Each tablet contains 2.5 mg everolimus. Excipient with known effect: Each tablet contains 74 mg lactose. For the full list of excipients, see section 6.1.

PHARMACEUTICAL FORM

Tablet. White to slightly yellow, elongated tablets with a bevelled edge and no score, engraved with "LCL" on one side and "NVR" on the other.

CLINICAL PARTICULARS

Posology and method of administration

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

For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets. 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 next prescribed dose as usual.

Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily. Table 1 summarises the dose adjustment recommendations for specific adverse reactions (see also section 4.4).

Table 1 Afinitor dose adjustment recommendations

Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment (see also sections 4.4 and 5.2).

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

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.

Contraindications

Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients listed in section 6.1.

Special warnings and precautions for use

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including everolimus. Non-infectious pneumonitis (including interstitial lung disease) has been described in 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 (Grade 2) or severe (Grade 3) the use of corticosteroids may be indicated until clinical symptoms resolve.

Everolimus 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 sepsis, 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, the Afinitor treatment should be promptly and permanently discontinued and the patient treated with appropriate antifungal therapy.

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).

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (e.g. swelling of the airways or tongue, with or without respiratory impairment) (see section 4.5).

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 mouthwashes containing alcohol, peroxide, iodine and thyme derivatives 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).

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 should be monitored particularly where patients have additional risk factors that may further impair renal function.

Elevations of serum creatinine, usually mild, and proteinuria have been reported (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.

Hyperglycaemia has been reported (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Afinitor therapy and periodically thereafter. More frequent monitoring is recommended when Afinitor is co-administered with other medicinal products that may induce hyperglycaemia. When possible optimal glycaemic control should be achieved before starting a patient on Afinitor.

Dyslipidaemia (including hypercholesterolaemia and hypertriglyceridaemia) has been reported. Monitoring of blood cholesterol and triglycerides prior to the start of Afinitor therapy and periodically thereafter, as well as management with appropriate medical therapy, is recommended.

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

In a randomised, double-blind, multi-centre trial in patients with carcinoid tumours, Afinitor plus depot octreotide 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.

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. Caution should be exercised when Afinitor is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Afinitor 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).

Exposure to everolimus was increased in patients with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment (see section 5.2). Afinitor is only recommended for use in patients with severe hepatic impairment (Child-Pugh C) if the potential benefit outweighs the risk (see sections 4.2 and 5.2). No clinical safety or efficacy data are currently available to support dose adjustment recommendations for the management of adverse reactions in patients with hepatic impairment.

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

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

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

Interaction with other medicinal products and other forms of interaction

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 2 below.

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

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 2 Effects of other active substances on 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. An interaction study in healthy subjects demonstrated that co-administration of an oral dose of midazolam, a sensitive CYP3A substrate probe, with everolimus resulted in a 25% increase in midazolam Cmax and a 30% increase in midazolam AUC(0-inf). 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 (see section 4.4). Co-administration of everolimus and depot octreotide increased octreotide Cmin 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. Co-administration of everolimus and exemestane increased exemestane Cmin and C2h by 45% and 64%, respectively. However, the corresponding oestradiol levels at steady state (4 weeks) were not different between the two treatment arms. No increase in adverse events related to exemestane was observed in patients with hormone receptor-positive advanced breast cancer receiving the combination. The increase in exemestane levels is unlikely to have an impact on efficacy or safety.

Patients taking concomitant ACE inhibitor (e.g. ramipril) therapy may be at increased risk for angioedema (see section 4.4).

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-Guerin), yellow fever, varicella, and TY21a typhoid vaccines.

Fertility, pregnancy and lactation

Women of childbearing potential must use a highly effective method of contraception (e.g. oral, injected, or implanted non-oestrogen-containing hormonal method of birth control, progesterone-based contraceptives, hysterectomy, tubal ligation, complete abstinence, barrier methods, intrauterine device [IUD], and/or female/male sterilisation) while receiving everolimus, and for up to 8 weeks after ending treatment. Male patients should not be prohibited from attempting to father children.

There are no adequate data from the use of everolimus in pregnant women. Studies in animals have shown reproductive toxicity effects including embryotoxicity and foetotoxicity (see section 5.3). The potential risk for humans is unknown. Everolimus is not recommended during pregnancy and in women of childbearing potential not using contraception.

It is not known whether everolimus is excreted in breast milk. However, in rats, everolimus and/or its metabolites readily pass into the milk (see section 5.3). Therefore, women taking everolimus should not breast-feed.

