post-marketing experience with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma via 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, lymphoedema
Respiratory, thoracic and mediastinal disorders Not known Pulmonary alveolar proteinosis
Skin and subcutaneous tissue disorders Not known Erythroderma

Paediatric population

The safety information in children and adolescents is based on the data of 12-months in renal and 24-months in hepatic paediatric transplant patients (see section 5.1).

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

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.

  1. PHARMACOLOGICAL PROPERTIES

5.1 Pharmacodynamic properties

Pharmacotherapeutic group: selective immunosuppressive agents.

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 G1 stage 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 that governs 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 to ciclosporin. 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 cells in general, such as vascular 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Phase III de novo adult renal transplant trials (B201 and B251). Mycophenolate mofetil (MMF) 1 g b.i.d was 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg/day, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 3 mg/day and MMF groups, respectively. In study B251, the incidences were 17.1%, 20.1%, and 23.5% for the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg/day, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 3 mg/day and MMF groups, respectively.

Reduced allograft function with elevated serum creatinine was observed more frequently among subjects using Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with full-dose ciclosporin for microemulsion than in MMF patients. This effect suggests that Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 3 ng/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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma comparative arm. A Phase III, multicentre, randomised, open-label, controlled trial (A2309) has been completed in which 833 de novo renal transplant recipients were randomised to one of two Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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/ml and 6-12 ng/ml, respectively. Sodium mycophenolate dosage was 1.44 g/d. Ciclosporin dosages were adapted to maintain target blood trough concentration windows as shown in Table6. The actual measured values for blood concentrations of everolimus and ciclosporin (C0 and C2) are shown in Table7.

Although the higher-dosage Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is recommended (see section 4.2).

Table 6 Study A2309: Target ciclosporin blood trough concentration windows

Target ciclosporin C0 (ng/ml) Mo 1 Mo 2-3 Mo 4-5 Mo 6-12
Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma groups

(low-dose ciclosporin)

MPA

(standard ciclosporin)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Table 8.

Table 8 Study A2309: Composite and individual efficacy endpoints at 6 and 12 months (incidence in ITT population)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg

N=277

% (n)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 3.0 mg

N=279

% (n)

MPA 1.44 g

N=277

% (n)

6 mo 12 mo 6 mo 12 mo 6 mo 12 mo
Composite endpoint (10 criterion) 19.1 (53) 25.3 (70) 16.8 (47) 21.5 (60) 18.8 (52) 24.2 (67)
Difference % (Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma – MPA)

95% CI

0.4%

(-6.2, 6.9)

1.1%

(-6.1, 8.3)

-1.9%

(-8.3, 4.4)

-2.7%

(-9.7, 4.3)

Individual endpoints (20 criteria)
Treated BPAR 10.8 (30) 16.2 (45) 10.0 (28) 13.3 (37) 13.7 (38) 17.0 (47)
Graft loss 4.0 (11) 4.3 (12) 3.9 (11) 4.7 (13) 2.9 (8) 3.2 (9)
Death 2.2 (6) 2.5 (7) 1.8 (5) 3.2 (9) 1.1 (3) 2.2 (6)
Loss to follow-up 3.6 (10) 4.3 (12) 2.5 (7) 2.5 (7) 1.8 (5) 3.2 (9)
Combined endpoints (20 criteria)
Graft loss / Death 5.8 (16) 6.5 (18) 5.7 (16) 7.5 (21) 4.0 (11) 5.4 (15)
Graft loss / Death / Loss to FU 9.4 (26) 10.8 (30) 8.2 (23) 10.0 (28) 5.8 (16) 8.7 (24)

mo = months, 1= primary, 2= secondary, CI = confidence interval, non-inferiority margin was 10%

Composite endpoint: treated biopsy-proven acute rejection (BPAR), graft loss, death, or loss to follow-up (FU)

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 Cmin values above 8 ng/ml.

Adverse events reported more frequently in the recommended (lower-dosage) Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma regimen than in the MPA control group have been included in Table4. A lower frequency of viral infections was reported for Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma-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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg

N=277

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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

Category of proteinuria (mg/mmol)
Treatment normal%(n)

(<3.39)

mild%(n)

(3.39-<33.9)

sub-nephrotic%(n)

(33.9-<339)

nephrotic%(n)

(>339)

Month 12

(TED)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg 0.4 (1) 64.2 (174) 32.5 (88) 3.0 (8)
Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 3 mg 0.7 (2) 59.2 (164) 33.9 (94) 5.8 (16)
MPA 1.44 g 1.8 (5) 73.1 (198) 20.7 (56) 4.1 (11)

1 mg/mmol = 8.84 mg/g

TED: Treatment endpoint (Mo 12 value or last observation carried forward)

Cardiac transplantation

In the Phase III cardiac study (B253), both Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 the incidence of acute rejection ≥ISHLT 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma were superior to AZA at 6, 12 and 24 months. The incidence of biopsy-proven acute rejection ≥ISHLT 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma doses were statistically significantly more effective than AZA in preventing allograft vasculopathy (defined as an increase in maximum intimal thickness from baseline ≥0.5 mm 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with full-dose ciclosporin for microemulsion than in AZA patients. These results indicated that Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma increases ciclosporin-induced nephrotoxicity.

