This medicinal product is subject to additional monitoring. This will allow quick identification of new safety information. Healthcare professionals are asked to report any suspected adverse reactions. See section 4.8 for how to report adverse reactions.

NAME OF THE MEDICINAL PRODUCT

QUALITATIVE AND QUANTITATIVE COMPOSITION

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 Votubia should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring.

Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see section 4.5). Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight is in kilograms and height (H) is in centimetres: BSA = (W0.425 x H0.725) x 0.007184 The recommended starting dose for Votubia for the treatment of patients with SEGA is 4.5 mg/m2. Different strengths of Votubia tablets can be combined to attain the desired dose. Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after commencing treatment. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. The dose may be increased to attain a higher trough concentration within the target range to obtain optimal efficacy, subject to tolerability. Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult SEGA population, except for patients with hepatic impairment (see "Hepatic impairment" below and section 5.2). SEGA volume should be evaluated approximately 3 months after commencing Votubia therapy, with subsequent dose adjustments taking changes in SEGA volume, corresponding trough concentration, and tolerability into consideration. Once a stable dose is attained, trough concentrations should be monitored every 3 to 6 months in patients with changing body surface area, or every 6 to 12 months in patients with stable body surface area, for the duration of treatment. If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.

Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Votubia therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is approximately 50% lower than the daily dose previously administered. For dose reductions below the lowest available strength, alternate day dosing should be considered. Table 1 summarises dose adjustment recommendations for specific adverse reactions (see also section 4.4).

Table 1 Votubia dose adjustment recommendations

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required for patients treated for SEGA. Trough concentrations should be assessed approximately 2 weeks after the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" below and section 5.2). Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is an option to be considered for patients treated for renal angiomyolipoma associated with TSC (see section 5.1) after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" below and section 5.2). When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment.

Dose adjustments should be made if a patient's hepatic (Child-Pugh) status changes during treatment. Patients with SEGA associated with TSC: Patients <18 years of age: Votubia is not recommended for patients <18 years of age with SEGA and hepatic impairment. Patients >=18 years of age:

Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after any change in hepatic status (Child-Pugh).

The safety and efficacy of Votubia in children aged 0 to 18 years with renal angiomyolipoma associated with TSC in the absence of SEGA have not been established. No data are available. The safety and efficacy of Votubia in children below the age of 1 year with TSC who have SEGA have not been established. No data are available (see section 5.1). The potential for growth/developmental delays with long-term treatment is unknown (see section 5.3). Method of administration Votubia must be administered orally once daily at the same time every day, consistently either with or without food (see section 5.2). Votubia tablets are to be swallowed whole with a glass of water. The tablets must not be chewed or crushed. For patients with TSC who have SEGA and are unable to swallow tablets, Votubia tablet(s) can be dispersed completely in a glass with approximately 30 ml of water by gently stirring until the tablet(s) is(are) fully disintegrated (approximately 7 minutes), immediately prior to drinking. After the dispersion has been swallowed, any residue must be re-dispersed in the same volume of water and swallowed (see section 5.2).

Votubia is available in two pharmaceutical forms: tablets and dispersible tablets. Votubia tablets and Votubia dispersible tablets are not to be used interchangeably. The two pharmaceutical forms must not be combined to achieve the desired dose. One pharmaceutical form or the other must be used. When switching pharmaceutical forms, the dose should be adjusted to the closest milligram strength of the new pharmaceutical form and the everolimus trough concentration should be assessed approximately 2 weeks later (see "Therapeutic drug monitoring" above).

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) was described very commonly in patients taking everolimus in the advanced renal cell carcinoma (RCC) setting (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 Votubia 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. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered. For cases where symptoms of non-infectious pneumonitis are severe, Votubia therapy should be discontinued and the use of corticosteroids may be indicated until clinical symptoms resolve. Votubia may be reinitiated at a daily dose approximately 50% lower than the dose previously administered depending on the individual clinical circumstances.