The potential for everolimus to cause infertility in male and female patients is unknown, however amenorrhoea (secondary amenorrhoea and other menstrual irregularities) and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients. Based on non-clinical findings, male and female fertility may be compromised by treatment with everolimus (see section 5.3).

Effects on ability to drive and use machines

Afinitor may have a minor or moderate influence on the ability to drive and use machines. Patients should be advised to be cautious when driving or using machines if they experience fatigue during treatment with Afinitor.

Undesirable effects

Summary of the safety profile

The safety profile is based on pooled data from 2,406 patients treated with Afinitor in eight clinical studies, consisting of four randomised, double-blind, placebo controlled phase III studies and four phase II studies, related to the approved indications. The most common adverse reactions (incidence >=1/10) from the pooled safety data were (in decreasing order): stomatitis, rash, fatigue, diarrhoea, infections, nausea, decreased appetite, anaemia, dysgeusia, pneumonitis, weight decreased, peripheral oedema, asthenia, pruritus, epistaxis, hyperglycaemia, hypercholesterolaemia, headache, and vomiting. The most frequent Grade 3-4 adverse reactions (incidence >=1/100 to <1/10) were stomatitis, anaemia, hyperglycaemia, fatigue, infections, pneumonitis, diarrhoea, asthenia, thrombocytopenia, neutropenia, dyspnoea, proteinuria, lymphopenia, hypophosphataemia, rash, and hypertension. The grades follow CTCAE Version 3.0.

Tabulated list of adverse reactions

Table 3 presents the frequency category of adverse reactions reported in the pooled analysis considered for the safety pooling. 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 3 Adverse reactions reported in clinical studies

Infections and infestations
Very common	Infections a, *
Blood and lymphatic system disorders
Very common	Anaemia
Common	Thrombocytopenia, neutropenia, leukopenia, lymphopenia
Uncommon	Pancytopenia
Rare	Pure red cell aplasia
Immune system disorders
Uncommon	Hypersensitivity
Metabolism and nutrition disorders
Very common	Decreased appetite, hyperglycaemia, hypercholesterolaemia
Common	Hypertriglyceridaemia, hypophosphataemia, diabetes mellitus, hyperlipidaemia, hypokalaemia, dehydration, hypocalcaemia
Psychiatric disorders
Common	Insomnia
Nervous system disorders
Very common	Dysgeusia, headache
Uncommon	Ageusia
Eye disorders
Common	Eyelid oedema
Uncommon	Conjunctivitis
Cardiac disorders
Uncommon	Congestive cardiac failure
Vascular disorders
Common	Hypertension, haemorrhage b
Uncommon	Flushing, deep vein thrombosis
Respiratory, thoracic and mediastinal disorders
Very common	Pneumonitis c , epistaxis
Common	Cough, dyspnoea
Uncommon	Haemoptysis, pulmonary embolism
Rare	Acute respiratory distress syndrome
Gastrointestinal disorders
Very common	Stomatitis d , diarrhoea, nausea, vomiting
Common	Dry mouth, abdominal pain, mucosal inflammation, oral pain, dyspepsia, dysphagia
Hepatobiliary disorders
Common	Alanine aminotransferase increased, aspartate aminotransferase increased
Skin and subcutaneous tissue disorders
Very common	Rash, pruritus
Common	Dry skin, nail disorders, mild alopecia, acne, erythema, onychoclasis, palmar-plantar erythrodysaesthesia syndrome, skin exfoliation, skin lesion
Rare	Angioedema
Musculoskeletal and connective tissue disorders
Common	Arthralgia
Renal and urinary disorders
Common	Proteinuria , blood creatinine increased, renal failure
Uncommon	Increased daytime urination, acute renal failure *
Reproductive system and breast disorders
Uncommon	Menstruation irregular
Rare	Amenorrhoea
General disorders and administration site conditions
Very common	Fatigue, peripheral oedema, asthenia
Common	Pyrexia
Uncommon	Non-cardiac chest pain
Rare	Impaired wound healing
Investigations
Very common	Weight decreased
* See also subsection "Description of selected adverse reactions"

Includes all reactions within the 'infections and infestations' system organ class including (common) pneumonia and (uncommon) herpes zoster, sepsis, and isolated cases of opportunistic infections [e.g. aspergillosis, candidiasis and hepatitis B (see also section 4.4)]
Includes different bleeding events not listed individually
Includes (common) pneumonitis, interstitial lung disease, lung infiltration and (rare) pulmonary alveolar haemorrhage, pulmonary toxicity, and alveolitis
Includes (very common) stomatitis, (common) aphthous stomatitis, mouth and tongue ulceration and (uncommon) glossodynia, glossitis

Description of selected adverse reactions

In clinical studies and post-marketing spontaneous reports, 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). In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases of amenorrhoea (secondary amenorrhoea and other menstrual irregularities).