Study A2411 was a randomised, 12-month, open-label study comparing Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with reduced doses of ciclosporin microemulsion and corticosteroids to mycophenolic mofetil (MMF) and standard doses of ciclosporin microemulsion and corticosteroids in de novo cardiac transplant patients. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma was initiated at 1.5 mg/day and the dose was adjusted to maintain target blood everolimus trough concentrations of 3-8 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 by month

Target ciclosporin C0 Mo 1 Mo 2 Mo 3-4 Mo 5-6 Mo 7-12
Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 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.

Table13 Study A2411: 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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma (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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma (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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma (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 Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

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 Phase III, multicentre, randomised, open-label study comparing two Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma/reduced-dose ciclosporin regimens against a standard mycophenolate mofetil (MMF)/ciclosporin regimen over 24 months. The use of induction therapy was centre-specific (no-induction or basiliximab or thymoglobulin). All patients received corticosteroids.

Starting doses in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma groups were 1.5 mg/d and 3 mg/d, and were adjusted to target blood trough everolimus concentrations of 3-8 ng/ml and 6-12 ng/ml, respectively. The MMF dose was 3 g/d. Ciclosporin dosages targeted the same blood trough concentration as in study A2411. Blood concentrations of everolimus and ciclosporin are shown in Table 15.

Recruitment to the experimental, higher-dosage Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma treatment arm was prematurely discontinued because of an increased rate of fatalities, due to infection and cardiovascular disorders, occurring within the first 90 days post-randomisation.

Table 15 Study A2310: Measured trough blood concentrations of ciclosporin (CsA) and everolimus

Visit window Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg/reduced-dose CsA

N=279

MMF 3 g/std-dose CsA

N=268

everolimus (C0 ng/ml) ciclosporin (C0 ng/ml)
Day 4 5.7 (4.6) 153 (103) 151 (101)
Month 1 5.2 (2.4) 247 (91) 269 (99)
Month 3 5.4 (2.6) 209 (86) 245 (90)
Month 6 5.7 (2.3) 151 (76) 202 (72)
Month 9 5.5 (2.2) 117 (77) 176 (64)
Month 12 5.4 (2.0) 102 (48) 167 (66)

Numbers are the mean (standard deviation) of measured values of C0=trough concentration

Efficacy outcome at 12 months is shown in Table16.

Table 16 Study A2310: Incidence rates of efficacy endpoints by treatment group (ITT population – 12-month analysis)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.5 mg

N=279

MMF

N=271

Efficacy endpoints n (%) n (%)
Primary: Composite efficacy failure 99 (35.1) 91 (33.6)
– AR associated with HDC 11 (3.9) 7 (2.6)
– BPAR of ISHLT grade ≥ 3A 63 (22.3) 67 (24.7)
– Death 22 (7.8) 13 (4.8)
– Graft loss/re-transplant 4 (1.4) 5 (1.8)
– Loss to follow-up 9 (3.2) 10 (3.7)

Composite efficacy failure: biopsy-proven acute rejection (BPAR) episodes of ISHLT grade ≥ 3A, acute rejection (AR) associated with haemodynamic compromise (HDC), graft loss/re-transplant, death, or loss to follow-up.

The higher fatality rate in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma arm relative to the MMF arm was mainly the result of an increased rate of fatalities from infection in the first three months among Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma patients receiving thymoglobulin induction therapy. The imbalance in fatalities within the thymoglobulin subgroup was particularly evident among patients hospitalised prior to transplantation and with L-ventricular assistance devices (see section 4.4).

Renal function over the course of study A2310, assessed by calculated glomerular filtration rate (GFR) using the MDRD formula, was 5.5 ml/min/1.73 m2 (97.5% CI -10.9, -0.2) lower for the everolimus 1.5 mg group at Month 12.

This difference was mainly observed in centres where the mean ciclosporin concentrations were similar throughout the study period in patients receiving Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and in patients randomised to the control arm. This finding underlines the importance of reducing the ciclosporin concentrations when combined with everolimus as indicated in Table 17 (see also section 4.2):

Table 17 Target ciclosporin trough concentrations per month

Target ciclosporin C0 Mo 1 Mo 2 Mo 3-4 Mo 5-6 Mo7-12
Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma group 200-350 150-250 100-200 75-150 50-100
MMF group 200-350 200-350 200-300 150-250 100-250

Additionally, the difference was mainly driven by a difference developed during the first month post-transplantation when patients are still in an unstable haemodynamic situation, possibly confounding the analysis of renal function. Thereafter, the decrease in mean GFR from Month 1 to Month 12 was significantly smaller in the everolimus group than in the control group (-6.4 vs. -13.7 ml/min, p=0.002).

Proteinuria, expressed as urinary protein: creatinine levels measured in spot urine samples, tended to be higher in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma-treated patients. Sub-nephrotic values were observed in 22% of the patients receiving Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma compared to MMF patients (8.6%). Nephrotic levels were also reported (0.8%), representing 2 patients in each treatment group (see section 4.4).

The adverse reactions for the everolimus 1.5 mg group in Study A2310 are consistent with the adverse drug reactions presented in Table4. A lower rate of viral infections was reported for Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma-treated patients, resulting principally from a lower reporting rate for CMV infection compared to MMF (7.2% vs. 19.4%).