Everolimus has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoal 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 everolimus in the oncology setting. 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 Votubia. Pre-existing infections should be treated appropriately and should have resolved fully before starting treatment with Votubia. While taking Votubia, 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 Votubia. If a diagnosis of invasive systemic fungal infection is made, Votubia 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 Votubia (see section 4.8). In such cases topical treatments are recommended, but alcohol- or hydrogen 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).

Serious cases of haemorrhage, some with a fatal outcome, have been reported in patients treated with everolimus in the oncology setting. No serious cases of renal haemorrhage were reported in the TSC setting. Caution is advised in patients taking Votubia, particularly during concomitant use with active substances known to affect platelet function or that can increase the risk of haemorrhage as well as in patients with a history of bleeding disorders. Healthcare professionals and patients should be vigilant for signs and symptoms of bleeding throughout the treatment period, especially if risk factors for haemorrhage are combined.

Cases of renal failure (including acute renal failure), some with a fatal outcome, have been observed in patients treated with Votubia (see section 4.8). Renal function of patients 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 in patients treated with Votubia (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 Votubia therapy and periodically thereafter.

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

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

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

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 Votubia may be required (see section 4.5). Concomitant treatment with potent CYP3A4 inhibitors result in dramatically increased blood concentrations of everolimus (see section 4.5). There are currently not sufficient data to allow dosing recommendations in this situation. Hence, concomitant treatment of Votubia and potent inhibitors is not recommended. Caution should be exercised when Votubia is taken in combination with orally administered CYP3A4 substrates with a narrow therapeutic index due to the potential for drug interactions. If Votubia 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).

Votubia is not recommended for use in patients: with renal angiomyolipoma associated with TSC and concomitant severe hepatic impairment (Child-Pugh C) unless the potential benefit outweighs the risk (see sections 4.2 and 5.2).

>=18 years of age with SEGA

and concomitant severe hepatic impairment (Child-Pugh C) (see sections 4.2 and 5.2).

<18 years of age with SEGA

and concomitant hepatic impairment (Child-Pugh A, B and C) (see sections 4.2 and 5.2).

The use of live vaccines should be avoided during treatment with Votubia (see section 4.5). For paediatric patients with SEGA who do not require immediate treatment, completion of the recommended childhood series of live virus vaccinations is advised prior to the start of therapy according to local treatment guidelines.

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

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

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).

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 Votubia. The use of live vaccines should be avoided during treatment with Votubia. 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. Pregnancy 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 secondary amenorrhoea and associated luteinising hormone (LH)/follicle stimulating hormone (FSH) imbalance has been observed in female patients (see also section 5.3 for preclinical observations on the male and female reproductive systems). 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

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 Votubia.

Undesirable effects

Summary of the safety profile

Two randomised, double-blind, placebo-controlled pivotal phase III studies and a phase II study contribute to the safety profile of Votubia.

EXIST-2 (CRAD001M2302): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=79) versus placebo (n=39) in patients with either TSC plus renal angiomyolipoma (n=113) or sporadic lymphangioleiomyomatosis (LAM) plus renal angiomyolipoma (n=5). The median duration of blinded study treatment was 48.1 weeks (range 2 to 115) for patients receiving Votubia and 45.0 weeks (range 9 to 115) for those receiving placebo. No difference was evident between the two arms as regards the proportion of patients who discontinued because of ADRs (2.5% on everolimus versus 2.6% on placebo).
EXIST-1 (CRAD001M2301): This was a randomised, double-blind, controlled, phase III trial of everolimus (n=78) versus placebo (n=39) in patients with TSC who have SEGA, irrespective of age. The median duration of blinded study treatment was 52.2 weeks (range 24 to 89) for patients receiving Votubia and 46.6 weeks (range 14 to 88) for those receiving placebo. No patients discontinued study drug because of ADRs.
CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus in patients with SEGA (n=28). At the last cut-off, 16 of the 28 SEGA patients had been exposed to everolimus for >=45 months.