Elderly patients

In the safety pooling, 36% of the Afinitor-treated patients were >=65 years of age. The number of patients with an adverse reaction leading to discontinuation of the medicinal product was higher in patients >=65 years of age (19% vs. 12%). The most common adverse reactions leading to discontinuation were pneumonitis, stomatitis, fatigue and dyspnoea.

Reporting of suspected adverse reactions

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

Overdose

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.

PHARMACOLOGICAL PROPERTIES

Pharmacodynamic properties

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

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. S6K1is thought to phosphorylate the activation function domain 1 of the oestrogen receptor, which is responsible for ligand-independent receptor activation. 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.

BOLERO-2 (study CRAD001Y2301), a randomised, double-blind, multicentre phase III study of Afinitor + exemestane versus placebo + exemestane, was conducted in postmenopausal women with oestrogen receptor-positive, HER2/neu negative advanced breast cancer with recurrence or progression following prior therapy with letrozole or anastrozole. Randomisation was stratified by documented sensitivity to prior hormonal therapy and by the presence of visceral metastasis. Sensitivity to prior hormonal therapy was defined as either (1) documented clinical benefit (complete response [CR], partial response [PR], stable disease >=24 weeks) from at least one prior hormonal therapy in the advanced setting or (2) at least 24 months of adjuvant hormonal therapy prior to recurrence. The primary endpoint for the study was progression-free survival (PFS) evaluated by RECIST (Response Evaluation Criteria in Solid Tumors), based on the investigator's assessment (local radiology). Supportive PFS analyses were based on an independent central radiology review. Secondary endpoints included overall survival (OS), objective response rate, clinical benefit rate, safety, change in quality of life (QoL) and time to ECOG PS (Eastern Cooperative Oncology Group performance status) deterioration. A total of 724 patients were randomised in a 2:1 ratio to the combination everolimus (10 mg daily) + exemestane (25 mg daily) (n=485) or to the placebo + exemestane arm (25 mg daily) (n=239). The median duration of treatment was 29.5 weeks (range 1.0-123.3 weeks) for patients receiving everolimus + exemestane and 14.1 weeks (range 1.0-101.0 weeks) for the placebo + exemestane group. The efficacy results were obtained from the final PFS analysis (see Table 4 and Figure 1). Patients in the placebo + exemestane arm did not cross over to everolimus at the time of progression.

Table 4 BOLERO-2 efficacy results

OS data are not mature at the time of the interim analysis and no statistically significant treatment-related difference in OS was noted [HR=0.77 (95% CI: 0.57, 1.04)].

Figure 1 BOLERO-2 Kaplan-Meier progression-free survival curves (investigator radiological review)

0 6 12 18 24 30 36 42 48 54 60 66 72 78 84 90 96 102 108 114 120
Number of Patients still at Risk	Time (weeks)
Time(weeks)	0	6	12	18	24	30	36	42	48	54	60	66	72	78	84	90	96	102	108	114	120
Everolimus	485	436	366	304	257	221	185	158	124	91	66	50	35	24	22	13	10	8	2	1	0
Placebo	239	190	132	96	67	50	39	30	21	15	10	8	5	3	1	1	1	0	0	0	0

The estimated PFS treatment effect was supported by planned subgroup analysis of PFS per investigator assessment. For all analysed subgroups (age, sensitivity to prior hormonal therapy, number of organs involved, status of bone-only lesions at baseline and presence of visceral metastasis, and across major demographic and prognostic subgroups) a positive treatment effect was seen with everolimus + exemestane with an estimated hazard ratio versus placebo + exemestane ranging from 0.25 to 0.60. No differences in the time to >=5% deterioration in the global and functional domain scores of QLQ-C30 were observed in the two arms.

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 5 and Figure 2). 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 5 RADIANT-3 - Progression-free survival results

Figure 2 RADIANT-3 - KaplanMeier progression-free survival curves (investigator radiological review)

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]).

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-a 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 6 and Figure 3).

Table 6 RECORD-1 - Progression-free survival results

Figure 3 RECORD-1 - KaplanMeier progression-free survival curves (independent central review)

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.

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).