Hepatic transplantation

In the Phase III adult hepatic transplant study (H2304), reduced exposure tacrolimus and Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1.0 mg twice daily was administered to patients, with the initial Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dose 4 weeks after transplantation, and was investigated versus standard exposure tacrolimus. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma was dose adjusted to maintain target blood everolimus trough concentrations between 3-8 ng/ml for the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma + reduced tacrolimus arm. Tacrolimus doses were subsequently adjusted to achieve target trough concentrations between 3-5 ng/ml during 12 months in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma + reduced tacrolimus arm.

Only 2.6% of study participants in H2304 were black so this study provides only limited efficacy and safety data on this population (see section 4.2)

Overall, in the 12-month analysis, the incidence of the composite endpoint (tBPAR, graft loss or death) was lower in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma + reduced tacrolimus arm (6.7%) compared to the tacrolimus control arm (9.7%) and consistent results were observed at 24 months (see Table 18).

The results of individual components of the composite endpoint are shown in Table 19.

Table 18 Study H2304: Comparison between treatment groups for Kaplan-Meier incidence rates of primary efficacy endpoints (ITT population – 12 and 24-month analysis)

Statistic EVR+Reduced TAC

N=245

TAC control

N=243

12-month 24-month 12-month 24-month
Number of composite efficacy failures (tBPAR, graft loss or death) from randomisation till Month 24/12 16 24 23 29
KM estimate of incidence rate of composite efficacy failure (tBPAR*, graft loss or death) at Month 24/12 6.7% 10.3% 9.7% 12.5%
Difference in KM estimates (vs. control) -3.0% 2.2%
97.5% CI for difference (-8.7%, 2.6%) (-8.8%, 4.4%)
P-value Z-test (EVR+Reduced TAC – Control = 0)

(No difference test)

0.230 0.452
P-value* Z-test (EVR+Reduced TAC – Control ≥0.12)

(Non-inferiority test)

<0.001 <0.001

*tBPAR = treated biopsy-proven acute rejection

Table 19 Study H2304: Comparison between treatment groups for incidence rates of secondary efficacy endpoints (ITT population – 12 and 24-month analysis)

Efficacy endpoints EVR/Reduced TAC

N=245

n (%)

TAC control

N=243

n (%)

Risk diff. (95% CI) P-value*
Graft loss
12-month 6 (2.4) 3 (1.2) 1.2 (-7.8, 10.2) 0.5038
24-month 9 (3.9) 7 (3.2) 0.8% (-3.2, 4.7) 0.661
Death
12-month 9 (3.7) 6 (2.5) 1.2 (-7.8, 10.1) 0.6015
24-month 12 (5.2) 10 (4.4) 0.8% (-3.7, 5.2) 0.701
BPAR1
12-month 10 (4.1) 26 (10.7) -6.6 (-11.2, -2.0) 0.0052
24-month 14 (6.1) 30 (13.3) -7.2% (-13.5, -0.9) 0.010
tBPAR2
12-month 7 (2.9) 17 (7.0) -4.1 (-8.0, -0.3) 0.0345
24-month 11 (4.8) 18 (7.7) -2.9% (-7.9, 2.2) 0.203
  1. BPAR = biopsy-proven acute rejection; 2. tBPAR = treated biopsy-proven acute rejection

*All p-values are for two-sided test and were compared to 0.05 significance level.

Comparison between treatment groups for change in eGFR (MDRD4) [ml/min/1.73 m2] from time of randomisation (day 30) to Month 12 and 24 demonstrated superior renal function for the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma + reduced tacrolimus arm (see Table 20).

Table 20 Study H2304: Comparison between treatment groups for eGFR (MDRD 4) at Month 12 (ITT population – 12 and 24-month analysis)

Difference vs. control
Treatment N LS mean (SE) LSM mean (SE) 97.5% CI P-value(1) P-value(2)
EVR+Reduced TAC
12-month 244 -2.23 (1.54) 8.50 (2.12) (3.74, 13.27) <0.001 <0.001
24-month 245 -7.94 (1.53) 6.66 (2.12) (1.9, 11.42) <0.0001 0.0018
TAC control
12-month 243 -10.73 (1.54)
24-month 243 -14.60 (1.54)

Least squares means, 97.5% confidence intervals and p-values are from an ANCOVA model containing treatment and HCV status as factors, and baseline eGFR as a covariate.

P-value (1): Non-inferiority test with NI margin = -6 ml/min/1.73m2, at one-sided 0.0125 level.

P-value (2): Superiority test at two-sided 0.025 levels.

Paediatric population

There is insufficient data in children and adolescents to recommend the use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in renal transplantation (see section 4.2). In hepatic transplant paediatric patients, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should not be used (see section 4.2).