The most frequent adverse reactions (incidence >=1/10 and suspected by the investigator to be related to treatment) from the pooled safety data are (in decreasing order): stomatitis, upper respiratory tract infections and hypercholesterolaemia. The most frequent grade 3-4 adverse reactions (incidence >=1%) were stomatitis, neutropenia, amenorrhoea and gastroenteritis viral. The grades follow CTCAE Version 3.0.

Tabulated summary of adverse reactions

Table 3 shows the incidence of adverse reactions based on pooled data of patients receiving everolimus in the three TSC studies (including both the double-blind and open-label extension phase, where applicable). Adverse reactions are listed according to MedDRA system organ class. 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 TSC studies

Infections and infestations
Very common	Upper respiratory tract infection
Common	Sinusitis, otitis media, nasopharyngitis, urinary tract infection, pharyngitis, cellulitis, pneumonia, gastroenteritis viral, pharyngitis streptococcal
Uncommon	Herpes zoster, bronchitis viral
Blood and lymphatic system disorders
Common	Anaemia, neutropenia, leucopenia,thrombocytopenia, lymphopenia
Immune system disorders
Uncommon	Hypersensitivity
Metabolism and nutrition disorders
Very common	Hypercholesterolaemia
Common	Decreased appetite, hyperlipidaemia, hypophosphataemia, hypertriglyceridaemia
Psychiatric disorders
Uncommon	Insomnia, aggression
Nervous system disorders
Common	Headache, dysgeusia
Vascular disorders
Common	Hypertension
Respiratory, thoracic and mediastinal disorders
Common	Cough, epistaxis
Uncommon	Pneumonitis
Gastrointestinal disorders
Very common	Stomatitis a
Common	Diarrhoea, nausea, vomiting, abdominal pain, oral pain, flatulence, constipation, gastritis, gingivitis
Skin and subcutaneous tissue disorders
Common	Acne, rash b , acneiform dermatitis, dry skin, pruritus, alopecia
Uncommon	Angioedema
Musculoskeletal and connective tissue disorders
Uncommon	Rhabdomyolysis
Renal and urinary disorders
Common	Proteinuria
Reproductive system and breast disorders
Common	Amenorrhoea, menstruation irregular, menstruation delayed, menorrhagia, vaginal haemorrhage, ovarian cyst
General disorders and administration site conditions
Common	Fatigue, pyrexia, irritability
Investigations
Common	Blood lactate dehydrogenase increased, blood luteinising hormone increased, weight decreased
Uncommon	Blood follicle stimulating hormone increased

Includes (very common) stomatitis, mouth ulceration, (common) aphthous stomatitis and (uncommon) gingival pain, glossitis, lip ulceration
Includes (common) rash and (uncommon) erythema, rash erythematous, rash macular, rash maculo-papular, rash generalised

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 reaction during periods of immunosuppression. In clinical studies and post-marketing spontaneous reports, everolimus has been associated with renal failure events (including fatal outcome), proteinuria and increased serum creatinine. Monitoring of renal function is recommended (see section 4.4). In clinical studies, everolimus has been associated with haemorrhage events. On rare occasions, fatal outcomes were observed in the oncology setting (see section 4.4). No serious cases of renal haemorrhage were reported in the TSC setting. Additional adverse reactions of relevance observed in oncology clinical studies and post-marketing spontaneous reports, were cardiac failure, pulmonary embolism, deep vein thrombosis, impaired wound healing and hyperglycaemia.

Paediatric population

In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years and in the pivotal phase III study, 101 of the 117 SEGA patients studied were below the age of 18 years. In the phase III study, frequency, type and severity of adverse reactions observed in children and adolescents have been generally consistent with those observed in adults, with the exception of infections which were reported at a higher frequency, especially in children below the age of 3 years.

Older people

In the oncology safety pooling, 37% of the patients treated with everolimus were >=65 years of age. The number of patients with an adverse reaction leading to discontinuation of everolimus was higher in patients >=65 years of age (23% vs. 14%). The most common adverse reactions leading to discontinuation were pneumonitis, fatigue, dyspnoea, and stomatitis.

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 in the adult population. It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive measures should be initiated in all cases of overdose. Everolimus is not considered dialysable to any relevant degree (less than 10% was removed within 6 hours of haemodialysis).