Pharmacokinetic properties

In patients with advanced solid tumours, peak everolimus concentrations (Cmax) 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. Cmax is dose-proportional between 5 and 10 mg. Everolimus is a substrate and moderate inhibitor of PgP.

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

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 in cancer patients given everolimus 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, Vd was 191 l for the apparent central compartment and 517 l for the apparent peripheral compartment.

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.

Mean oral clearance (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.

After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-t was dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within two weeks. Cmax is dose-proportional between 5 and 10 mg. tmax occurs at 1 to 2 hours post-dose. There was a significant correlation between AUC0-t and pre-dose trough concentration at steady-state.

The safety, tolerability and pharmacokinetics of everolimus were evaluated in two single oral dose studies of Afinitor tablets in 8 and 34 subjects with impaired hepatic function relative to subjects with normal hepatic function. In the first study, the average AUC of everolimus in 8 subjects with moderate hepatic impairment (Child-Pugh B) was twice that found in 8 subjects with normal hepatic function. In the second study of 34 subjects with different impaired hepatic function compared to normal subjects, there was a 1.6-fold, 3.3-fold and 3.6-fold increase in exposure (i.e. AUC0-inf) for subjects with mild (Child-Pugh A), moderate (Child-Pugh B) and severe (Child-Pugh C) hepatic impairment, respectively. Simulations of multiple dose pharmacokinetics support the dosing recommendations in subjects with hepatic impairment based on their Child-Pugh status. Based on the results of the two studies, dose adjustment is recommended for patients with hepatic impairment (see sections 4.2 and 4.4).

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.

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

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

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; 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 caused a reduction in male fertility. There was evidence of reversibility. In animal reproductive studies female fertility was not affected. However, oral doses of everolimus in female rats at >=0.1 mg/kg (approximately 4% of the AUC0-24h in patients receiving the 10 mg daily dose) resulted in increases in pre-implantation loss. 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.

PHARMACEUTICAL PARTICULARS

List of excipients

Butylated hydroxytoluene (E321) Magnesium stearate Lactose monohydrate Hypromellose Crospovidone type A Lactose anhydrous

Incompatibilities

Shelf life

Special precautions for storage

Do not store above 25degC. Store in the original package in order to protect from light and moisture.

Nature and contents of container

Aluminium/polyamide/aluminium/PVC blister containing 10 tablets. Packs containing 30 or 90 tablets.

Special precautions for disposal

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

MARKETING AUTHORISATION HOLDER

Novartis Europharm Limited Wimblehurst Road Horsham West Sussex, RH12 5AB United Kingdom

MARKETING AUTHORISATION NUMBER(S)

DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION

DATE OF REVISION OF THE TEXT

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

Adverse reaction	Severity 1	Afinitor dose adjustment
Non-infectious pneumonitis	Grade 2	Consider interruption of therapy until symptoms improve to Grade 1. Re-initiate treatment at 5 mg daily. Discontinue treatment if failure to recover within 4 weeks.
	Grade 3	Interrupt treatment until symptoms resolve to Grade 1. Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4	Discontinue treatment.
Stomatitis	Grade 2	Temporary dose interruption until recovery to Grade 1. Re-initiate treatment at same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade 1. Re-initiate treatment at 5 mg daily.
	Grade 3	Temporary dose interruption until recovery to Grade 1. Re-initiate treatment at 5 mg daily.
	Grade 4	Discontinue treatment.
Other non-haematological toxicities (excluding metabolic events)	Grade 2	If toxicity is tolerable, no dose adjustment required. If toxicity becomes intolerable, temporary dose interruption until recovery to Grade 1. Re-initiate treatment at same dose. If toxicity recurs at Grade 2, interrupt treatment until recovery to Grade 1. Re-initiate treatment at 5 mg daily.
	Grade 3	Temporary dose interruption until recovery to Grade 1. Consider re-initiating treatment at 5 mg daily. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4	Discontinue treatment.
Metabolic events (e.g. hyperglycaemia, dyslipidaemia)	Grade 2	No dose adjustment required.
	Grade 3	Temporary dose interruption. Re-initiate treatment at 5 mg daily.
	Grade 4	Discontinue treatment.
Thrombocytopenia	Grade 2 (<75, >=50x10 9 /l)	Temporary dose interruption until recovery to Grade 1 (>=75x10 9 /l). Re-initiate treatment at same dose.
Thrombocytopenia	Grade 3 & 4 (<50x10 9 /l)	Temporary dose interruption until recovery to Grade 1 (>=75x10 9 /l). Re-initiate treatment at 5 mg daily.
Neutropenia	Grade 2 (>=1x10 9 /l)	No dose adjustment required.
	Grade 3 (<1, >=0.5x10 9 /l)	Temporary dose interruption until recovery to Grade 2 (>=1x10 9 /l). Re-initiate treatment at same dose.
	Grade 4 (<0.5x10 9 /l)	Temporary dose interruption until recovery to Grade 2 (>=1x10 9 /l). Re-initiate treatment at 5 mg daily.
Febrile neutropenia	Grade 3	Temporary dose interruption until recovery to Grade 2 (>=1.25x10 9 /l) and no fever. Re-initiate treatment at 5 mg daily.
Febrile neutropenia	Grade 4	Discontinue treatment.
1 Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v3.0