Renal transplantation

In paediatric renal allograft recipients (1-18 years of age; n=106), Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma was assessed in a 12-month, multi-center, randomized, open-label trial with two parallel groups (1:1) evaluating the use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in combination with reduced tacrolimus and corticosteroid withdrawal at 6 months post transplantation in comparison to mycophenolate mofetil with standard tacrolimus. The efficacy for Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with reduced tacrolimus and steroid withdrawal was comparable to mycophenolate mofetil with standard tacrolimus [9.6% (5/52) vs 5.6% (3/54)] for the primary efficacy composite failure endpoint of BPAR, graft loss and death at 12 months. All of the events were BPAR; graft loss and death did not occur. Extrapolation from Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma adult kidney transplant data to Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma paediatric study data and literature showed that the primary efficacy composite endpoint was lower than that observed in adults. Renal function calculated by estimated glomerular filtration rate (eGFR) was numerically better with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma compared to mycophenolate mofetil with standard tacrolimus. The difference in mean eGFR from randomization to 12-months between groups was 3.8 mL/min/1.73m2.

Altogether 25% (13/52) patients in the Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma group vs. 11% (6/54) in the control group were withdrawn from study therapy due to AEs/Infections. Most of the AEs/infections leading to premature discontinuation of study medication were singular events and were not reported in more than one patient. One patient was reported with post-transplant lymphoproliferative disease.

Hepatic transplantation

In paediatric hepatic transplant recipients (month 1-18 years of age; n=56) receiving either a full-size liver allograft or a technically modified liver allograft from a deceased or living donor, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with reduced tacrolimus or ciclosporin was evaluated in a 24-month, multi-center, single arm study. Efficacy failure was defined as a composite endpoint (tBPAR, graft loss or death at 12 months). Out of 56 patients, two patients met the primary composite efficacy failure endpoint or any of its components. There were no deaths or graft losses over 24 months of treatment. An improvement in renal function, as measured by the gain in mean estimated glomerular filtration rate (eGFR) from randomization to 12-months was 6.3 mL/min/1.73m2. An improvement in renal function was also observed at 24-months, with an increase in mean eGFR from baseline of 4.5 mL/min/1.73m2.

In paediatric hepatic transplant recipients, there was no negative impact in growth or sexual maturation observed. However, three main safety concerns were identified from the analysis of the safety in paediatric hepatic transplant recipients compared to adults and published literature: high rates of premature discontinuation of study medication, serious infections leading to hospitalization and PTLD. Incidence rates for PTLD in the 2 – <18 years age group, and notably in EBV negative children under 2 years of age, were higher compared to adults and published literature. Based on the safety data the benefit/risk profile does not support recommendations for use.

5.2 Pharmacokinetic properties

Absorption

After oral administration, peak everolimus concentrations occur 1 to 2 hours post-dose. Everolimus blood concentrations are dose proportional over the dose range of 0.25 to 15 mg in transplant patients. The relative bioavailability of the dispersible tablet compared with the tablet is 0.90 (90% CI 0.76-1.07) based on the AUC ratio.

Food effect

Everolimus Cmax and AUC are reduced by 60% and 16% when the tablet formulation is given with a high-fat meal. To minimise variability, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should be taken consistently with or without food.

Distribution

The blood-to-plasma ratio of everolimus is concentration-dependent, ranging from 17% to 73% over the range of 5 to 5,000 ng/ml. Plasma protein binding is approximately 74% in healthy subjects and patients with moderate hepatic impairment. The distribution volume associated with the terminal phase (Vz/F) in maintenance renal transplant patients is 342 ± 107 litres.

Biotransformation

Everolimus is a substrate of CYP3A4 and P-glycoprotein. Following oral administration, it is the main circulating component in human blood. Six main metabolites of everolimus have been detected in human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal species used in toxicity studies, and showed approximately 100 times less activity than everolimus itself. Hence, the parent substance is considered to contribute the majority of the overall pharmacological activity of everolimus.

Elimination

After a single dose of radiolabelled everolimus to transplant patients receiving ciclosporin, the majority (80%) of radioactivity was recovered from the faeces, and only a minor amount (5%) was excreted in urine. Parent drug was not detected in urine and faeces.

Steady-state pharmacokinetics

Pharmacokinetics were comparable for kidney and heart transplant patients receiving everolimus twice daily simultaneously with ciclosporin for microemulsion. Steady-state is reached by day 4 with an accumulation in blood concentrations of 2 to 3-fold compared with exposure after the first dose. Tmax occurs at 1 to 2 hours post-dose. Cmax averages 11.1 ± 4.6 and 20.3 ± 8.0 ng/ml and AUC averages 75 ± 31 and 131 ± 59 ng.h/ml at 0.75 and 1.5 mg b.i.d., respectively. Pre-dose trough blood concentrations (Cmin) average 4.1 ± 2.1 and 7.1 ± 4.6 ng/ml at 0.75 and 1.5 mg b.i.d., respectively. Everolimus exposure remains stable over time in the first post-transplant year. Cmin is significantly correlated with AUC, yielding a correlation coefficient between 0.86 and 0.94. Based on a population pharmacokinetic analysis, oral clearance (CL/F) is 8.8 litres/hour (27% interpatient variation) and the central distribution volume (Vc/F) is 110 litres (36% interpatient variation). Residual variability in blood concentrations is 31%. The elimination half-life is 28 ± 7 hours.