A limited number of paediatric patients have been exposed to doses higher than 10 mg/m2/day. No signs of acute toxicity have been reported in these cases.

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. Everolimus can reduce levels of vascular endothelial growth factor (VEGF). In patients with TSC, treatment with everolimus increases VEGF-A and decreases VEGF-D levels. 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. Two primary regulators of mTORC1 signalling are the oncogene suppressors tuberin-sclerosis complexes 1 & 2 (TSC1, TSC2). Loss of either TSC1 or TSC2 leads to elevated rheb-GTP levels, a ras family GTPase, which interacts with the mTORC1 complex to cause its activation. mTORC1 activation leads to a downstream kinase signalling cascade, including activation of the S6 kinases. In tuberous sclerosis complex syndrome, inactivating mutations in either the TSC1 or the TSC2 gene lead to hamartoma formation throughout the body. TSC1 mutations account for 20-25% of all mutations identified, and TSC2 mutations account for the remainder. In a mouse neuronal model of TSC in which TSC1 is ablated in most neurons during cortical development, everolimus improved median survival from 33 days to more than 100 days, and behaviour, phenotype, and weight gain all also markedly improved. There was brain penetration, with accumulation over time with repetitive treatment, and effective reduction of levels of phospho-S6, a downstream marker of mTORC1. Neurofilament abnormalities, myelination and cell enlargement were all improved by the treatment, although dysplastic neuronal features persisted, and there were only modest changes in dendritic spine density and length. Strikingly, mice treated with everolimus for 23 days only (postnatal days 7-30) displayed a persistent improvement in phenotype, with median survival of 78 days. In summary, everolimus is a highly effective therapy for this neuronal model of TSC, with benefit apparently attributable to effects on mTORC1 and Akt signalling and, consequently, cell size and myelination. Although caution is appropriate, the results suggest the possibility that everolimus may have benefit in the treatment of TSC brain disease, including infantile spasms.

EXIST-2 (study CRAD001M2302), a randomised, controlled phase III study was conducted to evaluate the efficacy and safety of Votubia in patients with TSC plus renal angiomyolipoma. Presence of at least one angiomyolipoma >=3 cm in longest diameter using CT/MRI (based on local radiology assessment) was required for entry. The primary efficacy endpoint was angiomyolipoma response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomisation (yes/no). Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate. A total of 118 patients were randomised, 79 to Votubia 10 mg daily and 39 to placebo. Median age was 31 years (range: 18 to 61 years; 46.6% were <30 years at enrolment), 33.9% were male, and 89.0% were Caucasian. Of the enrolled patients, 83.1% had angiomyolipomas >=4 cm (28.8% >=8 cm), 78.0% had bilateral angiomyolipomas, and 39.0% had undergone prior renal embolisation/nephrectomy; 96.6% had skin lesions at baseline and 44.1% had target SEGAs (at least one SEGA >=1 cm in longest diameter). Results showed that the primary objective related to best overall angiomyolipoma response was met with response rates of 41.8% (95% CI: 30.8, 53.4) for the Votubia arm compared with 0% (95% CI: , 9.0) for the placebo arm (p<0.0001) (Table 4).

Table 4 EXIST-2 - Angiomyolipoma response

Primary analysis

Votubia Placebo p-value

n=79 n=39

Best overall angiomyolipoma response - %

>=50% reduction in the sum of angiomyolipoma volume relative to baseline, plus absence of new angiomyolipoma >=1.0 cm in longest diameter, plus no increase in renal volume >20%

