Novartis Ireland Limited

Afinitor 5 mg tablets

Each tablet contains 5 mg everolimus.

Excipients

Each tablet contains 149 mg lactose.

For a full list of excipients, see section 6.1.

Tablet.

White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other.

Neuroendocrine tumours of pancreatic origin

Afinitor is indicated for the treatment of unresectable or metastatic, well- or moderately-differentiated neuroendocrine tumours of pancreatic origin in adults with progressive disease.

Renal cell carcinoma

Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma, whose disease has progressed on or after treatment with VEGF-targeted therapy.

Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of anticancer therapies.

Posology

The recommended dose is 10 mg everolimus once daily. Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs.

If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.

Dose adjustment due to adverse reactions

Management of severe and/or intolerable suspected adverse reactions may require dose alterations. Afinitor may be dose reduced or temporarily withheld (e.g. for one week) followed by reintroduction at 5 mg daily. If dose reduction is required, the suggested dose is 5 mg daily (see also section 4.4).

Special populations

Paediatric population

The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available.

Elderly patients (65 years)

No dose adjustment is required (see section 5.2).

Renal impairment

No dose adjustment is required (see section 5.2).

Hepatic impairment

For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily. Everolimus has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) and is not recommended for use in this patient population (see sections 4.4 and 5.2).

Method of administration

Afinitor should be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.

Non-infectious pneumonitis

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Non-infectious pneumonitis (including interstitial lung disease) was described in 12% of patients taking Afinitor (see section 4.8). Some cases were severe and on rare occasions, a fatal outcome was observed. A diagnosis of non-infectious pneumonitis should be considered in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough or dyspnoea, and in whom infectious, neoplastic and other non-medicinal causes have been excluded by means of appropriate investigations. Patients should be advised to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue Afinitor therapy without dose adjustments If symptoms are moderate, consideration should be given to interruption of therapy until symptoms improve. The use of corticosteroids may be indicated. Afinitor may be re-initiated at 5 mg daily.

For cases where symptoms of non-infectious pneumonitis are severe, Afinitor therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with Afinitor may be re-initiated at 5 mg daily depending on the individual clinical circumstances.

Infections

Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens (see section 4.8). Localised and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus, have been described in patients taking Afinitor. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) and occasionally fatal.

Physicians and patients should be aware of the increased risk of infection with Afinitor. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Afinitor. While taking Afinitor, be vigilant for symptoms and signs of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor.

If a diagnosis of invasive systemic fungal infection is made, Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

Hypersensitivity reactions

Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnoea, flushing, chest pain or angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) have been observed with everolimus (see section 4.3).

Oral ulceration

Mouth ulcers, stomatitis and oral mucositis have been observed in patients treated with Afinitor (see section 4.8). In such cases topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed (see section 4.5).

Renal failure events

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Afinitor (see section 4.8). Renal function of patients should be monitored particularly where patients have additional risk factors that may further impair renal function.

Laboratory tests and monitoring

Renal function

Elevations of serum creatinine, usually mild, and proteinuria have been reported in clinical trials (see section 4.8). Monitoring of renal function, including measurement of blood urea nitrogen (BUN), urinary protein or serum creatinine, is recommended prior to the start of Afinitor therapy and periodically thereafter.

Blood glucose and lipids

Hyperglycaemia, hyperlipidaemia and hypertriglyceridaemia have been reported in clinical trials (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.

Haematological parameters

Decreased haemoglobin, lymphocytes, neutrophils and platelets have been reported in clinical trials (see section 4.8). Monitoring of complete blood count is recommended prior to the start of Afinitor therapy and periodically thereafter.

Carcinoid tumours

In a randomised, double-blind, multi-centre trial in patients with carcinoid tumours, Afinitor plus depot octreotide (Sandostatin LAR^®) was compared to placebo plus depot octreotide. The study did not meet the primary efficacy endpoint (progression-free-survival [PFS]) and the overall survival (OS) interim analysis numerically favoured the placebo plus depot octreotide arm. Therefore, the safety and efficacy of Afinitor in patients with carcinoid tumours have not been established.

Interactions

Co-administration with inhibitors and inducers of CYP3A4 and/or the multidrug efflux pump P-glycoprotein (PgP) should be avoided. If co-administration of a moderate CYP3A4 and/or PgP inhibitor or inducer cannot be avoided, dose adjustments of Afinitor can be taken into consideration based on predicted AUC (see section 4.5).

Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased plasma concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Afinitor and potent inhibitors is not recommended.

Hepatic impairment

Afinitor should not be used in patients with severe hepatic impairment (Child-Pugh class C) (see sections 4.2 and 5.2).