Special populations

Hepatic impairment

Relative to the AUC of everolimus in subjects with normal hepatic function, the average AUC in 6 patients with mild hepatic impairment (Child-Pugh Class A) was 1.6-fold higher; in two independently studied groups of 8 and 9 patients with moderate hepatic impairment (Child-Pugh Class B), the average AUC was 2.1-fold and 3.3-fold higher, respectively; and in 6 patients with severe hepatic impairment (Child-Pugh Class C), the average AUC was 3.6-fold higher. Mean half-lives were 52, 59 and 78 hours in mild, moderate and severe hepatic impairment. The prolonged half-lives delay the time to reach steady-state everolimus blood concentrations.

Renal impairment

Post-transplant renal impairment (CCr range 11-107 ml/min) did not affect the pharmacokinetics of everolimus.

Paediatric population

Fourteen paediatric de novo renal transplant patients (2 to 16 years) received Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dispersible tablets at a starting dose of 0.8 mg/m2 (maximum 1.5 mg) twice daily with ciclosporin for microemulsion. Their doses were subsequently individualised based on therapeutic drug monitoring to maintain everolimus pre-dose trough concentrations ≥3 ng/ml. At steady state, the everolimus trough level was 6.2 ± 2.4 ng/ml, Cmax was 18.2 ± 5.5 ng/ml, and AUC was 118 ± 28 ng.h/ml, which are comparable to adults receiving Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma targeted to similar pre-dose trough concentrations. The steady-state CL/F was 7.1 ± 1.7 l/h/m2 and the elimination half-life was 30 ± 11 h in paediatric patients.

Elderly patients

A limited reduction in everolimus oral clearance by 0.33% per year was estimated in adults (age range studied was 16-70 years). No dose adjustment is considered necessary.

Ethnicity

Based on a population pharmacokinetic analysis, oral clearance (CL/F) is, on average, 20% higher in black transplant patients. See section 4.2.

Exposure-response relationships

The average everolimus trough concentration over the first 6 months post-transplant was related to the incidence of biopsy-confirmed acute rejection and of thrombocytopenia in renal and cardiac transplant patients (see Table 21). In hepatic transplant patients, the relationship between average everolimus trough concentrations and the incidence of biopsy-proven acute rejection is less well defined. No correlation between higher everolimus exposure and adverse events such as thrombocytopenia has been observed (see Table21).

Table 21 Exposure-response relationships for everolimus in transplant patients

Renal transplantation:
Trough concentration (ng/ml) ≤3.4 3.5 – 4.5 4.6 – 5.7 5.8 – 7.7 7.8 – 15.0
Freedom from rejection 68% 81% 86% 81% 91%
Thrombocytopenia

(<100 x 109/l)

10% 9% 7% 14% 17%
Cardiac transplantation:
Trough concentration (ng/ml) ≤3.5 3.6 – 5.3 5.4 – 7.3 7.4 – 10.2 10.3 – 21.8
Freedom from rejection 65% 69% 80% 85% 85%
Thrombocytopenia

(<75 x 109/l)

5% 5% 6% 8% 9%
Hepatic transplantation:
Trough concentration (ng/ml) ≤3 3-8 ≥8
Freedom from treated BPAR 88% 98% 92%
Thrombocytopenia (≤75 x 109/l) 35% 13% 18%

5.3 Preclinical safety data

The preclinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and rabbits. The major target organs were male and female reproductive systems (testicular tubular degeneration, reduced sperm content in epididymides and uterine atrophy) in several species, and, in rats only, lungs (increased alveolar macrophages) and eyes (lenticular anterior suture line opacities). Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium) and the mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs.

Spontaneously occurring background diseases (chronic myocarditis in the rat, Coxsackie virus infection in plasma and heart in monkeys, coccidial infestation of GI tract in minipigs, skin lesions in mice and monkeys) appeared to be exacerbated by treatment with everolimus. These findings were generally observed at systemic exposure concentrations within the range of therapeutic exposure or above, with the exception of findings in rats, which occurred below therapeutic exposure due to high tissue distribution.

Ciclosporin in combination with everolimus caused higher systemic exposure to everolimus and increased toxicity. There were no new target organs in the rat. Monkeys showed haemorrhage and arteritis in several organs.

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm count and plasma testosterone levels were diminished at 5 mg/kg, which is within the range of therapeutic exposure and caused a decrease in male fertility. There was evidence of reversibility. Female fertility was not affected, but everolimus crossed the placenta and was toxic to the conceptus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below the therapeutic exposure, which was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations at 0.3 and 0.9 mg/kg (e.g. sternal cleft) was increased. In rabbits, embryotoxicity was evident by an increase in late resorptions.

Genotoxicity studies covering relevant genotoxicity endpoints showed no evidence of clastogenic or mutagenic activity. Administration of everolimus for up to 2 years did not indicate any oncogenic potential in mice and rats up to the highest doses, corresponding respectively to 8.6 and 0.3 times the estimated clinical exposure.

  1. PHARMACEUTICAL PARTICULARS

6.1 List of excipients

Butylated hydroxytoluene, Magnesium stearate, Lactose monohydrate, Hypromellose, Crospovidone, Lactose anhydrous

6.2 Incompatibilities

Not applicable

6.3 Shelf life

3 years.

6.4 Special precautions for storage

Store in the original package in order to protect from light and moisture.

6.5 Nature and contents of container

Aluminium/polyamide/aluminium/PVC blister.

Packs containing 50/60/100/250 tablets.

Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements.

  1. MANUFACTURED IN INDIA BY:


TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

PACKAGE LEAFLET: INFORMATION FOR THE USER

EVEROLIMUS TABLETS
5MG / 10MG
(EVEROTAJ)
TAJ PHARMA

Everolimus

Read all of this leaflet carefully before you start taking this medicine because it contains important information for you.

  • Keep this leaflet. You may need to read it again.
  • If you have any further questions, ask your doctor or pharmacist.
  • This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, even if their signs of illness are the same as yours.
  • If you get any side effects talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. See section 4.

WHAT IS IN THIS LEAFLET:

  1. What Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is and what it is used for
  2. What you need to know before you take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma
  3. How to take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma
  4. Possible side effects
  5. How to store Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma
  6. Contents of the pack and other information1. WHAT EVEROLIMUS TABLETS 5MG / 10MG (EVEROTAJ) TAJ PHARMA IS AND WHAT IT IS USED FOR

The active substance of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is everolimus.

Everolimus belongs to a group of medicines called immunosuppressants. It is used in adults to prevent the body’s immune system from rejecting a transplanted kidney, heart or liver.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is used together with other medicines, such as ciclosporin for kidney and heart transplantation, tacrolimus for liver transplantation, and corticosteroids.

  1. WHAT YOU NEED TO KNOW BEFORE YOU TAKE EVEROLIMUS TABLETS 5MG / 10MG (EVEROTAJ) TAJ PHARMA

Do not take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

  • if you are allergic (hypersensitive) to everolimus or any of the other ingredients of this medicine (listed in section 6).
  • if you are allergic (hypersensitive) to sirolimus.

If any of the above applies to you, tell your doctor and do not take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma.

Warnings and precautions

Talk to your doctor before taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma:

  • Medicines that suppress the immune system like Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma reduce your body´s ability to fight against infections. It is advisable to consult your doctor or transplant centre if you have a fever or generally feel unwell, or have local symptoms such as coughing or a burning sensation when urinating that are severe or persistent over several days. Consult your doctor or transplant centre right away if you feel confused, have problems speaking, memory loss, a headache, impaired vision or seizures, as these may be symptoms of a rare but very serious condition called progressive multiple leukoencephalopathy (PML).
  • If you have had recent major surgery, or if you still have an unhealed wound following surgery, Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma may increase the risk of wound-healing problems.
  • Medicines that suppress the immune system like Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma increase the risk of developing cancers, particularly of the skin and the lymphoid system. Therefore, you should limit your exposure to sunlight and UV light by wearing appropriate protective clothing and frequently applying a sunscreen with a high protection factor.
  • Your doctor will monitor your kidney function, the amounts of fats (lipids) and sugar in your blood as well as the amount of proteins in your urine.
  • If you have liver problems or have ever had a disease which may have affected your liver, please tell your doctor. Your doctor may need to modify the dose of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma you are taking.
  • If you experience respiratory symptoms (e.g. coughing, difficulty in breathing and wheezing), please inform your doctor. Your doctor may decide whether and how you need to continue Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, and/or whether you need to receive other medicines to resolve this condition.
  • Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma may reduce sperm production in men, thereby reducing the ability to father children. The effect is generally reversible. Male patients wanting to father children should discuss their treatment with their physician.

Older people (65 years and over)

There is limited experience with the administration of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in elderly people.

Children and adolescents (younger than 18 years of age)

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is not recommended for use in children and adolescents with a transplanted kidney because there is not enough experience in the use of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in this age group. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should not be used in children and adolescents with a transplanted liver.

Other medicines and Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

Tell your doctor or pharmacist if you are taking or have recently taken or might take any other medicines, including medicines obtained without a prescription.

Certain medicines may affect the way in which Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma works in the body. It is very important that you tell your doctor if you are taking any of the following medicines:

  • immunosuppressive medicines other than ciclosporin, tacrolimus or corticosteroids.
  • antibiotics, such as rifampicin, rifabutin, clarithromycin, erythromycin or telithromycin.
  • antiviral medicines, such as ritonavir, efavirenz, nevirapine, nelfinavir, indinavir or amprenavir, which are used to treat HIV infection.
  • medicines used to treat fungal infections, such as voriconazole, fluconazole, ketoconazole or itraconazole.
  • medicines used to treat epilepsy, such as phenytoin, phenobarbital or carbamazepine.
  • medicines used to treat high blood pressure or heart problems, such as verapamil, nicardipine or diltiazem.
  • dronedarone, a medicine used to help regulate your heart beat.
  • medicines used to lower blood cholesterol, such as atorvastatin, pravastatin or fibrates.
  • medicines used to treat acute seizures, or used as a sedative before or during surgery or other medical procedures, such as midazolam.
  • octreotide, a medicine used to treat acromegaly, a rare hormonal disorder that usually occurs in middle-aged adults.
  • imatinib, a medicine used to inhibit the growth of abnormal cells.
  • John’s wort (Hypericum perforatum), a herbal medicine used to treat depression.
  • If you need to have a vaccination, talk to your doctor first.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with food and drink

The presence of food can affect how much Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is absorbed. In order to keep constant levels in your body, you should always take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma in the same way. You should either always take it with food, or always on an empty stomach.

Do not take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma with grapefruit juice or grapefruit. They affect how Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma works in the body.

Pregnancy, breast-feeding and fertility

If you are pregnant, do not take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma unless your doctor thinks it is absolutely necessary. If you are a woman and you could get pregnant, you should use an effective method of contraception during treatment with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and for 8 weeks after stopping treatment.

If you think you may be pregnant, ask your doctor or pharmacist for advice before taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma.

You should not breast-feed while taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma. It is not known whether Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma passes into breast milk.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma may have an impact on male fertility.

Driving and using machines

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

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma contains

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma tablets contain lactose. If you do not tolerate certain sugars (glucose, galactose, lactose), you should talk to your doctor before taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma.

  1. HOW TO TAKE EVEROLIMUS TABLETS 5MG / 10MG (EVEROTAJ) TAJ PHARMA

Your doctor will decide exactly what dose of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma you should take and when you should take it.

Always take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma exactly as your doctor or pharmacist has told you. Check with your doctor or pharmacist if you are not sure.

How much to take

  • The usual starting dose is 1.5 mg/day in kidney and heart transplantation and 2.0 mg/day in liver transplantation.
  • This is usually divided into two doses, one in the morning and one in the evening.

How to take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma should only be taken by mouth.

Do not crush the tablets.

Swallow the tablets whole with a glass of water.

You should take the first dose of this medicine as early as possible after kidney and heart transplantation and approximately four weeks after liver transplantation.

You should take the tablets together with ciclosporin for microemulsion in kidney and heart transplantation, and with tacrolimus in liver transplantation.

Do not switch from Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma tablets to Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma dispersible tablets without first telling your doctor.

Monitoring during your treatment with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

Your doctor may adjust your dose depending on how much Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma there is in your blood and depending on how well you respond to the treatment. Your doctor will perform regular blood tests to measure the amount of everolimus and ciclosporin in your blood. Your doctor will also carefully monitor your kidney function, blood lipids and blood sugar, as well as the amount of proteins in your urine.

If you take more Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma than you should

If you take more of this medicine than you should, talk to your doctor immediately.

If you forget to take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

If you have forgotten to take your dose of Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, take it as soon as you remember and then take the next dose at the usual time. Ask your doctor for advice. Do not take a double dose to make up for a forgotten tablet.

If you stop taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma

Do not stop taking the tablets unless your doctor tells you to. You will need to take this medicine for as long as you need to have immunosuppressants to prevent the rejection of your transplanted kidney, heart or liver. If you stop taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma, you will have a greater risk of your body rejecting the transplanted organ.

If you have any further questions on the use of this medicine, ask your doctor or pharmacist.

  1. POSSIBLE SIDE EFFECTS

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Because you take Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma together with other medicines, it is not always clear whether the side effects are caused by Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma or by the other medicines.

The following side effects need immediate medical attention:

  • infections,
  • inflammation of the lungs,
  • allergic reactions,
  • fever and bruising under the skin that may appear as red dots, with or without unexplained tiredness, confusion, yellowing of the skin or eyes, reduced urine output (thrombotic microangiopathy, haemolytic uraemic syndrome).

Should you develop any of the following:

  • persistent or worsening lung/breathing symptoms such as coughing, difficulty breathing, or wheezing,
  • fever, generally feeling unwell, chest or abdominal pain, chills, burning sensation when urinating,
  • swelling of face, lips, tongue or throat,
  • difficulty swallowing,
  • spontaneous bruising or bleeding for no obvious reason,
  • rash,
  • pain, unusual warmth, swelling or oozing from the site of surgery

you should stop taking Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma and tell your doctor straight away.

Other reported side effects include:

Very common(may affect more than 1 in 10 patients)

  • infections (viral, bacterial and fungal infections),
  • lower respiratory tract infections, such as lung infections, including pneumonia
  • upper respiratory tract infections, such as inflammation of the pharynx, and common cold,
  • urinary tract infections,
  • anaemia (reduced red blood cell count),
  • low levels of white blood cells, leading to a higher risk of infection, reduced blood platelet count, which can lead to bleeding and/or bruising underneath the skin,
  • high level of fats (lipids, cholesterol and triglycerides) in the blood,
  • onset of diabetes (high level of sugar in the blood),
  • reduced level of potassium in the blood,
  • anxiety,
  • problems falling asleep (insomnia),
  • headache,
  • fluid collection in the sac around the heart, which if severe, can decrease the heart’s ability to pump blood,
  • high blood pressure,
  • venous thrombosis (blockage of a major vein by a blood clot),
  • fluid collection on the lungs and in the chest cavity, which, if severe, could make you breathless,
  • coughing,
  • breathlessness,
  • diarrhoea,
  • feeling sick (nausea),
  • being sick (vomiting),
  • stomach (abdominal) pain,
  • general pain,
  • fever,
  • accumulation of fluid in the tissues,
  • abnormal wound healing.

Common(may affect up to 1 in 10 patients)

  • blood poisoning,
  • wound infection,
  • cancers and benign tumours,
  • skin cancer,
  • kidney damage with low blood platelets and low red blood cell counts, with or without a rash (thrombocytopenic purpura/haemolytic uraemic syndrome),
  • breakdown of red blood cells,
  • low levels of red blood cells and platelets,
  • fast heart beat,
  • nose bleeds,
  • reduced numbers of blood cells (symptoms may include weakness, bruising and frequent infections),
  • clotting in the blood vessels of the kidney, which may result in graft loss mostly within the first 30 days after kidney transplantation,
  • bleeding disorders,
  • cyst containing lymph fluid,
  • pain in the mouth or throat,
  • inflammation of the pancreas,
  • mouth sores,
  • acne,
  • hives (urticaria) and other allergic symptoms, such as swelling of the face or throat (angiooedema),
  • rash,
  • joint pain,
  • muscle pain,
  • protein in the urine,
  • kidney disorders,
  • impotence,
  • hernia at the site of surgery,
  • abnormal liver test results,
  • menstrual disorders (including absent or heavy periods).

Uncommon(may affect up to 1 in 100 patients):

  • cancer of the lymph tissue (lymphoma/post-transplant lymphoproliferative disorder),
  • low levels of testosterone,
  • inflammation of the lungs,
  • inflammation of the liver,
  • jaundice,
  • ovarian cysts.

Other side effects:

Other side effects have occurred in a small number of people, but their exact frequency is unknown:

  • abnormal accumulation of protein in the lungs (symptoms may include persistent dry cough, fatigue and difficulty breathing),
  • inflammation of blood vessels,
  • swelling, feeling of heaviness or tightness, pain, limited mobility of body parts (this could occur anywhere in the body and is a potential sign of an abnormal build-up of fluid in soft tissue due to a blockage in the lymphatic system, also known as lymphoedema)
  • severe rash with skin swelling.

If you have concerns regarding any of these effects, tell your doctor.

There may also be side effects of which you are not aware, such as abnormal results of laboratory tests, including tests of kidney function. This means that your doctor will perform blood tests to monitor any changes to your kidneys during your treatment with Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma.

Reporting of side effects

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects not listed in this leaflet. You can also report side effects directly via the internet at www.mhra.gov.uk/yellowcard. By reporting side effects you can help provide more information on the safety of this medicine.

  1. HOW TO STORE EVEROLIMUS TABLETS 5MG / 10MG (EVEROTAJ) TAJ PHARMA
  • Keep Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma out of the sight and reach of children.
  • Do not use Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma after the expiry date which is stated on the carton after EXP. The expiry date refers to the last day of that month.
  • Store the blister packs in the original carton in order to protect from light and moisture.
  • Do not use any Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma pack that is damaged or shows signs of tampering.
  • Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to throw away medicines you no longer use. These measures will help protect the environment.
  1. CONTENT OF THE PACK AND OTHER INFORMATION

What Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma contains

a) Each tablet contains:
Everolimus………………………..5mg
Excipients………………………….q.s.

b) Each tablet contains:
Everolimus………………………..10mg
Excipients………………………….q.s.

The other ingredients are:

butylhydroxytoluene, magnesium stearate, lactose monohydrate, hypromellose, crospovidone and anhydrous lactose.

What Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma looks like and contents of the pack

  • Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 0.25 mg tablets are white to yellowish, marbled, round, flat tablets of 6 mm, engraved “C” on one side and “NVR” on the other.
  • Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 0.5 mg tablets are white to yellowish, marbled, round, flat tablets of 7 mm, engraved “CH” on one side and “NVR” on the other.
  • Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 0.75 mg tablets are white to yellowish, marbled, round, flat tablets of 8.5 mm, engraved “CL” on one side and “NVR” on the other.
  • Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma 1 mg tablets are white to yellowish, marbled, round, flat tablets of 9 mm, engraved “CU” on one side and “NVR” on the other.

Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma tablets are supplied in packs containing 50, 60, 100 or 250 tablets. Not all pack sizes may be marketed. Everolimus Tablets 5mg / 10mg (EVEROTAJ) Taj Pharma is also available in the form of dispersible tablets.

  1. MANUFACTURED IN INDIA BY:


TAJ PHARMACEUTICALS LTD.
Mumbai, India
Unit No. 214.Old Bake House,
Maharashtra chambers of  Commerce Lane,
Fort, Mumbai – 400001
at:Gujarat, INDIA.
Customer Service and Product Inquiries:
1-800-TRY-FIRST (1-800-222-434 & 1-800-222-825)
Monday through Saturday 9:00 a.m. to 7:00 p.m. EST
E-mail: tajgroup@tajpharma.com

Related Products

Taj Generics (Taj Pharma) provides a wide range of products to the Indian market, including an extensive range of generics and specialty products; Our products cover a vast array of therapeutic categories, and we offer an extensive range of dosage forms and delivery systems including oral solids, controlled-release, steriles, injectables, topicals, liquids, transdermals, semi-solids and high-potency products. Our Generics portfolio offers over 1500 products in the major therapeutic areas of gastro-intestinal, cardiovascular, pain management, oncology, anti-infectives, paediatrics and dermatology.