Consistent treatment effects on angiomyolipoma response rate were observed across all subgroups evaluated (i.e. EIAED use vs. EIAED non-use, sex, age and race). Angiomyolipoma shrinkage was evident within the initial 12 weeks of treatment with Votubia: 75.7% of patients had >=30% reductions and 41.9% had >=50% reductions at the time of the first radiological evaluation. Sustained responses were evident at subsequent timepoints: at Week 24, 80.3% of patients had >=30% reductions and 54.9% had >=50% reductions. Median time to angiomyolipoma progression was 11.4 months in the placebo arm and was not reached in the everolimus arm (HR 0.08; 95% CI: 0.02, 0.37; p<0.0001). Progressions were observed in 3.8% of patients in the everolimus arm compared with 20.5% in the placebo arm. Estimated progression-free rates at 6 months were 98.4% for the everolimus arm and 83.4% for the placebo arm. Skin lesion response rates of 26.0% (95% CI: 16.6, 37.2) for the Votubia arm and 0% (95% CI: 0.0, 9.5) for the placebo arm were observed (p=0.0002). Further clinical benefit, such as improvement in disease-related symptoms or reduction of serious risks, has not been demonstrated. Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) demonstrated that angiomyolipoma response rate is reduced below the threshold of 5 ng/ml (Table 5).

Table 5 EXIST-2 - Angiomyolipoma response rates by time-averaged Cmin category

Phase III study in SEGA patients EXIST-1 (Study CRAD001M2301), a randomised, double-blind, multicentre phase III study of Votubia versus placebo, was conducted in patients with SEGA, irrespective of age. Patients were randomised in a 2:1 ratio to receive either Votubia or matching placebo. Presence of at least one SEGA lesion >=1.0 cm in longest diameter using MRI (based on local radiology assessment) was required for entry. In addition, serial radiological evidence of SEGA growth, presence of a new SEGA lesion >=1 cm in longest diameter, or new or worsening hydrocephalus was required for entry. The primary efficacy endpoint was SEGA response rate based on independent central radiology review. The analysis was stratified by use of enzyme-inducing antiepileptic drugs (EIAEDs) at randomisation (yes/no). Key secondary endpoints in hierarchal order of testing included the absolute change in frequency of total seizure events per 24-hour EEG from baseline to week 24, time to SEGA progression, and skin lesion response rate. A total of 117 patients were randomised, 78 to Votubia and 39 to placebo. The two treatment arms were generally well balanced with respect to demographic and baseline disease characteristics and history of prior anti-SEGA therapies. In the total population, 57.3% of patients were male and 93.2% were Caucasian. The median age for the total population was 9.5 years (age range for the Votubia arm: 1.0 to 23.9; age range for the placebo arm: 0.8 to 26.6), 69.2% of the patients were aged 3 to <18 years and 17.1% were <3 years at enrolment. Of the enrolled patients, 79.5% had bilateral SEGAs, 42.7% had >=2 target SEGA lesions, 25.6% had inferior growth, 9.4% had evidence of deep parenchymal invasion, 6.8% had radiographic evidence of hydrocephalus, and 6.8% had undergone prior SEGA-related surgery. 94.0% had skin lesions at baseline and 37.6% had target renal angiomyolipomas (at least one angiomyolipoma >=1 cm in longest diameter). The median duration of blinded study treatment was 9.6 months (range: 5.5 to 18.1) for patients receiving Votubia and 8.3 months (range: 3.2 to 18.3) for those receiving placebo. Results showed that Votubia was superior to placebo for the primary endpoint of best overall SEGA response (p<0.0001). Response rates were 34.6% (95% CI: 24.2, 46.2) for the Votubia arm compared with 0% (95% CI: 0.0, 9.0) for the placebo arm (Table 6). In addition, all 8 patients on the Votubia arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume and no patient required surgical intervention during the course of this study.

Adverse reaction	Severity 1	Votubia dose adjustment
Non-infectious pneumonitis	Grade 2	Consider interruption of therapy until symptoms improve to Grade 1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered. Discontinue treatment if failure to recover within 4 weeks.
	Grade 3	Interrupt Votubia until symptoms resolve to Grade 1. Consider re-initiating Votubia at approximately 50% lower than the daily dose previously administered. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4	Discontinue Votubia.
Stomatitis	Grade 2	Temporary dose interruption until recovery to Grade 1. Re-initiate Votubia at same dose. If stomatitis recurs at Grade 2, interrupt dose until recovery to Grade 1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
	Grade 3	Temporary dose interruption until recovery to Grade 1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
	Grade 4	Discontinue Votubia.
Other non-haematologica l 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 Votubia at same dose. If toxicity recurs at Grade 2, interrupt Votubia until recovery to Grade 1. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
	Grade 3	Temporary dose interruption until recovery to Grade 1. Consider re-initiating Votubia at approximately 50% lower than the daily dose previously administered. If toxicity recurs at Grade 3, consider discontinuation.
	Grade 4	Discontinue Votubia.
Metabolic events (e.g. hyperglycaemia, dyslipidaemia)	Grade 2	No dose adjustment required.
	Grade 3	Temporary dose interruption. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
	Grade 4	Discontinue Votubia.
Thrombocytopenia	Grade 2 (<75, >=50x10 9 /l)	Temporary dose interruption until recovery to Grade 1 (>=75x10 9 /l). Re-initiate Votubia at same dose.
	Grade 3 & 4 (<50x10 9 /l)	Temporary dose interruption until recovery to Grade 1 (>=75x10 9 /l). Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
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 Votubia at same dose.
Grade 4 (<0.5x10 9 /l)		Temporary dose interruption until recovery to Grade 2 (>=1x10 9 /l). Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
Febrile neutropenia	Grade 3	Temporary dose interruption until recovery to Grade 2 (>=1.25x10 9 /l) and no fever. Re-initiate Votubia at approximately 50% lower than the daily dose previously administered.
	Grade 4	Discontinue Votubia.
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 Votubia 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. For patients with renal angiomyolipoma associated with TSC: If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, dose reduction to 5 mg 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 (see also Therapeutic drug monitoring in section 4.2). For patients with SEGA associated with TSC: If patients require co-administration of a moderate CYP3A4 or PgP inhibitor, reduce the daily dose by approximately 50%. Further dose reduction may be required to manage adverse reactions (see sections 4.2 and 4.4). Everolimus trough concentrations should be assessed approximately 2 weeks after the addition of a moderate CYP3A4 or PgP inhibitor. If the moderate inhibitor is discontinued the Votubia dose should be returned to the dose used prior to initiation of the moderate CYP3A4 or PgP inhibitor and the everolimus trough concentration should be re-assessed approximately 2 weeks later (see sections 4.2 and 4.4)
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 CYP3A4 inducers
Rifampicin	AUC \|63% (range 0-80%) C m ax \|58% (range 10-70%)	Avoid the use of concomitant potent CYP3A4 inducers. For patients with renal angiomyolipoma associated with TSC: If patients require co-administration of a potent CYP3A4 inducer, a Votubia dose increase from 10 mg daily up to 20 mg daily should be considered using 5 mg increments applied on Day 4 and 8 following start of the inducer. This dose of Votubia 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, the Votubia dose should be returned to the dose used prior to initiation of the co-administration (see also Therapeutic drug monitoring in section 4.2). For patients with SEGA associated with TSC: Patients receiving concomitant potent CYP3A4 inducers may require an increased Votubia dose to achieve the same exposure as patients not taking potent inducers. Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, checking the trough level and assessing tolerability before increasing the dose. If the potent inducer is discontinued the Votubia dose should be returned to the dose used prior to initiation of the potent CYP3A4 inducer and the everolimus trough concentrations should be assessed approximately 2 weeks later (see sections 4.2 and 4.4)
Corticosteroids (e.g. dexamethasone, prednisone, prednisolone)	Not studied. Decreased exposure expected.
Antiepileptic agents (e.g. 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

Response	41.8	0
Stable disease	40.5	79.5
Progression	1.3	5.1
Not evaluable	16.5	15.4

Time-averaged C m in category	Number of patients	Response rate	95% confidence interval
<=5 ng/ml	20	0.300	0.099, 0.501
>5 ng/ml	42	0.524	0.373, 0.675
Difference 1		-0.224	-0.475, 0.027
1 Difference is "<=5 ng/ml" minus ">5 ng/ml"

ANNEX I

SUMMARY OF PRODUCT CHARACTERISTICS