Active substance by interaction	Interaction - Change in Everolimus AUC/C m ax Geometric mean ratio (observed range)	Recommendations concerning co-administration

Potent CYP3A4/PgP inhibitors
Ketoconazole	AUC \|15.3-fold (range 11.2-22.5) C m ax \|4.1-fold (range 2.6-7.0)	Concomitant treatment of Afinitor and potent inhibitors is not recommended.
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) C m ax \|2.0-fold (range 0.9-3.5)	Use caution when co-administration of moderate CYP3A4 inhibitors or PgP inhibitors cannot be avoided. If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg daily or 2.5 mg daily may be considered. However, there are no clinical data with this dose adjustment. Due to between subject variability the recommended dose adjustments may not be optimal in all individuals, therefore close monitoring of side effects is recommended. If the moderate inhibitor is discontinued, consider a washout period of at least 2 to 3 days (average elimination time for most commonly used moderate inhibitors) before the Afinitor dose is returned to the dose used prior to initiation of the co-administration.
Imatinib	AUC \| 3.7-fold C m ax \| 2.2-fold
Verapamil	AUC \|3.5-fold (range 2.2-6.3) C m ax \|2.3-fold (range1.3-3.8)
Ciclosporin oral	AUC \|2.7-fold (range 1.5-4.7) C m ax \|1.8-fold (range 1.3-2.6)
Fluconazole	Not studied. Increased exposure expected.
Diltiazem	Not studied. Increased exposure expected.
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.

Potent and moderate CYP3A4 inducers
Rifampicin	AUC \|63% (range 0-80%) C m ax \|58% (range 10-70%)	Avoid the use of concomitant potent CYP3A4 inducers. If patients require co-administration of a potent CYP3A4 inducer, an Afinitor dose increase from 10 mg daily up to 20 mg daily should be considered using 5 mg increments or less applied on Day 4 and 8 following start of the inducer. This dose of Afinitor is predicted to adjust the AUC to the range observed without inducers. However, there are no clinical data with this dose adjustment. If treatment with the inducer is discontinued, consider a washout period of at least 3 to 5 days (reasonable time for significant enzyme de-induction), before the Afinitor dose is returned to the dose used prior to initiation of the co-administration.
Dexamethasone	Not studied. Decreased exposure expected.
Carbamazepine, phenobarbital, phenytoin	Not studied. Decreased exposure expected.
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

Analysis	Afinitor a n=485	Placebo a n=239	Hazard ratio	p value
Median progression-free survival (months) (95% CI)
Investigator radiological review	7.8 (6.9 to 8.5)	3.2 (2.8 to 4.1)	0.45 (0.38 to 0.54)	<0.0001
Independent radiological review	11.0 (9.7 to 15.0)	4.1 (2.9 to 5.6)	0.38 (0.31 to 0.48)	<0.0001
Best overall response (%) (95% CI)
Objective response rate b	12.6% (9.8 to 15.9)	1.7% (0.5 to 4.2)	n/a d	<0.0001 e

Clinical benefit rate c	51.3% (46.8 to 55.9)	26.4% (20.9 to 32.4)	n/a d	<0.0001 e
>=24 weeks

Population	n	Afinitor n=207	Placebo n=203	Hazard ratio (95% CI)	p-value
	410	Median progression-free survival (months) (95% CI)
Investigator radiological	410	11.04	4.60	0.35	<0.0001
review	410	(8.41, 13.86)	(3.06, 5.39)	(0.27, 0.45)	<0.0001
Independent radiological	410	13.67	5.68	0.38	<0.0001
review	410	(11.17, 18.79)	(5.39, 8.31)	(0.28, 0.51)	<0.0001

Afinitor 207	189	153	126	114	80	49	36	28	21	10	6	2	0	0	0
Placebo 203	117	98	59	52	24	16	7	4	3	2	1	1	1	1	0

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION