1. Name Of The Medicinal Product
2. Qualitative And Quantitative Composition
Each tablet contains 2.5 mg everolimus.
Excipients
Each tablet contains 74 mg lactose.
For a full list of excipients, see section 6.1.
3. 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.
4. Clinical Particulars
4.1 Therapeutic Indications
Votubia is indicated for the treatment of patients aged 3 years and older with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery.
The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.
4.2 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.
Posology
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).
The recommended starting dose of Votubia for treatment of patients with SEGA is according to Table 1.
Table 1 Recommended starting dose of Votubia for treatment of patients with SEGA
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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. If concentrations are below 5 ng/ml, the daily dose may be increased by 2.5 mg every 2 weeks, subject to tolerability. The dose of Votubia should be reduced if trough concentrations >15 ng/ml are observed.
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.
Management of severe or intolerable adverse reactions may require temporary dose reduction and/or interruption of therapy (see section 4.4). If dose reduction is required for patients receiving 2.5 mg daily, alternate day dosing should be considered.
If a dose is missed, the patient should not take an additional dose, but take the usual prescribed next dose.
Therapeutic drug monitoring
Therapeutic drug monitoring of everolimus blood concentrations is required for patients treated for SEGA using a validated assay. Trough concentrations should be assessed approximately 2 weeks after the initial dose, after any change in dose or after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see sections 4.4 and 4.5).
Special populations
Paediatric population
The safety and efficacy of Votubia in children aged 0 to less than 3 years have not been established. No data are available.
The potential for growth/developmental delays with long-term treatment is unknown (see section 5.3).
Dosing recommendations for paediatric patients aged 3 years and older with SEGA are consistent with those for the adult SEGA population.
The safety and efficacy of Votubia in paediatric cancer patients have not been established. No data are available.
Elderly patients (
No dose adjustment is required (see section 5.2).
Renal impairment
No dose adjustment is required (see section 5.2).
Hepatic impairment
Dose should be reduced by approximately 50% to maintain target trough concentrations of 5 to 15 ng/ml.
Patients with severe hepatic impairment (Child-Pugh class C):
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
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 unable to swallow tablets, Votubia tablet(s) can be dispersed completely in a glass with approximately 30 ml of water by gently stirring, 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).
4.3 Contraindications
Hypersensitivity to the active substance, to other rapamycin derivatives or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Non-infectious pneumonitis
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.
Infections
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 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
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 Votubia (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 everolimus (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 Votubia therapy and periodically thereafter.
Blood glucose and lipids
Hyperglycaemia, hyperlipidaemia and hypertrigylceridaemia have been reported in clinical trials (see section 4.8). Monitoring of fasting serum glucose is recommended prior to the start of Votubia therapy and periodically thereafter. When possible optimal glycaemic control should be achieved before starting a patient on Votubia.
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 Votubia therapy and periodically thereafter.
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 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.
Hepatic impairment
Votubia 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 Votubia (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 Votubia. Caution should therefore be exercised with the use of Votubia in the peri-surgical period.
4.5 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.
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 2 Effects of other active substances on everolimus
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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.
Vaccinations
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-Guérin), yellow fever, varicella, and TY21a typhoid vaccines.
4.6 Pregnancy And Lactation
Pregnancy
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.
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.
Male patients should not be prohibited from attempting to father children.
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 (see section 5.3). Therefore, women taking everolimus should not breast-feed.
Fertility
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).
4.7 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.
4.8 Undesirable Effects
a) Summary of safety profile
The overall safety profile of Votubia is based on a phase II study for the treatment of SEGA (n=28) and a randomised phase III study for the treatment of metastatic renal cell carcinoma (everolimus, n=274; placebo, n=137) and in further studies in cancer patients. In the pivotal phase II study, 16 of the 28 SEGA patients were exposed to Votubia for
The most common adverse reactions (incidence
b) Tabulated summary of adverse reactions
Table 3 shows the incidence of adverse reactions reported in at least one of the pivotal studies, showing the highest frequency reported. Adverse reactions are listed according to MedDRA system organ class. Frequency categories are defined using the following convention: very common (
Table 3 Adverse reactions reported in a phase II study for the treatment of SEGA and in phase III studies
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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 reaction 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).
d) Paediatric population
In the pivotal phase II study, 22 of the 28 SEGA patients studied were below the age of 18 years. Frequency, type and severity of adverse reactions in children are expected to be the same as in adults.
4.9 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).
Paediatric population
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.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
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.
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.
Clinical efficacy and safety
A prospective, open-label, single-arm phase II study was conducted to evaluate the safety and efficacy of Votubia in patients with SEGA. Radiological evidence of serial SEGA growth was required for entry.
Change in SEGA volume during the core 6-month treatment phase, as assessed via an independent central radiology review, was the primary efficacy endpoint. After the core treatment phase, patients could be enrolled into an extension phase where SEGA volume was assessed every 6 months.
In total, 28 patients received treatment with Votubia; median age was 11 years (range 3 to 34), 61% male, 86% Caucasian. Thirteen patients (46%) had a secondary smaller SEGA, including 12 in the contralateral ventricle.
Primary SEGA volume was reduced at month 6 compared to baseline (p<0.001 [see Table 4]). No patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none required surgical resection or other therapy for SEGA.
Table 4 Change in primary SEGA volume over time
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