Vaccinations

The use of live vaccines should be avoided during treatment with Afinitor (see section 4.5).

Lactose

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

Wound healing complications

Impaired wound healing is a class effect of rapamycin derivatives, including Afinitor. Caution should therefore be exercised with the use of Afinitor in the peri-surgical period.

Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of PgP. Therefore, absorption and subsequent elimination of everolimus may be influenced by products that affect CYP3A4 and/or PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

Known and theoretical interactions with selected inhibitors and inducers of CYP3A4 and PgP are listed in Table 1 below.

CYP3A4 and PgP inhibitors increasing everolimus concentrations

Substances that are inhibitors of CYP3A4 or PgP may increase everolimus blood concentrations by decreasing metabolism or the efflux of everolimus from intestinal cells.

CYP3A4 and PgP inducers decreasing everolimus concentrations

Substances that are inducers of CYP3A4 or PgP may decrease everolimus blood concentrations by increasing metabolism or the efflux of everolimus from intestinal cells.

Table 1 Effects of other active substances on everolimus

Agents whose plasma concentration may be altered by everolimus

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; hence everolimus may affect the bioavailability of co-administered substances which are CYP3A4 and/or PgP substrates.

Co-administration of everolimus and depot octreotide increased octreotide C_min with a geometric mean ratio (everolimus/placebo) of 1.47. A clinically significant effect on the efficacy response to everolimus in patients with advanced neuroendocrine tumours could not be established.

Vaccinations

The immune response to vaccination may be affected and, therefore, vaccination may be less effective during treatment with Afinitor. The use of live vaccines should be avoided during treatment with Afinitor (see section 4.4). Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG (Bacillus Calmette-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.

Pregnancy

There are no or limited amount of data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects (see section 5.3).

Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception. Women of childbearing potential must use an effective method of contraception while receiving everolimus.

Breast-feeding

It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk. Therefore, women taking everolimus should not breast-feed.

Fertility

Based on non-clinical findings, male fertility may be compromised by treatment with everolimus (see section 5.3).

No studies on the effects on the ability to drive and use machines have been performed. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Afinitor.

a) Summary of safety profile

Two randomised, double-blind, placebo controlled pivotal phase III studies contribute to the safety profile. The respective exposure in the phase III studies was:

• RADIANT-3 (CRAD001C2324): everolimus plus best supportive care in patients with advanced neuroendocrine tumours of pancreatic origin. In total, 63 (30.9%) patients were exposed to everolimus 10 mg/day for 52 weeks. The rates of adverse reactions resulting in permanent discontinuation were 13.7% and 2.0% for the everolimus and placebo treatment groups, respectively.

• RECORD-1 (CRAD001C2240): everolimus plus best supportive care in patients with metastatic renal cell carcinoma. In total, 165 patients were exposed to everolimus 10 mg/day for 4 months. The rates of adverse reactions resulting in permanent discontinuation were 7% and 0% for the everolimus and placebo treatment groups, respectively. Most adverse reactions were grade 1 or 2 in severity.

The most frequent grade 3-4 adverse reactions (incidence 2% in at least one pivotal study) were anaemia, fatigue, diarrhoea, infections, stomatitis, hyperglycaemia, thrombocytopenia, lymphopenia, neutropenia, hypophosphataemia, hypercholesterolaemia, diabetes mellitus, and pneumonitis. The grades follow CTCAE Version 3.0.

b) Tabulated summary of adverse reactions

Table 2 shows the incidence of adverse reactions reported for patients receiving everolimus 10 mg/day in at least one of the pivotal studies. All terms included are based on the highest frequency reported in a pivotal study. Adverse reactions are listed according to MedDRA system organ class and frequency category. Frequency categories are defined using the following convention: very common (1/10); common (1/100 to <1/10); uncommon (1/1,000 to <1/100); rare (1/10,000 to <1/1,000); very rare (<1/10,000); not known (cannot be estimated from the available data). Within each frequency grouping, adverse reactions are presented in order of decreasing seriousness.

Table 2 Adverse reactions

c) Description of selected adverse reactions

In clinical studies, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcome. Reactivation of infection is an expected event during periods of immunosuppression.

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome) and proteinuria. Monitoring of renal function is recommended (see section 4.4).

Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability. General supportive measures should be initiated in all cases of overdose.

Pharmacotherapeutic group: Antineoplastic agents, other antineoplastic agents, protein kinase inhibitors, ATC code: L01XE10

Mechanism of action

Everolimus is a selective mTOR (mammalian target of rapamycin) inhibitor. mTOR is a key serine-threonine kinase, the activity of which is known to be upregulated in a number of human cancers. Everolimus binds to the intracellular protein FKBP-12, forming a complex that inhibits mTOR complex-1 (mTORC1) activity. Inhibition of the mTORC1 signalling pathway interferes with the translation and synthesis of proteins by reducing the activity of S6 ribosomal protein kinase (S6K1) and eukaryotic elongation factor 4E-binding protein (4EBP-1) that regulate proteins involved in the cell cycle, angiogenesis and glycolysis. Everolimus reduces levels of vascular endothelial growth factor (VEGF), which potentiates tumour angiogenic processes. Everolimus is a potent inhibitor of the growth and proliferation of tumour cells, endothelial cells, fibroblasts and blood-vessel-associated smooth muscle cells and has been shown to reduce glycolysis in solid tumours in vitro and in vivo.

Clinical efficacy and safety

Advanced neuroendocrine tumours of pancreatic origin (pNET)

RADIANT-3 (study CRAD001C2324), a phase III, multicentre, randomised, double-blind study of Afinitor plus best supportive care (BSC) versus placebo plus BSC in patients with advanced pNET, demonstrated a statistically significant clinical benefit of Afinitor over placebo by a 2.4-fold prolongation of median progression-free-survival (PFS) (11.04 months versus 4.6 months), (HR 0.35; 95% CI: 0.27, 0.45; p<0.0001) (see Table 3 and Figure 1).

RADIANT-3 involved patients with well- and moderately-differentiated advanced pNET whose disease had progressed within the prior 12 months. Treatment with somatostatin analogues was allowed as part of BSC.

The primary endpoint for the study was PFS evaluated by RECIST (Response Evaluation Criteria in Solid Tumors). Following documented radiological progression, patients could be unblinded by the investigator. Those randomised to placebo were then able to receive open-label Afinitor.

Secondary endpoints included safety, objective response rate, response duration and overall survival (OS).

In total, 410 patients were randomised 1:1 to receive either Afinitor 10 mg/day (n=207) or placebo (n=203). Demographics were well balanced (median age 58 years, 55% male, 78.5% Caucasian). Fifty-eight percent of the patients in both arms received prior systemic therapy. The median duration of blinded study treatment was 37.3 weeks (range 1.1-129.9 weeks) for patients receiving everolimus and 16.1 weeks (range 0.4-146.0 weeks) for those receiving placebo.

Table 3 RADIANT-3 – Progression-free survival results

Figure 1 RADIANT-3 – KaplanMeier progression-free survival curves

Following disease progression 172 of the 203 patients (84.7%) initially randomised to placebo crossed over to open-label Afinitor. The overall survival results show no statistically significant difference in OS (HR=0.89 [95% CI: 0.64, 1.23]).

Advanced renal cell carcinoma

RECORD-1 (study CRAD001C2240), a phase III, international, multicentre, randomised, double-blind study comparing everolimus 10 mg/day and placebo, both in conjunction with best supportive care, was conducted in patients with metastatic renal cell carcinoma whose disease had progressed on or after treatment with VEGFR-TKI (vascular endothelial growth factor receptor tyrosine kinase inhibitor) therapy (sunitinib, sorafenib, or both sunitinib and sorafenib). Prior therapy with bevacizumab and interferon-α was also permitted. Patients were stratified according to Memorial Sloan-Kettering Cancer Center (MSKCC) prognostic score (favourable- vs. intermediate- vs. poor-risk groups) and prior anticancer therapy (1 vs. 2 prior VEGFR-TKIs).

Progression-free survival, documented using RECIST (Response Evaluation Criteria in Solid Tumours) and assessed via a blinded, independent central review, was the primary endpoint. Secondary endpoints included safety, objective tumour response rate, overall survival, disease-related symptoms, and quality of life. After documented radiological progression, patients could be unblinded by the investigator: those randomised to placebo were then able to receive open-label everolimus 10 mg/day. The Independent Data Monitoring Committee recommended termination of this trial at the time of the second interim analysis as the primary endpoint had been met.

In total, 416 patients were randomised 2:1 to receive Afinitor (n=277) or placebo (n=139). Demographics were well balanced (pooled median age [61 years; range 27-85], 78% male, 88% Caucasian, number of prior VEGFR-TKI therapies [1-74%, 2-26%]). The median duration of blinded study treatment was 141 days (range 19-451 days) for patients receiving everolimus and 60 days (range 21-295 days) for those receiving placebo.

Afinitor was superior to placebo for the primary endpoint of progression-free survival, with a statistically significant 67% reduction in the risk of progression or death (see Table 4 and Figure 2).

Table 4 RECORD-1 – Progression-free survival results

^a Stratified log-rank test

Figure 2 RECORD-1 – KaplanMeier progression-free survival curves

Six-month PFS rates were 36% for Afinitor therapy compared with 9% for placebo.

Confirmed objective tumour responses were observed in 5 patients (2%) receiving Afinitor, while none were observed in patients receiving placebo. Therefore, the progression-free survival advantage primarily reflects the population with disease stabilisation (corresponding to 67% of the Afinitor treatment group).

No statistically significant treatment-related difference in overall survival was noted (hazard ratio 0.87; confidence interval: 0.65-1.17; p=0.177). Crossover to open-label Afinitor following disease progression for patients allocated to placebo confounded the detection of any treatment-related difference in overall survival.

Paediatric population

The European Medicines Agency has waived the obligation to submit the results of studies with Afinitor in all subsets of the paediatric population in neuroendocrine tumours of pancreatic origin and in renal cell carcinoma (see section 4.2 for information on paediatric use).

Absorption

In patients with advanced solid tumours, peak everolimus concentrations (C_max) are reached at a median time of 1 hour after daily administration of 5 and 10 mg everolimus under fasting conditions or with a light fat-free snack. C_max is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.

Food effect

In healthy subjects, high fat meals reduced systemic exposure to Afinitor 10 mg (as measured by AUC) by 22% and the peak plasma concentration C_max by 54%. Light fat meals reduced AUC by 32% and C_max by 42%. Food, however, had no apparent effect on the post absorption phase concentration-time profile.

Distribution

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is confined to plasma of cancer patients given Afinitor 10 mg/day. Plasma protein binding is approximately 74% both in healthy subjects and in patients with moderate hepatic impairment. In patients with advanced solid tumours, V_d was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.

Biotransformation

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus 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, everolimus is considered to contribute the majority of the overall pharmacological activity.

Elimination

Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. The mean elimination half-life of everolimus is approximately 30 hours.

No specific excretion studies have been undertaken in cancer patients; however, data are available from the studies in transplant patients. Following the administration of a single dose of radiolabelled everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, while 5% was excreted in the urine. The parent substance was not detected in urine or faeces.

Steady-state pharmacokinetics

After administration of everolimus in patients with advanced solid tumours, steady-state AUC_0-τ was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. C_max is dose-proportional between 5 and 10 mg. t_max occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC_0-τ and pre-dose trough concentration at steady-state.

Special populations

Hepatic impairment

The average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh class B) was twice that found in 8 subjects with normal hepatic function. AUC was positively correlated with serum bilirubin concentration and with prolongation of prothrombin time and negatively correlated with serum albumin concentration. The impact of severe hepatic impairment (Child-Pugh class C) on the pharmacokinetics of everolimus has not been assessed (see sections 4.2 and 4.4).

Renal impairment

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of everolimus in transplant patients.

Elderly patients

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age (27-85 years) on oral clearance of everolimus was detected.

Ethnicity

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver functions. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% higher in black transplant patients.

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; lungs (increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat (exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse (exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or minipigs.

Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at systemic exposure levels within the range of therapeutic exposure or above, with the exception of the findings in rats, which occurred below therapeutic exposure due to a high tissue distribution.

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is within the range of therapeutic exposure and which caused a reduction in male fertility. There was evidence of reversibility. Female fertility was not affected, but everolimus crossed the placenta and was toxic to the foetus. In rats, everolimus caused embryo/foetotoxicity at systemic exposure below the therapeutic level. This was manifested as mortality and reduced foetal weight. The incidence of skeletal variations and malformations (e.g. sternal cleft) was increased at 0.3 and 0.9 mg/kg. In rabbits, embryotoxicity was evident in 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 3.9 and 0.2 times the estimated clinical exposure.

Butylated hydroxytoluene (E321)

Magnesium stearate

Lactose monohydrate

Hypromellose

Crospovidone type A

Lactose anhydrous

Not applicable.

3 years.

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

Aluminium/polyamide/aluminium/PVC blister containing 10 tablets.

Packs containing 10, 30, 60 or 90 tablets.

Not all pack sizes may be marketed.

Any unused product or waste material should be disposed of in accordance with local requirements.

Novartis Europharm Limited

Wimblehurst Road

Horsham

West Sussex, RH12 5AB

United Kingdom

EU/1/09/538/001

EU/1/09/538/002

EU/1/09/538/003

EU/1/09/538/007

03.08.2009

24 August 2011

Detailed information on this product is available on the website of the European Medicines Agency http://www.ema.europa.eu