Votubia

1 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX I 
 

SUMMARY OF PRODUCT CHARACTERISTICS 



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1. NAME OF THE MEDICINAL PRODUCT 
 

Votubia 2.5 mg tablets 

Votubia 5 mg tablets 

Votubia 10 mg tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Votubia 2.5 mg tablets 

 

Each tablet contains 2.5 mg everolimus. 

 

Excipient with known effect 

Each tablet contains 74 mg lactose. 

 

Votubia 5 mg tablets 

 

Each tablet contains 5 mg everolimus. 

 

Excipient with known effect 

Each tablet contains 149 mg lactose. 

 

Votubia 10 mg tablets 

 

Each tablet contains 10 mg everolimus. 

 

Excipient with known effect 

Each tablet contains 297 mg lactose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Tablet. 

 

Votubia 2.5 mg tablets 

 

White to slightly yellow, elongated tablets of approximately 10.1 mm in length and 4.1 mm in width, 

with a bevelled edge and no score, engraved with “LCL” on one side and “NVR” on the other. 

 

Votubia 5 mg tablets 

 

White to slightly yellow, elongated tablets of approximately 12.1 mm in length and 4.9 mm in width, 

with a bevelled edge and no score, engraved with “5” on one side and “NVR” on the other. 

 

Votubia 10 mg tablets 

 

White to slightly yellow, elongated tablets of approximately 15.1 mm in length and 6.0 mm in width, 

with a bevelled edge and no score, engraved with “UHE” on one side and “NVR” on the other. 

 

 



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4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Renal angiomyolipoma associated with tuberous sclerosis complex (TSC) 

 

Votubia is indicated for the treatment of adult patients with renal angiomyolipoma associated with 

TSC who are at risk of complications (based on factors such as tumour size or presence of aneurysm, 

or presence of multiple or bilateral tumours) but who do not require immediate surgery. 

 

The evidence is based on analysis of change in sum of angiomyolipoma volume. 

 

Subependymal giant cell astrocytoma (SEGA) associated with TSC 

 

Votubia is indicated for the treatment of adult and paediatric patients with SEGA associated with 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 

 

Renal angiomyolipoma associated with TSC 

The recommended dose is 10 mg of everolimus once daily. Treatment should continue as long as 

clinical benefit is observed or until unacceptable toxicity occurs. 

 

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

dose. 

 

SEGA associated with TSC 

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 

(W) 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. A 

higher starting dose of 7 mg/m2 is recommended for patients 1 to less than 3 years of age based on 

pharmacokinetic simulations (see section 5.2). Different strengths of Votubia tablets can be combined 

to attain the desired dose. 

 

Everolimus whole blood trough concentrations should be assessed at least 1 week 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. 

 



4 

Individualised dosing should be titrated by increasing the dose by increments of 2.5 mg to attain the 

target trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, and 

the current trough concentration should be considered when planning for dose titration. Individualised 

dose titration can be based on simple proportion: 

New everolimus dose = current dose x (target concentration / current concentration) 

 

For example, a patient’s current dose based on BSA is 2.5 mg with a steady state concentration of 

4 ng/ml. In order to achieve a target concentration above the lower Cmin limit of 5 ng/ml, e.g. 8 ng/ml, 

the new everolimus dose would be 5 mg (an increase of 2.5 mg from the current daily dose). In cases 

where the revised dose is not a multiple of 2.5 mg, it should be rounded to the next available tablet 

strength. 

 

Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult 

SEGA population, except for patients in the range from 1 year to less than 3 years of age, and those 

with hepatic impairment (see section “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 BSA, or every 6 to 12 months in patients with stable BSA, for the duration of 

treatment. 

 

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. 

 

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

dose. 

 

Dose adjustments due to adverse reactions 

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 

 

Adverse reaction Severity1 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. 



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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-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 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, ≥50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate Votubia at same dose. 

 Grade 3 & 4 

(<50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate Votubia at approximately 50% lower 

than the daily dose previously administered. 

Neutropenia Grade 2 

(≥1x109/l) 

No dose adjustment required. 

 Grade 3 

(<1, ≥0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/l). Re-initiate Votubia at same dose. 

 Grade 4 

(<0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/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 

(≥1.25x109/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 

 



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Therapeutic drug monitoring 

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required 

for patients treated for SEGA. Trough concentrations should be assessed at least 1 week after the 

initial dose, after any change in dose or pharmaceutical form, after initiation of or change in 

co-administration of CYP3A4 inhibitors (see sections 4.4 and 4.5) or after any change in hepatic status 

(Child-Pugh) (see section “Hepatic impairment” below and section 5.2). Trough concentrations should 

be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see 

sections 4.4 and 4.5) since the natural degradation time of the induced enzymes has to be taken into 

account. 

 

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 section “Hepatic impairment” below 

and section 5.2). 

 

When possible, the same assay and laboratory for therapeutic drug monitoring should be used 

throughout the treatment. 

 

Switching pharmaceutical forms 

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. The same pharmaceutical form must be used consistently, as 

appropriate for the indication being treated. 

 

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 at least 

1 week later (see section “Therapeutic drug monitoring” above). 

 

Special populations 

Elderly 

No dose adjustment is required (see section 5.2). 

 

Renal impairment 

No dose adjustment is required (see section 5.2). 

 

Hepatic impairment 

Patients with renal angiomyolipoma associated with TSC: 

 Mild hepatic impairment (Child-Pugh A): The recommended dose is 7.5 mg daily. 

 Moderate hepatic impairment (Child-Pugh B): The recommended dose is 5 mg daily. 

 Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefit 
outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded (see sections 4.4 

and 5.2). 

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. 

 

  



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Patients ≥18 years of age: 

 Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated 
based on BSA (rounded to the nearest strength) 

 Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dose 
calculated based on BSA (rounded to the nearest strength) 

 Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefit 
outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the 

nearest strength) must not be exceeded. 

Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in 

hepatic status (Child-Pugh). 

 

Paediatric population 

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, efficacy and pharmacokinetic profile of Votubia in children below the age of 1 year with 

TSC who have SEGA have not been established. No data are available (see sections 5.1 and 5.2). 

 

Clinical study results did not show an impact of Votubia on growth and pubertal development. 

 

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). 

 

4.3 Contraindications 
 

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

listed in section 6.1. 

 

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. 

Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be 

ruled out in the differential diagnosis of non-infectious pneumonitis (see section “Infections” below). 

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. 

 



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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. 

 

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 

prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered. 

 

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, candidiasis or pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral 

infections including reactivation of hepatitis B virus, have been described in patients taking 

everolimus. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], 

respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients (see section 4.8). 

 

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. 

 

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have been 

reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of 

corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered 

when concomitant use of corticosteroids or other immunosuppressive agents are required. 

 

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). 

 

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors 

 

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). 

 

Stomatitis 

 

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse 

reaction in patients treated with Votubia (see section 4.8). Stomatitis mostly occurs within the first 

8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with 

Afinitor (everolimus) plus exemestane suggested that an alcohol-free corticosteroid oral solution, 

administered as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and 

severity of stomatitis (see section 5.1). Management of stomatitis may therefore include prophylactic 

(in adults) and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral 

solution as a mouthwash. However products containing alcohol, hydrogen peroxide, iodine and thyme 

derivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment of 

fungal infection is recommended, especially in patients being treated with steroid-based medicinal 



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products. Antifungal agents should not be used unless fungal infection has been diagnosed (see 

section 4.5). 

 

Haemorrhage 

 

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. 

 

Renal failure events 

 

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. 

 

Laboratory tests and monitoring 

 

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. 

 

Blood glucose 

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. 

 

Blood lipids 

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. 

 

Haematological parameters 

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. 

 

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. 



10 

 

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, ergot alkaloid derivatives or carbamazepine), the patient 

should be monitored for undesirable effects described in the product information of the orally 

administered CYP3A4 substrate (see section 4.5). 

 

Hepatic impairment 

 

Votubia is not recommended for use in patients: 

 ≥18 years of age 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 hepatic impairment (Child-Pugh A, B and 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). 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. 

 

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. 

 

Lactose 

 

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 

glucose-galactose malabsorption should not take this medicinal product. 

 

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. 

 



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Table 2 Effects of other active substances on everolimus 

 

Active substance by 

interaction 

 

Interaction – Change in 

Everolimus AUC/Cmax 

Geometric mean ratio 

(observed range) 

Recommendations concerning 

co-administration 

Potent CYP3A4/PgP inhibitors 

Ketoconazole AUC ↑15.3-fold 

(range 11.2-22.5) 

Cmax ↑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) 

Cmax ↑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. 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 Votubia dose is 

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: 

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 

Imatinib AUC ↑ 3.7-fold 
Cmax ↑ 2.2-fold 

Verapamil AUC ↑3.5-fold 

(range 2.2-6.3) 

Cmax ↑2.3-fold 

(range1.3-3.8) 

Ciclosporin oral AUC ↑2.7-fold 

(range 1.5-4.7) 

Cmax ↑1.8-fold 

(range 1.3-2.6) 

Fluconazole Not studied. Increased exposure 

expected. Diltiazem 

Dronedarone Not studied. Increased exposure 

expected. 

Amprenavir, 

fosamprenavir 

Not studied. Increased exposure 

expected. 



12 

and 4.4). Everolimus trough 

concentrations should be assessed at 

least 1 week after the addition of a 

moderate CYP3A4 or PgP inhibitor. 

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 Votubia dose is returned 

to the dose used prior to initiation of 

the co-administration. The 

everolimus trough concentration 

should be assessed at least 1 week 

later (see sections 4.2 and 4.4). 

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%) 

Cmax ↓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 or 

less 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, consider a 

washout period of at least 3 to 5 days 

(reasonable time for significant 

enzyme de-induction) before the 

Votubia dose is 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 

Dexamethasone Not studied. Decreased 

exposure expected. 

Antiepileptics (e.g. 

carbamazepine, 

phenobarbital, phenytoin) 

Not studied. Decreased 

exposure expected. 

Efavirenz, nevirapine Not studied. Decreased 

exposure expected. 



13 

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. 

 

The addition of another concomitant 

strong CYP3A4 inducer may not 

require additional dose adjustment. 

Assess the everolimus trough level 

2 weeks after initiating the additional 

inducer. Adjust the dose by 

increments of 2.5 mg as necessary to 

maintain the target trough 

concentration. 

 

Discontinuation of one of multiple 

strong CYP3A4 inducers may not 

require additional dose adjustment. 

Assess the everolimus trough level 

2 weeks after discontinuation of one 

of multiple strong CYP3A4 

inducers. If all potent inducers are 

discontinued, consider a washout 

period of at least 3 to 5 days 

(reasonable time for significant 

enzyme de-induction) before the 

Votubia dose is returned to the dose 

used prior to initiation of the 

co-administration. The everolimus 

trough concentrations should be 

assessed 2 to 4 weeks later since the 

natural degradation time of the 

induced enzymes has to be taken into 

account (see sections 4.2 and 4.4). 

St John’s Wort 

(Hypericum perforatum) 

Not studied. Large decrease in 

exposure expected. 

Preparations containing St John’s 

Wort should not be used during 

treatment with everolimus 

 

Agents whose plasma 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. 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). 

 

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the 

antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 

10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically 

significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, 

may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are 

substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide). 

 



14 

Concomitant use of ACE inhibitors 

 

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

angioedema (see section 4.4). 

 

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 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception in males and females 

 

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. 

 

Breast-feeding 

 

It is not known whether everolimus is excreted in human 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 during treatment and for 2 weeks after the last dose. 

 

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). Based on non-clinical findings, male and female fertility 

may be compromised by treatment with everolimus (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 
 

Votubia has 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 Votubia. 

 



15 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Three randomised, double-blind, placebo-controlled pivotal phase III studies, including double-blind 

and open label treatment periods, and a non-randomised, open-label, single-arm phase II study 

contribute to the safety profile of Votubia (n=612, including 409 patients <18 years of age; median 

duration of exposure 36.8 months [range 0.5 to 83.2]). 

 EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial 
comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of 

3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119), 

in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The 

median duration of the double-blind period was 18 weeks. The cumulative median duration 

exposure to Votubia (361 patients who took at least one dose of everolimus) was 30.4 months 

(range 0.5 to 48.8). 

 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. The cumulative median duration of exposure to Votubia (112 patients who took at least 

one dose of everolimus) was 46.9 months (range 0.5 to 63.9). 

 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. The 

cumulative median duration of exposure to Votubia (111 patients who took at least one dose of 

everolimus) was 47.1 months (range 1.9 to 58.3). 

 CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus 
in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to 

83.2). 

 

The adverse events considered to be associated with the use of Votubia (adverse reactions), based 

upon the review and medical assessment of all adverse events reported in the above studies, are 

described below. 

 

The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing 

order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, 

cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation 

irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia, and hypertension. 

 

The most frequent grade 3-4 adverse reactions (incidence ≥1%) were pneumonia, stomatitis, 

amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea, and 

cellulitis. The grades follow CTCAE Version 3.0 and 4.03. 

 

Tabulated list 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. 

 



16 

Table 3 Adverse reactions reported in TSC studies 

 

Infections and infestations 

Very common Nasopharyngitis, upper respiratory tract infection, pneumonia a, urinary tract 

infection, sinusitis, pharyngitis 

Common Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis 

Uncommon Herpes zoster, sepsis, bronchitis viral 

Blood and lymphatic system disorders 

Common Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia 

Immune system disorders 

Common Hypersensitivity 

Metabolism and nutrition disorders 

Very common Decreased appetite, hypercholesterolaemia 

Common Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia 

Psychiatric disorders 

Common Insomnia, aggression, irritability 

Nervous system disorders 

Very common Headache 

Uncommon Dysgeusia 

Vascular disorders 

Very common Hypertension 

Common Lymphoedema 

Respiratory, thoracic and mediastinal disorders 

Very common Cough 

Common Epistaxis, pneumonitis 

Gastrointestinal disorders 

Very common Stomatitis b, diarrhoea, vomiting 

Common Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis 

Skin and subcutaneous tissue disorders 

Very common Rash c, acne 

Common Dry skin, acneiform dermatitis, pruritus, alopecia 

Uncommon Angioedema 

Musculoskeletal and connective tissue disorders 

Uncommon Rhabdomyolysis 

Renal and urinary disorders 

Common Proteinuria 

Reproductive system and breast disorders 

Very common Amenorrhoea d, menstruation irregular d 

Common Menorrhagia, ovarian cyst, vaginal haemorrhage 

Uncommon Menstruation delayed d 

General disorders and administration site conditions 

Very common Pyrexia, fatigue 

Investigations 

Common Blood lactate dehydrogenase increased, blood luteinising hormone increased, 

weight decreased 

Uncommon Blood follicle stimulating hormone increased 
a Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) 
b Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongue 

ulceration, lip ulceration and (uncommon) gingival pain, glossitis 
c Includes (very common) rash; (common) rash erythematous, erythema and (uncommon) rash 

generalised, rash maculo-papular, rash macular 
d Frequency based upon number of women from 10 to 55 years of age while on treatment in the 

pooled data 

 



17 

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. 

 

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases 

of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see section 4.4). 
 

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. 

 

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and 

without concomitant use of ACE inhibitors (see section 4.4). 

 

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 pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied 

were below the age of 18 years. The overall type, frequency 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 and severity in children below the 

age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade 3/4 infections, 

compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged 

≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving 

everolimus. 

 

Elderly 

 

In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age. 

The number of oncology patients with an adverse reaction leading to discontinuation of everolimus 

was higher in patients ≥65 years of age (20% versus 13%). The most common adverse reactions 

leading to discontinuation were pneumonitis (including interstitial lung disease), 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. 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


18 

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 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 

TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation 

throughout the body. 

 

Clinical efficacy and safety 

 

Renal angiomyolipoma associated with TSC 

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 antiepileptics at 

randomisation (yes/no). 

 

Key secondary endpoints included time to angiomyolipoma progression and skin lesion response rate. 

 



19 

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 best overall response rates of 41.8% (95% CI: 30.8, 53.4) for the Votubia arm compared with 0% 

(95% CI: 0.0, 9.0) for the placebo arm (p<0.0001) (Table 4). 

 

Patients initially treated with placebo were allowed to cross over to everolimus at the time of 

angiomyolipoma progression and upon recognition that treatment with everolimus was superior to 

treatment with placebo. At the time of the final analysis (4 years following the last patient 

randomisation), the median duration of exposure to everolimus was 204.1 weeks (range 2 to 278). The 

angiomyolipoma best overall response rate had increased to 58.0% (95% CI: 48.3, 67.3), with a rate of 

stable disease of 30.4% (Table 4). 

 

Among patients treated with everolimus during the study, no cases of angiomyolipoma-related 

nephrectomy and only one case of renal embolisation were reported. 

 

Table 4 EXIST-2 - Angiomyolipoma response 

 

 Primary analysis3 Final 

analysis4 

 Votubia Placebo p-value Votubia 

 n=79 n=39  n=112 

Primary analysis  

 Angiomyolipoma response rate1,2 – % 41.8 0 <0.0001 58.0 

 95% CI 30.8, 53.4 0.0, 9.0  48.3, 67.3 

Best overall angiomyolipoma response – %  

 Response 41.8 0  58.0 

 Stable disease 40.5 79.5  30.4 

 Progression 1.3 5.1  0.9 

 Not evaluable 16.5 15.4  10.7 
1 According to independent central radiology review 
2 Angiomyolipoma responses were confirmed with a repeat scan. Response was defined as: 

≥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% 

from nadir, plus absence of grade ≥2 angiomyolipoma-related bleeding. 
3 Primary analysis for double blind period 
4 Final analysis includes patients who crossed over from the placebo group; median duration of 

exposure to everolimus of 204.1 weeks 

 

Consistent treatment effects on angiomyolipoma response rate were observed across all subgroups 

evaluated (i.e. enzyme-inducing antiepileptic use versus enzyme-inducing antiepileptic non-use, sex, 

age and race) at the primary efficacy analysis. 

 

In the final analysis, reduction in angiomyolipoma volume improved with longer term treatment with 

Votubia. At weeks 12, 96 and 192, ≥ 30% reductions in volume were observed in 75.0%, 80.6%, and 

85.2% of the treated patients, respectively. Similarly, at the same timepoints, ≥50% reductions in 

volume were observed in 44.2%, 63.3%, and 68.9% of the treated patients, respectively. 

 



20 

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. At the final 

analysis, median time to angiomyolipoma progression was not reached. Angiomyolipoma progressions 

were observed in 14.3% of the patients. The estimated angiomyolipoma progression-free rates at 

24 months and 48 months were 91.6% and 83.1%, respectively. 

 

At the primary analysis, 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). At the final analysis, the 

skin lesion response rate had increased to 68.2% (95% CI: 58.5, 76.9), with one patient reporting a 

confirmed complete clinical skin lesion response and no patients experiencing progressive disease as 

their best response. 

 

In an exploratory analysis of patients with TSC with angiomyolipoma who also had SEGA, the SEGA 

response rate (proportion of patients with ≥50% reduction from baseline in target lesion volumes in 

the absence of progression) was 10.3% in the everolimus arm in the primary analysis (versus no 

responses reported in the 13 patients randomised to placebo with a SEGA lesion at baseline) and 

increased to 48.0% in the final analysis. 

 

Post-hoc sub-group analysis of EXIST-2 (study CRAD001M2302) carried out at time of primary 

analysis 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, at 

primary analysis 

 

Time-averaged Cmin 

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 

Difference1  -0.224 -0.475, 0.027 
1 Difference is “≤5 ng/ml” minus “>5 ng/ml” 

 

SEGA associated with TSC 

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 antiepileptics 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. 

 



21 

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 angiomyolipoma lesions (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. 

 

Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGA 

progression and upon recognition that treatment with everolimus was superior to treatment with 

placebo. All patients receiving at least one dose of everolimus were followed until medicinal product 

discontinuation or study completion. At the time of the final analysis, the median duration of exposure 

among all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA response rate 

had increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis. 

 

No patient required surgical intervention for SEGA during the entire course of the study. 

 

Table 6 EXIST-1 – SEGA response 

 

 Primary analysis3  Final analysis4 

 Votubia Placebo p-value Votubia 

 N=78 N=39  N=111 

 SEGA response rate1,2 - (%) 34.6 0 <0.0001 57.7 

 95% CI 24.2, 46.2 0.0, 9.0  47.9, 67.0 

Best overall SEGA response - (%)     

 Response 34.6 0  57.7 

 Stable disease 62.8 92.3  39.6 

 Progression 0 7.7  0 

 Not evaluable 2.6 0  2.7 
1 according to independent central radiology review 
2 SEGA responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction in 

the sum of SEGA volume relative to baseline, plus no unequivocal worsening of non-target SEGA 

lesions, plus absence of new SEGA ≥1 cm in longest diameter, plus no new or worsening 

hydrocephalus 
3 Primary analysis for double blind period 
4 Final analysis includes patients who crossed over from the placebo group; median duration of 

exposure to everolimus of 204.9 weeks 

 

  



22 

Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducing 

antiepileptic use versus enzyme-inducing antiepileptic non-use, sex and age) at the primary analysis. 

 

During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of 

Votubia treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had 

≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patients 

had ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume. 

 

In the everolimus treated population (N=111) of the study, including patients who crossed over from 

the placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustained 

at later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was 

45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly, 

the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and 

77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment. 

 

Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus, 

despite the fact that positive results were observed for the two subsequent secondary endpoints (time 

to SEGA progression and skin lesion response rate), they could not be declared formally statistically 

significant. 

 

Median time to SEGA progression based on central radiology review was not reached in either 

treatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimated 

progression-free rates at 6 months were 100% for the Votubia arm and 85.7% for the placebo arm. The 

long-term follow-up of patients randomised to everolimus and patients randomised to placebo who 

thereafter crossed over to everolimus demonstrated durable responses. 

 

At the time of the primary analysis, Votubia demonstrated clinically meaningful improvements in skin 

lesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Votubia arm 

and 10.5% (95% CI: 2.9, 24.8) for the placebo arm. At the final analysis, the skin lesion response rate 

increased to 58.1% (95% CI: 48.1, 67.7). 

 

Phase II study in patients with SEGA 

A prospective, open-label, single-arm phase II study (Study CRAD001C2485) 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 7]). No 

patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none 

required surgical resection or other therapy for SEGA. 

 



23 

Table 7 Change in primary SEGA volume over time 

 

SEGA 

volume 

(cm3) 

Independent central review 

 Baseline 

n=28 

Month 6 

n=27 

Month 12 

n=26 

Month 24 

n=24 

Month 36 

n=23 

Month 48 

n=24 

Month 60 

n=23 

Primary tumour volume 

Mean 

(standard 

deviation) 

2.45 

(2.813) 

1.33 

(1.497) 

1.26 

(1.526) 

1.19 

(1.042) 

1.26 

(1.298) 

1.16 

(0.961) 

1.24 

(0.959) 

Median 1.74 0.93 0.84 0.94 1.12 1.02 1.17 

 Range 0.49 - 14.

23 

0.31 - 7.9

8 

0.29 - 8.1

8 

0.20 - 4.6

3 

0.22 - 6.5

2 

0.18 - 4.1

9 

0.21 - 4.3

9 

Reduction from baseline 

Mean 

(standard 

deviation) 

 1.19 

(1.433) 

1.07 

(1.276) 

1.25 

(1.994) 

1.41 

(1.814) 

1.43 

(2.267) 

1.44 

(2.230) 

Median  0.83 0.85 0.71 0.71 0.83 0.50 

 Range  0.06 - 6.2

5 

0.02 - 6.0

5 

-0.55 - 9.6

0 

0.15 - 7.7

1 

0.00 - 10.

96 

-0.74 - 9.8

4 

Percentage reduction from baseline, n (%) 

 ≥50%  9 (33.3) 9 (34.6) 12 (50.0) 10 (43.5) 14 (58.3) 12 (52.2) 

 ≥30%  21 (77.8) 20 (76.9) 19 (79.2) 18 (78.3) 19 (79.2) 14 (60.9) 

 >0%  27 

(100.0) 

26 

(100.0) 

23 

(95.8) 

23 

(100.0) 

23 

(95.8) 

21 

(91.3) 

 No 

change 

 0 0 0 0 1 (4.2) 0 

 Increase  0 0 1 (4.2) 0 0 2 (8.7) 

 

The robustness and consistency of the primary analysis were supported by the: 

 change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0% 
and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively 

 change in total SEGA volume as per independent central review (p<0.001) or local investigator 
assessment (p<0.001). 

 

One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume) 

and was temporarily taken off trial therapy; however, SEGA re-growth was evident at the next 

assessment at 4.5 months and treatment was restarted. 

 

Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustained 

efficacy. 

 

Other studies 

Stomatitis is the most commonly reported adverse reaction in patients treated with Votubia (see 

sections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advanced 

breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral 

solution was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to 

patients at the time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane 

(25 mg/day) to reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 

stomatitis at 8 weeks was 2.4% (n=2/85 evaluable patients) which was lower than historically 

reported. The incidence of Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 

stomatitis were reported. The overall safety profile in this study was consistent with that 

established for everolimus in the oncology and TSC settings, with the exception of a slightly 

increased frequency of oral candidiasis which was reported in 2.2% (n=2/92) of patients. 



24 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Votubia in all subsets of the paediatric population in angiomyolipoma (see section 4.2 for information 

on paediatric use). 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Votubia in one or more subsets of the paediatric population in refractory epilepsy associated with TSC 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Absorption 

 

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. 

 

Food effect 

In healthy subjects, high fat meals reduced systemic exposure to Votubia 10 mg tablets (as measured 

by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 

32% and Cmax by 42%. 

 

In healthy subjects taking a single 9 mg dose (3 x 3 mg) of Votubia dispersible tablets in suspension, 

high fat meals reduced AUC by 11.7% and the peak blood concentration Cmax by 59.8%. Light fat 

meals reduced AUC by 29.5% and Cmax by 50.2%. 

 

Food, however, had no apparent effect on the post absorption phase concentration-time profile 

24 hours post-dose of either dosage form. 

 

Relative bioavailability/bioequivalence 

In a relative bioavailability study, AUC0-inf of 5 x 1 mg everolimus tablets when administered as 

suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and 

Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets. 

 

In a bioequivalence study, AUC0-inf of the 5 mg dispersible tablet when administered as suspension in 

water was equivalent to 5 x 1 mg intact everolimus tablets, and Cmax of the 5 mg dispersible tablet in 

suspension was 64% of 5 x 1 mg intact everolimus tablets. 

 

Distribution 

 

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 

5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is 

confined to plasma of cancer patients given Votubia 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. 

 

  



25 

Nonclinical studies in rats indicate: 

 A rapid uptake of everolimus in the brain followed by a slow efflux. 

 The radioactive metabolites of [3H]everolimus do not significantly cross the blood-brain 
barrier. 

 A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of 
saturation of an efflux pump present in the brain capillary endothelial cells. 

 The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus 
in the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier. 

 

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in 

rats demonstrated distribution into the brain following administration by both the intravenous and oral 

routes. 

 

Biotransformation 

 

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main 

circulating component in human blood. Six main metabolites of everolimus have been detected in 

human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, 

and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal 

species used in toxicity studies and showed approximately 100 times less activity than everolimus 

itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological 

activity. 

 

Elimination 

 

Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. 

The mean elimination half-life of everolimus is approximately 30 hours. 

 

No specific excretion studies have been undertaken in cancer patients; however, data are available 

from the studies in transplant patients. Following the administration of a single dose of radiolabelled 

everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, 

while 5% was excreted in the urine. The parent substance was not detected in urine or faeces. 

 

Steady-state pharmacokinetics 

 

After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was 

dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 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-τ and pre-dose trough concentration at steady-state. 

 

Special populations 

 

Hepatic impairment 

The safety, tolerability and pharmacokinetics of Votubia were evaluated in two single oral dose 

studies of Votubia tablets in 8 and 34 adult 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. 

 

  



26 

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). 

 

Renal impairment 

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant 

influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant 

renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of 

everolimus in transplant patients. 

 

Paediatric population 

In patients with SEGA, everolimus Cmin was approximately dose-proportional within the dose range 

from 1.35 mg/m2 to 14.4 mg/m2. 

 

In patients with SEGA, the geometric mean Cmin values normalised to mg/m2 dose in patients aged 

<10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults 

(>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data 

in patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher in 

patients with low BSA (BSA of 0.556 m2) than in adults. Therefore it is assumed that steady-state 

could be reached earlier in patients <3 years of age (see section 4.2 for dosing recommendations). 

 

The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is 

reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life, 

which could affect the clearance in this patient population. 

 

A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to 

27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m2 to 0.74 m2) showed 

that BSA-normalised clearance is in general higher in younger patients. Population pharmacokinetic 

model simulations showed that a starting dose of 7 mg/m2 would be necessary to attain Cmin within the 

5 to 15 ng/ml range in patients younger than 3 years of age. A higher starting dose of 7 mg/m2 is 

therefore recommended for patients 1 to less than 3 years of age with SEGA (see section 4.2). 

 

Elderly 

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age 

(27-85 years) on oral clearance of everolimus was detected. 

 

Ethnicity 

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver 

functions. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% 

higher in black transplant patients. 

 

5.3 Preclinical safety data 
 

The non-clinical 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. 

 



27 

Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, 

coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal 

tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at 

systemic exposure levels within the range of therapeutic exposure or above, with the exception of the 

findings in rats, which occurred below therapeutic exposure due to a high tissue distribution. 

 

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm 

motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is 

within the range of therapeutic exposure and which caused a reduction in male fertility. There was 

evidence of reversibility. 

 

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. 

 

In juvenile rat toxicity studies, systemic toxicity included decreased body weight gain, food 

consumption, and delayed attainment of some developmental landmarks, with full or partial recovery 

after cessation of dosing. With the possible exception of the rat-specific lens finding (where young 

animals appeared to be more susceptible), it appears that there is no significant difference in the 

sensitivity of juvenile animals to the adverse reactions of everolimus as compared to adult animals. 

Toxicity study with juvenile monkeys did not show any relevant toxicity. 

 

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 4.3 and 0.2 times the 

estimated clinical exposure. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Butylated hydroxytoluene (E321) 

Magnesium stearate 

Lactose monohydrate 

Hypromellose 

Crospovidone type A 

Lactose anhydrous 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

3 years. 

 

  



28 

6.4 Special precautions for storage 
 

Do not store above 25°C. 

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

 

6.5 Nature and contents of container 

 

Aluminium/polyamide/aluminium/PVC perforated unit-dose blister containing 10 x 1 tablets. 

 

Votubia 2.5 mg tablets 

 

Packs containing 10 x 1, 30 x 1 or 100 x 1 tablets. 

 

Votubia 5 mg tablets 

 

Packs containing 30 x 1 or 100 x 1 tablets. 

 

Votubia 10 mg tablets 

 

Packs containing 10 x 1, 30 x 1 or 100 x 1 tablets. 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 
 

The extent of absorption of everolimus through topical exposure is not known. Therefore caregivers 

are advised to avoid contact with the suspension. Hands should be washed thoroughly before and after 

preparation of the suspension. 

 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Votubia 2.5 mg tablets 

 

EU/1/11/710/001-003 

 

Votubia 5 mg tablets 

 

EU/1/11/710/004-005 

 

Votubia 10 mg tablets 

 

EU/1/11/710/006-008 

 

 



29 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 02 September 2011 

Date of latest renewal: 28 July 2015 

 

 

10. 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 

 

http://www.ema.europa.eu/


30 

1. NAME OF THE MEDICINAL PRODUCT 
 

Votubia 1 mg dispersible tablets 

Votubia 2 mg dispersible tablets 

Votubia 3 mg dispersible tablets 

Votubia 5 mg dispersible tablets 

 

 

2. QUALITATIVE AND QUANTITATIVE COMPOSITION 
 

Votubia 1 mg dispersible tablets 

 

Each dispersible tablet contains 1 mg everolimus. 

 

Excipient with known effect 

Each dispersible tablet contains 0.98 mg lactose. 

 

Votubia 2 mg dispersible tablets 

 

Each dispersible tablet contains 2 mg everolimus. 

 

Excipient with known effect 

Each dispersible tablet contains 1.96 mg lactose. 

 

Votubia 3 mg dispersible tablets 

 

Each dispersible tablet contains 3 mg everolimus. 

 

Excipient with known effect 

Each dispersible tablet contains 2.94 mg lactose. 

 

Votubia 5 mg dispersible tablets 

 

Each dispersible tablet contains 5 mg everolimus. 

 

Excipient with known effect 

Each dispersible tablet contains 4.90 mg lactose. 

 

For the full list of excipients, see section 6.1. 

 

 

3. PHARMACEUTICAL FORM 

 

Dispersible tablet. 

 

Votubia 1 mg dispersible tablets 

 

White to slightly yellowish, round, flat tablets of approximately 7.1 mm in diameter, with a bevelled 

edge and no score, engraved with “D1” on one side and “NVR” on the other. 

 

Votubia 2 mg dispersible tablets 

 

White to slightly yellowish, round, flat tablets of approximately 9.1 mm in diameter, with a bevelled 

edge and no score, engraved with “D2” on one side and “NVR” on the other. 

 



31 

Votubia 3 mg dispersible tablets 

 

White to slightly yellowish, round, flat tablets of approximately 10.1 mm in diameter, with a bevelled 

edge and no score, engraved with “D3” on one side and “NVR” on the other. 

 

Votubia 5 mg dispersible tablets 

 

White to slightly yellowish, round, flat tablets of approximately 12.1 mm in diameter, with a bevelled 

edge and no score, engraved with “D5” on one side and “NVR” on the other. 

 

 

4. CLINICAL PARTICULARS 
 

4.1 Therapeutic indications 
 

Refractory seizures associated with tuberous sclerosis complex (TSC) 

 

Votubia is indicated as adjunctive treatment of patients aged 2 years and older whose refractory 

partial-onset seizures, with or without secondary generalisation, are associated with TSC. 

 

Subependymal giant cell astrocytoma (SEGA) associated with TSC 

 

Votubia is indicated for the treatment of adult and paediatric patients with SEGA associated with 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). 

 

Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight 

(W) is in kilograms and height (H) is in centimetres: 

BSA = (W0.425 x H0.725) x 0.007184 

 

Starting dose and target trough concentrations in SEGA associated with TSC 

The recommended starting dose for Votubia for the treatment of patients with SEGA is 4.5 mg/m2. A 

higher starting dose of 7 mg/m2 is recommended for patients 1 to less than 3 years of age based on 

pharmacokinetic simulations (see section 5.2). Different strengths of Votubia dispersible tablets can be 

combined to attain the desired dose. 

 

Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult 

SEGA population, except for patients in the range from 1 year to less than 3 years of age, and those 

with hepatic impairment (see section “Hepatic impairment” below and section 5.2). 

 

  



32 

Starting dose and target trough concentrations in TSC with refractory seizures 

The recommended starting dose for Votubia for the treatment of patients with seizures is shown in 

Table 1. Different strengths of Votubia dispersible tablets can be combined to attain the desired dose. 

 

Table 1 Votubia starting dose for patients with TSC and refractory seizures 

 

Age Starting dose without 

co-administration of 

CYP3A4/PgP inducer 

Starting dose with 

co-administration of 

CYP3A4/PgP inducer 

<6 years 6 mg/m2 9 mg/m2 

≥6 years 5 mg/m2 8 mg/m2 

 

Dosing recommendations for paediatric patients with seizures are consistent with those for the adult 

population, except for patients in the range from 2 years to less than 6 years of age, and those with 

hepatic impairment (see section “Hepatic impairment” below and section 5.2). 

 

Dose monitoring 

Everolimus whole blood trough concentrations should be assessed at least 1 week 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. 

 

Titration 

Individualised dosing should be titrated by increasing the dose by increments of 1 to 4 mg to attain the 

target trough concentration for optimal clinical response. Efficacy, safety, concomitant therapy, and 

the current trough concentration should be considered when planning for dose titration. Individualised 

dose titration can be based on simple proportion: 

New everolimus dose = current dose x (target concentration / current concentration) 

 

For example, a patient’s current dose based on BSA is 4 mg with a steady-state concentration of 

4 ng/ml. In order to achieve a target concentration above the lower Cmin limit of 5 ng/ml, e.g. 8 ng/ml, 

the new everolimus dose would be 8 mg (an increase of 4 mg from the current daily dose). 

 

Long-term monitoring 

For patients with TSC who have SEGA, 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. 

 

For patients with TSC who have SEGA and patients with TSC and refractory seizures, once a stable 

dose is attained, trough concentrations should be monitored every 3 to 6 months in patients with 

changing BSA, or every 6 to 12 months in patients with stable BSA, for the duration of treatment. 

 

Treatment should continue as long as clinical benefit is observed or until unacceptable toxicity occurs. 

 

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

dose. 

 

Dose adjustments due to adverse reactions 

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 2 summarises dose adjustment recommendations for specific adverse reactions (see also 

section 4.4). 

 



33 

Table 2 Votubia dose adjustment recommendations 

 

Adverse reaction Severity1 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-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 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, ≥50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate Votubia at same dose. 

 Grade 3 & 4 

(<50x109/l) 
Temporary dose interruption until recovery to Grade 1 

(≥75x109/l). Re-initiate Votubia at approximately 50% lower 

than the daily dose previously administered. 

Neutropenia Grade 2 

(≥1x109/l) 

No dose adjustment required. 

 Grade 3 

(<1, ≥0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/l). Re-initiate Votubia at same dose. 

 Grade 4 

(<0.5x109/l) 
Temporary dose interruption until recovery to Grade 2 

(≥1x109/l). Re-initiate Votubia at approximately 50% lower 

than the daily dose previously administered. 



34 

Febrile neutropenia Grade 3 Temporary dose interruption until recovery to Grade 2 

(≥1.25x109/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 

 

Therapeutic drug monitoring 

Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required. 

Trough concentrations should be assessed at least 1 week after the initial dose, after any change in 

dose or pharmaceutical form, after initiation of or change in co-administration of CYP3A4 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). Trough concentrations should be assessed 2 to 4 weeks after 

initiation of or change in co-administration of CYP3A4 inducers (see sections 4.4 and 4.5) since the 

natural degradation time of the induced enzymes has to be taken into account. When possible, the 

same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment. 

 

Switching pharmaceutical forms 

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. The same pharmaceutical form must be used consistently, as 

appropriate for the indication being treated. 

 

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 at least 

1 week later (see section “Therapeutic drug monitoring” above). 

 

Special populations 

Elderly 

No dose adjustment is required (see section 5.2). 

 

Renal impairment 

No dose adjustment is required (see section 5.2). 

 

Hepatic impairment 

Patients <18 years of age: 

Votubia is not recommended for patients <18 years of age with SEGA or refractory seizures and 

hepatic impairment. 

 

Patients ≥18 years of age: 

 Mild hepatic impairment (Child-Pugh A): 75% of the recommended starting dose calculated 
based on BSA (rounded to the nearest strength) 

 Moderate hepatic impairment (Child-Pugh B): 50% of the recommended starting dose 
calculated based on BSA (rounded to the nearest strength) 

 Severe hepatic impairment (Child-Pugh C): Votubia is only recommended if the desired benefit 
outweighs the risk. In this case, 25% of the dose calculated based on BSA (rounded to the 

nearest strength) must not be exceeded. 

Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in 

hepatic status (Child-Pugh). 

 

  



35 

Paediatric population 

The safety, efficacy and pharmacokinetic profile of Votubia in children below the age of 1 year with 

TSC who have SEGA have not been established. No data are available (see sections 5.1 and 5.2). 

 

The safety, efficacy and pharmacokinetic profile of Votubia in children below the age of 2 years with 

TSC and refractory seizures have not been established. No data are available (see sections 5.1 and 

5.2). 

 

Clinical study results did not show an impact of Votubia on growth and pubertal development. 

 

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 dispersible tablets are to be taken as a suspension only and must not be swallowed whole, 

chewed, or crushed. The suspension can be prepared either in an oral syringe or in a small glass. Care 

should be taken to ensure the entire dose is ingested. 

 

The suspension must be administered immediately after preparation. If not administered within 

30 minutes of preparation when using an oral syringe or 60 minutes when using a small glass, the 

suspension must be discarded and a new suspension must be prepared (see section 6.3). Only water 

should be used as the vehicle. 

 

For further details on handling, see section 6.6. 

 

4.3 Contraindications 
 

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

listed in section 6.1. 

 

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. 

Opportunistic infections such as pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) should be 

ruled out in the differential diagnosis of non-infectious pneumonitis (see section “Infections” below). 

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. 

 



36 

For patients who require use of corticosteroids for treatment of non-infectious pneumonitis, 

prophylaxis for pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) may be considered. 

 

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, candidiasis or pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) and viral 

infections including reactivation of hepatitis B virus, have been described in patients taking 

everolimus. Some of these infections have been severe (e.g. leading to sepsis [including septic shock], 

respiratory or hepatic failure) and occasionally fatal in adult and paediatric patients (see section 4.8). 

 

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. 

 

Cases of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome, have been 

reported in patients who received everolimus. PJP/PCP may be associated with concomitant use of 

corticosteroids or other immunosuppressive agents. Prophylaxis for PJP/PCP should be considered 

when concomitant use of corticosteroids or other immunosuppressive agents are required. 

 

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). 

 

Concomitant use of angiotensin-converting enzyme (ACE) inhibitors 

 

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). 

 

Stomatitis 

 

Stomatitis, including mouth ulcerations and oral mucositis, is the most commonly reported adverse 

reaction in patients treated with Votubia (see section 4.8). Stomatitis mostly occurs within the first 

8 weeks of treatment. A single-arm study in postmenopausal breast cancer patients treated with 

Afinitor (everolimus) plus exemestane suggested that an alcohol-free corticosteroid oral solution, 

administered as a mouthwash during the initial 8 weeks of treatment, may decrease the incidence and 

severity of stomatitis (see section 5.1). Management of stomatitis may therefore include prophylactic 

(in adults) and/or therapeutic use of topical treatments, such as an alcohol-free corticosteroid oral 

solution as a mouthwash. However products containing alcohol, hydrogen peroxide, iodine and thyme 

derivatives should be avoided as they may exacerbate the condition. Monitoring for and treatment of 

fungal infection is recommended, especially in patients being treated with steroid-based medicinal 

products. Antifungal agents should not be used unless fungal infection has been diagnosed (see 

section 4.5). 

 



37 

Haemorrhage 

 

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. 

 

Renal failure events 

 

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. 

 

Laboratory tests and monitoring 

 

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. 

 

Blood glucose 

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. 

 

Blood lipids 

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. 

 

Haematological parameters 

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. 

 

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. 

 



38 

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, ergot alkaloid derivatives or carbamazepine), the patient 

should be monitored for undesirable effects described in the product information of the orally 

administered CYP3A4 substrate (see section 4.5). 

 

Hepatic impairment 

 

Votubia is not recommended for use in patients: 

 ≥18 years of age with SEGA or refractory seizures 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 or refractory seizures and concomitant hepatic impairment 
(Child-Pugh A, B and 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). For 

paediatric patients 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. 

 

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. 

 

Lactose 

 

Patients with rare hereditary problems of galactose intolerance, total lactase deficiency or 

glucose-galactose malabsorption should not take this medicinal product. 

 

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 3 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. 

 



39 

Table 3 Effects of other active substances on everolimus 

 

Active substance by 

interaction 

 

Interaction – Change in 

Everolimus AUC/Cmax 

Geometric mean ratio 

(observed range) 

Recommendations concerning 

co-administration 

Potent CYP3A4/PgP inhibitors 

Ketoconazole AUC ↑15.3-fold 

(range 11.2-22.5) 

Cmax ↑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) 

Cmax ↑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, 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 at 

least 1 week after the addition of a 

moderate CYP3A4 or PgP inhibitor. 

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 Votubia dose is returned 

to the dose used prior to initiation of 

the co-administration. The 

everolimus trough concentration 

should be assessed at least 1 week 

later (see sections 4.2 and 4.4). 

Imatinib AUC ↑ 3.7-fold 
Cmax ↑ 2.2-fold 

Verapamil AUC ↑3.5-fold 

(range 2.2-6.3) 

Cmax ↑2.3-fold 

(range1.3-3.8) 

Ciclosporin oral AUC ↑2.7-fold 

(range 1.5-4.7) 

Cmax ↑1.8-fold 

(range 1.3-2.6) 

Fluconazole Not studied. Increased exposure 

expected. Diltiazem 

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. 



40 

Potent and moderate CYP3A4 inducers 

Rifampicin AUC ↓63% 

(range 0-80%) 

Cmax ↓58% 

(range 10-70%) 

Avoid the use of concomitant potent 

CYP3A4 inducers. 

 

SEGA 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 as 

described below. 

 

Patients with seizures receiving 

concomitant strong CYP3A4 

inducers (e.g., enzyme inducing 

antiepileptics carbamazepine, 

phenobarbital, and phenytoin) at the 

start of treatment with everolimus 

require an increased starting dose to 

attain trough concentrations of 5 to 

15 ng/ml (see Table 1). 

 

For patients not receiving 

concomitant strong inducers at the 

start of everolimus treatment, the 

co-administration may require an 

increased Votubia dose. If 

concentrations are below 5 ng/ml, 

the daily dose may be increased by 

increments of 1 to 4 mg, checking 

the trough level and assessing 

tolerability before increasing the 

dose. 

 

The addition of another concomitant 

strong CYP3A4 inducer may not 

require additional dose adjustment. 

Assess the everolimus trough level 

2 weeks after initiating the additional 

inducer. Adjust the dose by 

increments of 1 to 4 mg as necessary 

to maintain the target trough 

concentration. 

 

Discontinuation of one of multiple 

strong CYP3A4 inducers may not 

require additional dose adjustment. 

Assess the everolimus trough level 

2 weeks after discontinuation of one 

of multiple strong CYP3A4 

inducers. If all potent inducers are 

discontinued, consider a washout 

period of at least 3 to 5 days 

(reasonable time for significant 

enzyme de-induction) before the 

Dexamethasone Not studied. Decreased 

exposure expected. 

Antiepileptics (e.g. 

carbamazepine, 

phenobarbital, phenytoin) 

Not studied. Decreased 

exposure expected. 

Efavirenz, nevirapine Not studied. Decreased 

exposure expected. 



41 

Votubia dose is returned to the dose 

used prior to initiation of the 

co-administration. The everolimus 

trough concentrations should be 

assessed 2 to 4 weeks later since the 

natural degradation time of the 

induced enzymes has to be taken into 

account (see sections 4.2 and 4.4). 

St John’s Wort 

(Hypericum perforatum) 

Not studied. Large decrease in 

exposure expected. 

Preparations containing St John’s 

Wort should not be used during 

treatment with everolimus 

 

Agents whose plasma 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. 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). 

 

In EXIST-3 (Study CRAD001M2304), everolimus increased pre-dose concentrations of the 

antiepileptics carbamazepine, clobazam, and the clobazam metabolite N-desmethylclobazam by about 

10%. The increase in the pre-dose concentrations of these antiepileptics may not be clinically 

significant but dose adjustments for antiepileptics with a narrow therapeutic index, e.g carbamazepine, 

may be considered. Everolimus had no impact on pre-dose concentrations of antiepileptics that are 

substrates of CYP3A4 (clonazepam, diazepam, felbamate and zonisamide). 

 

Concomitant use of ACE inhibitors 

 

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

angioedema (see section 4.4). 

 

Concomitant ketogenic diet 

 

The effect of a ketogenic diet may be mediated through mTOR inhibition. In the absence of clinical 

data, the possibility of an additive effect on adverse events cannot be excluded when everolimus is 

given in conjunction with a ketogenic diet. 

 

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. 

 

  



42 

4.6 Fertility, pregnancy and lactation 
 

Women of childbearing potential/Contraception in males and females 

 

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. 

 

Breast-feeding 

 

It is not known whether everolimus is excreted in human 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 during treatment and for 2 weeks after the last dose. 

 

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). Based on non-clinical findings, male and female fertility 

may be compromised by treatment with everolimus (see section 5.3). 

 

4.7 Effects on ability to drive and use machines 
 

Votubia has 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 Votubia. 

 

  



43 

4.8 Undesirable effects 

 

Summary of the safety profile 

 

Three randomised, double-blind, placebo-controlled pivotal phase III studies, including double-blind 

and open label treatment periods, and a non-randomised, open-label, single-arm phase II study 

contribute to the safety profile of Votubia (n=612, including 409 patients <18 years of age; median 

duration of exposure 36.8 months [range 0.5 to 83.2]). 

 EXIST-3 (CRAD001M2304): This was a randomised, double-blind, controlled, phase III trial 
comparing adjunctive treatment of low and high everolimus exposure (low trough [LT] range of 

3-7 ng/ml [n=117] and high trough [HT] range of 9-15 ng/ml [n=130]) versus placebo (n=119), 

in patients with TSC and refractory partial-onset seizures receiving 1 to 3 antiepileptics. The 

median duration of the double-blind period was 18 weeks. The cumulative median duration 

exposure to Votubia (361 patients who took at least one dose of everolimus) was 30.4 months 

(range 0.5 to 48.8). 

 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. The cumulative median duration of exposure to Votubia (112 patients who took at least 

one dose of everolimus) was 46.9 months (range 0.5 to 63.9). 

 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. The 

cumulative median duration of exposure to Votubia (111 patients who took at least one dose of 

everolimus) was 47.1 months (range 1.9 to 58.3). 

 CRAD001C2485: This was a prospective, open-label, single-arm phase II study of everolimus 
in patients with SEGA (n=28). The median duration of exposure was 67.8 months (range 4.7 to 

83.2). 

 

The adverse events considered to be associated with the use of Votubia (adverse reactions), based 

upon the review and medical assessment of all adverse events reported in the above studies, are 

described below. 

 

The most frequent adverse reactions (incidence ≥1/10) from the pooled safety data are (in decreasing 

order): stomatitis, pyrexia, nasopharyngitis, diarrhoea, upper respiratory tract infection, vomiting, 

cough, rash, headache, amenorrhoea, acne, pneumonia, urinary tract infection, sinusitis, menstruation 

irregular, pharyngitis, decreased appetite, fatigue, hypercholesterolaemia, and hypertension. 

 

The most frequent grade 3-4 adverse reactions (incidence ≥1%) were pneumonia, stomatitis, 

amenorrhoea, neutropenia, pyrexia, menstruation irregular, hypophosphataemia, diarrhoea, and 

cellulitis. The grades follow CTCAE Version 3.0 and 4.03. 

 

Tabulated list of adverse reactions 

 

Table 4 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. 

 



44 

Table 4 Adverse reactions reported in TSC studies 

 

Infections and infestations 

Very common Nasopharyngitis, upper respiratory tract infection, pneumonia a, urinary tract 

infection, sinusitis, pharyngitis 

Common Otitis media, cellulitis, pharyngitis streptococcal, gastroenteritis viral, gingivitis 

Uncommon Herpes zoster, sepsis, bronchitis viral 

Blood and lymphatic system disorders 

Common Anaemia, neutropenia, leucopenia, thrombocytopenia, lymphopenia 

Immune system disorders 

Common Hypersensitivity 

Metabolism and nutrition disorders 

Very common Decreased appetite, hypercholesterolaemia 

Common Hypertriglyceridaemia, hyperlipidaemia, hypophosphataemia, hyperglycaemia 

Psychiatric disorders 

Common Insomnia, aggression, irritability 

Nervous system disorders 

Very common Headache 

Uncommon Dysgeusia 

Vascular disorders 

Very common Hypertension 

Common Lymphoedema 

Respiratory, thoracic and mediastinal disorders 

Very common Cough 

Common Epistaxis, pneumonitis 

Gastrointestinal disorders 

Very common Stomatitis b, diarrhoea, vomiting 

Common Constipation, nausea, abdominal pain, flatulence, oral pain, gastritis 

Skin and subcutaneous tissue disorders 

Very common Rash c, acne 

Common Dry skin, acneiform dermatitis, pruritus, alopecia 

Uncommon Angioedema 

Musculoskeletal and connective tissue disorders 

Uncommon Rhabdomyolysis 

Renal and urinary disorders 

Common Proteinuria 

Reproductive system and breast disorders 

Very common Amenorrhoea d, menstruation irregular d 

Common Menorrhagia, ovarian cyst, vaginal haemorrhage 

Uncommon Menstruation delayed d 

General disorders and administration site conditions 

Very common Pyrexia, fatigue 

Investigations 

Common Blood lactate dehydrogenase increased, blood luteinising hormone increased, 

weight decreased 

Uncommon Blood follicle stimulating hormone increased 
a Includes pneumocystis jirovecii (carinii) pneumonia (PJP, PCP) 
b Includes (very common) stomatitis, mouth ulceration, aphthous ulcer; (common) tongue 

ulceration, lip ulceration and (uncommon) gingival pain, glossitis 
c Includes (very common) rash; (common) rash erythematous, erythema, and (uncommon) rash 

generalised, rash maculo-papular, rash macular 
d Frequency based upon number of women from 10 to 55 years of age while on treatment in the 

pooled data 

 



45 

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. 

 

In clinical studies and post-marketing spontaneous reports, everolimus has been associated with cases 

of pneumocystis jirovecii (carinii) pneumonia (PJP, PCP), some with fatal outcome (see section 4.4). 
 

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. 

 

In clinical studies and post-marketing spontaneous reports, angioedema has been reported with and 

without concomitant use of ACE inhibitors (see section 4.4). 

 

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 pivotal phase III study in patients with TSC and refractory seizures, 299 of the 366 patients studied 

were below the age of 18 years. The overall type, frequency 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 and severity in children below the 

age of 6 years. A total of 49 out of 137 patients (36%) aged <6 years had Grade 3/4 infections, 

compared to 53 out of 272 patients (19%) aged 6 to <18 years and 27 out of 203 patients (13%) aged 

≥18 years. Two fatal cases due to infection were reported in 409 patients aged <18 years receiving 

everolimus. 

 

Elderly 

 

In the oncology safety pooling, 37% of the patients treated with everolimus were ≥65 years of age. 

The number of oncology patients with an adverse reaction leading to discontinuation of everolimus 

was higher in patients ≥65 years of age (20% versus 13%). The most common adverse reactions 

leading to discontinuation were pneumonitis (including interstitial lung disease), 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. 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


46 

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 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 

TSC syndrome, inactivating mutations in the TSC1 or the TSC2 gene lead to hamartoma formation 

throughout the body. Besides pathological changes in brain tissue (such as cortical tubers) which may 

cause seizures, the mTOR pathway is also implicated in the pathogenesis of epilepsy in TSC. The 

mTOR regulates protein synthesis and multiple downstream cellular functions that may influence 

neuronal excitability and epileptogenesis. Overactivation of mTOR results in neuronal dysplasia, 

aberrant axonogenesis and dendrite formation, increased excitatory synaptic currents, reduced 

myelination, and disruption of the cortical laminar structure causing abnormalities in neuronal 

development and function. Preclinical studies in models of mTOR dysregulation in the brain 

demonstrated that treatment with an mTOR inhibitor such as everolimus could prolong survival, 

suppress seizures, prevent the development of new-onset seizures and prevent premature death. In 

summary, everolimus is highly active in this neuronal model of TSC, with benefit apparently 

attributable to effects on mTORC1 inhibition. However, the exact mechanism of action in the 

reduction of seizures associated with TSC is not fully elucidated. 

 



47 

Clinical efficacy and safety 

 

Phase III study in patients with TSC and refractory seizures 

EXIST-3 (Study CRAD001M2304), a randomised, double-blind, multicentre, three-arm, 

parallel-group phase III study of Votubia versus placebo as adjunctive therapy was conducted in TSC 

patients with refractory partial-onset seizures. In the study, partial-onset seizures were defined as all 

electroencephalogram (EEG)-confirmed sensory seizures or motor seizures in which a generalised 

onset had not been demonstrated on a past EEG. Patients were treated with concomitant and stable 

dose of 1 to 3 antiepileptics prior to study entry. The study consisted of three phases: an 8-week 

baseline observation phase; an 18-week double-blind, placebo-controlled core treatment phase 

(composed of titration and maintenance periods), an extension phase of ≥48 weeks in which all 

patients received Votubia and a post-extension phase of ≤48 weeks in which all patients received 

Votubia. 

 

The study independently tested two different primary endpoints: 1) response rate defined as at least a 

50% reduction from baseline in frequency of partial-onset seizures during the maintenance period of 

the core phase; and 2) percentage reduction from baseline in frequency of partial-onset seizures during 

the maintenance period of the core phase. 

 

Secondary endpoints included seizure freedom, proportion of patients with >25% seizure frequency 

reduction from baseline, distribution of reduction from baseline in seizure frequency (≤-25%, >-25% 

to <25%; ≥25% to <50%; ≥50% to <75%; ≥75% to <100%; 100%), long-term evaluation of seizure 

frequency and overall quality of life. 

 

A total of 366 patients were randomised in a 1:1.09:1 ratio to Votubia (n=117) low trough (LT) range 

(3 to 7 ng/ml), Votubia (n=130) high trough (HT) range (9 to 15 ng/ml) or placebo (n=119). The 

median age for the total population was 10.1 years (range: 2.2-56.3; 28.4% <6 years, 30.9% 6 to 

<12 years, 22.4% 12 to <18 years and 18.3% >18 years). Median duration of treatment was 18 weeks 

for all three arms in the core phase and 90 weeks (21 months) when considering both the core and 

extension phases. 

 

At baseline, 19.4% of patients had focal seizures with retained awareness (sensory previously 

confirmed on EEG or motor), 45.1% had focal seizures with impaired awareness (predominantly 

non-motor), 69.1% had focal motor seizures (i.e. focal motor seizures with impaired awareness and/or 

secondary generalised seizures), and 1.6% had generalised onset seizures (previously confirmed by 

EEG). The median baseline seizure frequency across the treatment arms was 35, 38, and 42 seizures 

per 28 days for the Votubia LT, Votubia HT, and placebo groups, respectively. The majority of 

patients (67%) failed 5 or more antiepileptics prior to the study and 41.0% and 47.8% of patients were 

taking 2 and ≥3 antiepileptics during the study. The baseline data indicated mild to moderate mental 

retardation in patients 6-18 years of age (scores of 60-70 on the Adaptive Behavior Composite and 

Communication, Daily Living Skills, and Socialization Domain Scores). 

 

  



48 

The efficacy results for the primary endpoint are summarised in Table 5. 

 

Table 5 EXIST-3 – Seizure frequency response rate (primary endpoint) 

 

 Votubia Placebo 

 

LT target of 

3-7 ng/ml 

HT target of 

9-15 ng/ml  

Statistic N=117 N=130 N=119 

Responders – n (%) 33 (28.2) 52 (40.0) 18 (15.1) 

 Response rate 95% CI a 20.3, 37.3 31.5, 49.0 9.2, 22.8 

Odds ratio (versus placebo) b 2.21 3.93  

 95% CI 1.16, 4.20 2.10, 7.32  

 p-value (versus placebo) c 0.008 <0.001  

 Statistically significant per Bonferroni-Holm 

procedure d 

Yes Yes  

Non-responders – n (%) 84 (71.8) 78 (60.0) 101 (84.9) 
a Exact 95% CI obtained using Clopper-Pearson method 
b Odds ratio and its 95% CI obtained using logistic regression stratified by age subgroup. Odds ratio 

>1 favours everolimus arm. 
c p-values computed from the Cochran-Mantel-Haenszel test stratified by age subgroup 
d Family-wise error rate of 2.5% one-sided 

 

Consistent results were found for the supportive analysis of the median percentage reduction from 

baseline in seizure frequency (other primary endpoint): 29.3% (95% CI: 18.8, 41.9) in the Votubia LT 

arm, 39.6% (95% CI: 35.0, 48.7) in the Votubia HT arm and 14.9% (95% CI: 0.1, 21.7) in the placebo 

arm. The p-values for superiority versus placebo were 0.003 (LT) and <0.001 (HT). 

 

The seizure-free rate (the proportion of patients who became seizure-free during the maintenance 

period of the core phase) was 5.1% (95% CI: 1.9, 10.8) and 3.8% (95% CI: 1.3, 8.7) in the Votubia LT 

and HT arms, respectively, versus 0.8% (95% CI: 0.0, 4.6) of patients in the placebo arm. 

 

  



49 

Higher proportions of responders were evident for all response categories in the Votubia LT and HT 

arms relative to placebo (Figure 1). Furthermore, almost twice as many patients in the placebo arm 

experienced seizure exacerbation relative to the Votubia LT and HT arms. 

 

Figure 1 EXIST-3 – Distribution of reduction from baseline in seizure frequency 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A homogeneous and consistent everolimus effect was observed across all subgroups evaluated for the 

primary efficacy endpoints by: age categories (Table 6), gender, race and ethnicity, seizure types, 

seizure frequency at baseline, number and name of concomitant antiepileptics, and TSC features 
(angiomyolipoma, SEGA, cortical tuber status). The effect of everolimus on infantile/epileptic spasms 

or on seizures associated with Lennox-Gastaut syndrome has not been studied and is not established 

for generalised-onset seizures and subjects without cortical tubers. 

 

Table 6 EXIST-3 – Seizure frequency response rate by age 

 

 Votubia Placebo 

 LT target of 

3-7 ng/ml 

HT target of 

9-15 ng/ml 

 

Age category N=117 N=130 N=119 

<6 years n=33 n=37 n=34 

 Response rate (95% CI) a 30.3 (15.6, 48.7) 59.5 (42.1, 75.2) 17.6 (6.8, 34.5) 

6 to <12 years n=37 n=39 n=37 

 Response rate (95% CI) a 29.7 (15.9, 47.0) 28.2 (15.0, 44.9) 10.8 (3.0, 25.4) 

12 to <18 years n=26 n=31 n=25 

 Response rate (95% CI) a 23.1 (9.0, 43.6) 32.3 (16.7, 51.4) 16.0 (4.5, 36.1) 

≥18 years b n=21 n=23 n=23 

 Response rate (95% CI) a 28.6 (11.3, 52.2) 39.1 (19.7, 61.5) 17.4 (5.0, 38.8) 
a Exact 95% CI obtained using Clopper-Pearson method 
b No efficacy data available in elderly patients 

 

0 

10 

20 

30 

40 

50 

Exacerbation 

≤-25 

No change 

>-25 to <25 

25% resp. 

25 to <50 

50% resp. 

50 to <75 

75% resp. 

75 to <100 

Seizure-free 

100 

Missing 

Reduction from baseline in seizure frequency (%) 

P
ro

p
o

rt
io

n
 o

f 
p

at
ie

n
ts

 (
%

) 

  

 

 

Votubia 3-7 ng/ml 

Votubia 9-15 ng/ml 

Placebo 

12.8 
11.5 

20.2 

35.0 

18.5 

41.2 

23.9 

30.0 

22.7 

17.1 

20.8 

9.2 

6.0 

15.4 

5.0 5.1 
3.8 

0.8 0.8 



50 

At the end of the core phase, overall quality of life in patients aged 2 to <11 years (as measured by the 

mean change from baseline in overall Quality Of Life score [total score] in the Childhood Epilepsy 

Questionnaire [QOLCE]) was maintained in each Votubia treatment arm as well as in the placebo arm. 

 

Reduction in seizure frequency was sustained over an evaluation period of approximately 2 years. 

Based on a sensitivity analysis considering patients who prematurely discontinued everolimus as 

non-responders, response rates of 38.4% (95% CI: 33.4, 43.7) and 44.4% (95% CI: 38.2, 50.7) were 

observed after 1 and 2 years of exposure to everolimus, respectively. 

 

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 antiepileptics 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 angiomyolipoma lesions (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 7). In addition, all 8 patients on the Votubia 

arm who had radiographic evidence of hydrocephalus at baseline had a decrease in ventricular volume. 

 

Patients initially treated with placebo were allowed to cross over to everolimus at the time of SEGA 

progression and upon recognition that treatment with everolimus was superior to treatment with 

placebo. All patients receiving at least one dose of everolimus were followed until medicinal product 

discontinuation or study completion. At the time of the final analysis, the median duration of exposure 

among all such patients was 204.9 weeks (range: 8.1 to 253.7). The best overall SEGA response rate 

had increased to 57.7% (95% CI: 47.9, 67.0) at the final analysis. 

 

No patient required surgical intervention for SEGA during the entire course of the study. 

 



51 

Table 7 EXIST-1 – SEGA response 

 

 Primary analysis3  Final analysis4 

 Votubia Placebo p-value Votubia 

 N=78 N=39  N=111 

 SEGA response rate1,2 - (%) 34.6 0 <0.0001 57.7 

 95% CI 24.2, 46.2 0.0, 9.0  47.9, 67.0 

Best overall SEGA response - (%)     

 Response 34.6 0  57.7 

 Stable disease 62.8 92.3  39.6 

 Progression 0 7.7  0 

 Not evaluable 2.6 0  2.7 
1 according to independent central radiology review 
2 SEGA responses were confirmed with a repeat scan. Response was defined as: ≥50% reduction in 

the sum of SEGA volume relative to baseline, plus no unequivocal worsening of non-target SEGA 

lesions, plus absence of new SEGA ≥1 cm in longest diameter, plus no new or worsening 

hydrocephalus 
3 Primary analysis for double blind period 
4 Final analysis includes patients who crossed over from the placebo group; median duration of 

exposure to everolimus of 204.9 weeks 

 

Consistent treatment effects were observed across all subgroups evaluated (i.e. enzyme-inducing 

antiepileptic use versus enzyme-inducing antiepileptic non-use, sex and age) at the primary analysis. 

 

During the double-blind period, reduction of SEGA volume was evident within the initial 12 weeks of 

Votubia treatment: 29.7% (22/74) of patients had ≥50% reductions in volume and 73.0% (54/74) had 

≥30% reductions in volume. Sustained reductions were evident at week 24, 41.9% (31/74) of patients 

had ≥50% reductions and 78.4% (58/74) of patients had ≥30% reductions in SEGA volume. 

 

In the everolimus treated population (N=111) of the study, including patients who crossed over from 

the placebo group, tumour response, starting as early as after 12 weeks on everolimus, was sustained 

at later time points. The proportion of patients achieving at least 50% reductions in SEGA volume was 

45.9% (45/98) and 62.1% (41/66) at weeks 96 and 192 after start of everolimus treatment. Similarly, 

the proportion of patients achieving at least 30% reductions in SEGA volume was 71.4% (70/98) and 

77.3% (51/66) at weeks 96 and 192 after start of everolimus treatment. 

 

Analysis of the first key secondary endpoint, change in seizure frequency, was inconclusive; thus, 

despite the fact that positive results were observed for the two subsequent secondary endpoints (time 

to SEGA progression and skin lesion response rate), they could not be declared formally statistically 

significant. 

 

Median time to SEGA progression based on central radiology review was not reached in either 

treatment arm. Progressions were only observed in the placebo arm (15.4%; p=0.0002). Estimated 

progression-free rates at 6 months were 100% for the Votubia arm and 85.7% for the placebo arm. The 

long-term follow-up of patients randomised to everolimus and patients randomised to placebo who 

thereafter crossed over to everolimus demonstrated durable responses. 

 

At the time of the primary analysis, Votubia demonstrated clinically meaningful improvements in skin 

lesion response (p=0.0004), with response rates of 41.7% (95% CI: 30.2, 53.9) for the Votubia arm 

and 10.5% (95% CI: 2.9, 24.8) for the placebo arm. At the final analysis, the skin lesion response rate 

increased to 58.1% (95% CI: 48.1, 67.7). 

 

  



52 

Phase II study in patients with SEGA 

A prospective, open-label, single-arm phase II study (Study CRAD001C2485) 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 8]). No 

patient developed new lesions, worsening hydrocephalus or increased intracranial pressure, and none 

required surgical resection or other therapy for SEGA. 

 

Table 8 Change in primary SEGA volume over time 

 

SEGA 

volume 

(cm3) 

Independent central review 

 Baseline 

n=28 

Month 6 

n=27 

Month 12 

n=26 

Month 24 

n=24 

Month 36 

n=23 

Month 48 

n=24 

Month 60 

n=23 

Primary tumour volume 

Mean 

(standard 

deviation) 

2.45 

(2.813) 

1.33 

(1.497) 

1.26 

(1.526) 

1.19 

(1.042) 

1.26 

(1.298) 

1.16 

(0.961) 

1.24 

(0.959) 

Median 1.74 0.93 0.84 0.94 1.12 1.02 1.17 

 Range 0.49 - 14.

23 

0.31 - 7.9

8 

0.29 - 8.1

8 

0.20 - 4.6

3 

0.22 - 6.5

2 

0.18 - 4.1

9 

0.21 - 4.3

9 

Reduction from baseline 

Mean 

(standard 

deviation) 

 1.19 

(1.433) 

1.07 

(1.276) 

1.25 

(1.994) 

1.41 

(1.814) 

1.43 

(2.267) 

1.44 

(2.230) 

Median  0.83 0.85 0.71 0.71 0.83 0.50 

 Range  0.06 - 6.2

5 

0.02 - 6.0

5 

-0.55 - 9.6

0 

0.15 - 7.7

1 

0.00 - 10.

96 

-0.74 - 9.8

4 

Percentage reduction from baseline, n (%) 

 ≥50%  9 (33.3) 9 (34.6) 12 (50.0) 10 (43.5) 14 (58.3) 12 (52.2) 

 ≥30%  21 (77.8) 20 (76.9) 19 (79.2) 18 (78.3) 19 (79.2) 14 (60.9) 

 >0%  27 

(100.0) 

26 

(100.0) 

23 

(95.8) 

23 

(100.0) 

23 

(95.8) 

21 

(91.3) 

 No 

change 

 0 0 0 0 1 (4.2) 0 

 Increase  0 0 1 (4.2) 0 0 2 (8.7) 

 

The robustness and consistency of the primary analysis were supported by the: 

 change in primary SEGA volume as per local investigator assessment (p<0.001), with 75.0% 
and 39.3% of patients experiencing reductions of ≥30% and ≥50%, respectively 

 change in total SEGA volume as per independent central review (p<0.001) or local investigator 
assessment (p<0.001). 

 



53 

One patient met the pre-specified criteria for treatment success (>75% reduction in SEGA volume) 

and was temporarily taken off trial therapy; however, SEGA re-growth was evident at the next 

assessment at 4.5 months and treatment was restarted. 

 

Long-term follow-up to a median duration of 67.8 months (range: 4.7 to 83.2) demonstrated sustained 

efficacy. 

 

Other studies 

Stomatitis is the most commonly reported adverse reaction in patients treated with Votubia (see 

sections 4.4 and 4.8). In a post-marketing single-arm study in postmenopausal women with advanced 

breast cancer (N=92), topical treatment with dexamethasone 0.5 mg/5 ml alcohol-free oral solution 

was administered as a mouthwash (4 times daily for the initial 8 weeks of treatment) to patients at the 

time of initiating treatment with Afinitor (everolimus, 10 mg/day) plus exemestane (25 mg/day) to 

reduce the incidence and severity of stomatitis. The incidence of Grade ≥2 stomatitis at 8 weeks was 

2.4% (n=2/85 evaluable patients) which was lower than historically reported. The incidence of 

Grade 1 stomatitis was 18.8% (n=16/85) and no cases of Grade 3 or 4 stomatitis were reported. The 

overall safety profile in this study was consistent with that established for everolimus in the oncology 

and TSC settings, with the exception of a slightly increased frequency of oral candidiasis which was 

reported in 2.2% (n=2/92) of patients. 

 

Paediatric population 

 

The European Medicines Agency has waived the obligation to submit the results of studies with 

Votubia in all subsets of the paediatric population in angiomyolipoma (see section 4.2 for information 

on paediatric use). 

 

The European Medicines Agency has deferred the obligation to submit the results of studies with 

Votubia in one or more subsets of the paediatric population in refractory epilepsy associated with TSC 

(see section 4.2 for information on paediatric use). 

 

5.2 Pharmacokinetic properties 
 

Absorption 

 

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. 

 

Food effect 

In healthy subjects, high fat meals reduced systemic exposure to Votubia 10 mg tablets (as measured 

by AUC) by 22% and the peak blood concentration Cmax by 54%. Light fat meals reduced AUC by 

32% and Cmax by 42%. 

 

In healthy subjects taking a single 9 mg dose (3 x 3 mg) of Votubia dispersible tablets in suspension, 

high fat meals reduced AUC by 11.7% and the peak blood concentration Cmax by 59.8%. Light fat 

meals reduced AUC by 29.5% and Cmax by 50.2%. 

 

Food, however, had no apparent effect on the post absorption phase concentration-time profile 

24 hours post-dose of either dosage form. 

 

  



54 

Relative bioavailability/bioequivalence 

In a relative bioavailability study, AUC0-inf of 5 x 1 mg everolimus tablets when administered as 

suspension in water was equivalent to 5 x 1 mg everolimus tablets administered as intact tablets, and 

Cmax of 5 x 1 mg everolimus tablets in suspension was 72% of 5 x 1 mg intact everolimus tablets. 

 

In a bioequivalence study, AUC0-inf of the 5 mg dispersible tablet when administered as suspension in 

water was equivalent to 5 x 1 mg intact everolimus tablets, and Cmax of the 5 mg dispersible tablet in 

suspension was 64% of 5 x 1 mg intact everolimus tablets. 

 

Distribution 

 

The blood-to-plasma ratio of everolimus, which is concentration-dependent over the range of 5 to 

5,000 ng/ml, is 17% to 73%. Approximately 20% of the everolimus concentration in whole blood is 

confined to plasma of cancer patients given Votubia 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. 

 

Nonclinical studies in rats indicate: 

 A rapid uptake of everolimus in the brain followed by a slow efflux. 

 The radioactive metabolites of [3H]everolimus do not significantly cross the blood-brain barrier. 

 A dose-dependent brain penetration of everolimus, which is consistent with the hypothesis of 
saturation of an efflux pump present in the brain capillary endothelial cells. 

 The co-administration of the PgP inhibitor, cyclosporine, enhances the exposure of everolimus in 
the brain cortex, which is consistent with the inhibition of PgP at the blood-brain barrier. 

 

There are no clinical data on the distribution of everolimus in the human brain. Non-clinical studies in 

rats demonstrated distribution into the brain following administration by both the intravenous and oral 

routes. 
 

Biotransformation 

 

Everolimus is a substrate of CYP3A4 and PgP. Following oral administration, everolimus is the main 

circulating component in human blood. Six main metabolites of everolimus have been detected in 

human blood, including three monohydroxylated metabolites, two hydrolytic ring-opened products, 

and a phosphatidylcholine conjugate of everolimus. These metabolites were also identified in animal 

species used in toxicity studies and showed approximately 100 times less activity than everolimus 

itself. Hence, everolimus is considered to contribute the majority of the overall pharmacological 

activity. 

 

Elimination 

 

Mean CL/F of everolimus after 10 mg daily dose in patients with advanced solid tumours was 24.5 l/h. 

The mean elimination half-life of everolimus is approximately 30 hours. 

 

No specific excretion studies have been undertaken in cancer patients; however, data are available 

from the studies in transplant patients. Following the administration of a single dose of radiolabelled 

everolimus in conjunction with ciclosporin, 80% of the radioactivity was recovered from the faeces, 

while 5% was excreted in the urine. The parent substance was not detected in urine or faeces. 

 

Steady-state pharmacokinetics 

 

After administration of everolimus in patients with advanced solid tumours, steady-state AUC0-τ was 

dose-proportional over the range of 5 to 10 mg daily dose. Steady-state was achieved within 2 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-τ and pre-dose trough concentration at steady-state. 

 



55 

Special populations 

 

Hepatic impairment 

The safety, tolerability and pharmacokinetics of Votubia were evaluated in two single oral dose 

studies of Votubia tablets in 8 and 34 adult 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). 

 

Renal impairment 

In a population pharmacokinetic analysis of 170 patients with advanced solid tumours, no significant 

influence of creatinine clearance (25-178 ml/min) was detected on CL/F of everolimus. Post-transplant 

renal impairment (creatinine clearance range 11-107 ml/min) did not affect the pharmacokinetics of 

everolimus in transplant patients. 

 

Paediatric population 

In patients with SEGA, everolimus Cmin was approximately dose-proportional within the dose range 

from 1.35 mg/m2 to 14.4 mg/m2. 

 

In patients with SEGA, the geometric mean Cmin values normalised to mg/m2 dose in patients aged 

<10 years and 10-18 years were lower by 54% and 40%, respectively, than those observed in adults 

(>18 years of age), suggesting that everolimus clearance was higher in younger patients. Limited data 

in patients <3 years of age (n=13) indicate that BSA-normalised clearance is about two-fold higher in 

patients with low BSA (BSA of 0.556 m2) than in adults. Therefore it is assumed that steady-state 

could be reached earlier in patients <3 years of age (see section 4.2 for dosing recommendations). 

 

The pharmacokinetics of everolimus have not been studied in patients younger than 1 year of age. It is 

reported, however, that CYP3A4 activity is reduced at birth and increases during the first year of life, 

which could affect the clearance in this patient population. 

 

A population pharmacokinetic analysis including 111 patients with SEGA who ranged from 1.0 to 

27.4 years (including 18 patients 1 to less than 3 years of age with BSA 0.42 m2 to 0.74 m2) showed 

that BSA-normalised clearance is in general higher in younger patients. Population pharmacokinetic 

model simulations showed that a starting dose of 7 mg/m2 would be necessary to attain Cmin within the 

5 to 15 ng/ml range in patients younger than 3 years of age. A higher starting dose of 7 mg/m2 is 

therefore recommended for patients 1 to less than 3 years of age with SEGA (see section 4.2). 

 

In patients with TSC and refractory seizures receiving Votubia dispersible tablets, a trend was 

observed toward lower Cmin normalised to dose (as mg/m2) in younger patients. Median Cmin 

normalised to mg/m2 dose was lower for the younger age groups, indicating that everolimus clearance 

(normalised to BSA) was higher in younger patients. 

 

Elderly 

In a population pharmacokinetic evaluation in cancer patients, no significant influence of age 

(27-85 years) on oral clearance of everolimus was detected. 



56 

 

Ethnicity 

Oral clearance (CL/F) is similar in Japanese and Caucasian cancer patients with similar liver 

functions. Based on analysis of population pharmacokinetics, oral clearance (CL/F) is on average 20% 

higher in black transplant patients. 

 

Pharmacokinetic/pharmacodynamic relationship(s) 

 

In patients with TSC and refractory seizures, a conditional logistic regression analysis based on the 

core phase of Study CRAD001M2304 to estimate the probability of seizure response versus Time 

Normalised (TN)-Cmin stratified by age sub-group, indicated that a 2-fold increase in TN-Cmin was 

associated with a 2.172-fold increase (95% CI: 1.339, 3.524) in the odds for a seizure response over 

the observed TN-Cmin ranges of 0.97 ng/ml to 16.40 ng/ml. Baseline seizure frequency was a 

significant factor in the seizure response (with an odds ratio of 0.978 [95% CI: 0.959, 0.998]). This 

outcome was consistent with the results of a linear regression model predicting the log of absolute 

seizure frequency during the maintenance period of the core phase, which indicated that for a 2-fold 

increase in TN-Cmin there was a statistically significant 28% reduction (95% CI: 12%, 42%) in 

absolute seizure frequency. Baseline seizure frequency and TN-Cmin were both significant factors 

(α=0.05) in predicting the absolute seizure frequency in the linear regression model. 

 

5.3 Preclinical safety data 
 

The non-clinical safety profile of everolimus was assessed in mice, rats, minipigs, monkeys and 

rabbits. The major target organs were male and female reproductive systems (testicular tubular 

degeneration, reduced sperm content in epididymides and uterine atrophy) in several species; lungs 

(increased alveolar macrophages) in rats and mice; pancreas (degranulation and vacuolation of 

exocrine cells in monkeys and minipigs, respectively, and degeneration of islet cells in monkeys), and 

eyes (lenticular anterior suture line opacities) in rats only. Minor kidney changes were seen in the rat 

(exacerbation of age-related lipofuscin in tubular epithelium, increases in hydronephrosis) and mouse 

(exacerbation of background lesions). There was no indication of kidney toxicity in monkeys or 

minipigs. 

 

Everolimus appeared to spontaneously exacerbate background diseases (chronic myocarditis in rats, 

coxsackie virus infection of plasma and heart in monkeys, coccidian infestation of the gastrointestinal 

tract in minipigs, skin lesions in mice and monkeys). These findings were generally observed at 

systemic exposure levels within the range of therapeutic exposure or above, with the exception of the 

findings in rats, which occurred below therapeutic exposure due to a high tissue distribution. 

 

In a male fertility study in rats, testicular morphology was affected at 0.5 mg/kg and above, and sperm 

motility, sperm head count, and plasma testosterone levels were diminished at 5 mg/kg, which is 

within the range of therapeutic exposure and which caused a reduction in male fertility. There was 

evidence of reversibility. 

 

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. 

 



57 

In juvenile rat toxicity studies, systemic toxicity included decreased body weight gain, food 

consumption, and delayed attainment of some developmental landmarks, with full or partial recovery 

after cessation of dosing. With the possible exception of the rat-specific lens finding (where young 

animals appeared to be more susceptible), it appears that there is no significant difference in the 

sensitivity of juvenile animals to the adverse reactions of everolimus as compared to adult animals. 

Toxicity study with juvenile monkeys did not show any relevant toxicity. 

 

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 4.3 and 0.2 times the 

estimated clinical exposure. 

 

 

6. PHARMACEUTICAL PARTICULARS 

 

6.1 List of excipients 
 

Butylated hydroxytoluene (E321) 

Magnesium stearate 

Lactose monohydrate 

Hypromellose 

Crospovidone type A 

Mannitol 

Cellulose microcrystalline 

Silica colloidal anhydrous 

 

6.2 Incompatibilities 
 

Not applicable. 

 

6.3 Shelf life 
 

Votubia 1 mg dispersible tablets 

 

2 years. 

 

Votubia 2 mg dispersible tablets 

 

3 years. 

 

Votubia 3 mg dispersible tablets 

 

3 years. 

 

Votubia 5 mg dispersible tablets 

 

3 years. 

 

The stability of the ready to use suspension has been demonstrated for 30 minutes when using an oral 

syringe or 60 minutes when using a small glass. The suspension must be administered immediately 

after preparation. If not administered within 30 minutes of preparation when using an oral syringe or 

60 minutes when using a small glass, the suspension must be discarded and a new suspension must be 

prepared. 

 

  



58 

6.4 Special precautions for storage 
 

This medicinal product does not require any special temperature storage conditions. 

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

 

6.5 Nature and contents of container 

 

Aluminium/polyamide/aluminium/PVC perforated unit-dose blister containing 10 x 1 dispersible 

tablets. 

 

Votubia 1 mg dispersible tablets 

 

Packs containing 30 x 1 dispersible tablets. 

 

Votubia 2 mg dispersible tablets 

 

Packs containing 10 x 1, 30 x 1 or 100 x 1 dispersible tablets. 

 

Votubia 3 mg dispersible tablets 

 

Packs containing 30 x 1 or 100 x 1 dispersible tablets 

 

Votubia 5 mg dispersible tablets 

 

Packs containing 30 x 1 or 100 x 1 dispersible tablets 

 

Not all pack sizes may be marketed. 

 

6.6 Special precautions for disposal and other handling 
 

Instructions for use and handling 

 

Using an oral syringe 

The prescribed dose of Votubia dispersible tablets should be placed in a 10 ml oral dosing syringe 

graduated in 1 ml increments. A total of 10 mg of Votubia dispersible tablets per syringe using a 

maximum of 5 dispersible tablets must not be exceeded. If a higher dose or number of tablets is 

required, an additional syringe must be prepared. The dispersible tablets must not be broken or 

crushed. Approximately 5 ml of water and 4 ml of air should be drawn into the syringe. The filled 

syringe should be placed into a container (with the tip pointing up) for 3 minutes, until the Votubia 

dispersible tablets are in suspension. The syringe should be gently inverted 5 times immediately prior 

to administration. After administration of the prepared suspension, approximately 5 ml of water and 

4 ml of air should be drawn into the same syringe, and the contents should be swirled to suspend 

remaining particles. The entire contents of the syringe should be administered. 

 

Using a small glass 

The prescribed dose of Votubia dispersible tablets should be placed in a small glass (maximum size 

100 ml) containing approximately 25 ml of water. A total of 10 mg of Votubia dispersible tablets per 

glass using a maximum of 5 dispersible tablets must not be exceeded. If a higher dose or number of 

tablets is required, an additional glass must be prepared. The dispersible tablets must not be broken or 

crushed. Three minutes must be allowed for suspension to occur. The contents should be gently stirred 

with a spoon and then administered immediately. After administration of the prepared suspension, 

25 ml of water should be added and be stirred with the same spoon to re-suspend any remaining 

particles. The entire contents of the glass should be administered. 

 

A complete and illustrated set of instructions for use is provided at the end of the package leaflet 

“Instructions for use”. 

 



59 

Important information for caregivers 

 

The extent of absorption of everolimus through topical exposure is not known. Therefore caregivers 

are advised to avoid contact with the suspension. Hands should be washed thoroughly before and after 

preparation of the suspension. 

 

Disposal 

 

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

requirements. 

 

 

7. MARKETING AUTHORISATION HOLDER 
 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

8. MARKETING AUTHORISATION NUMBER(S) 

 

Votubia 1 mg dispersible tablets 

 

EU/1/11/710/016 

 

Votubia 2 mg dispersible tablets 

 

EU/1/11/710/009-011 

 

Votubia 3 mg dispersible tablets 

 

EU/1/11/710/012-013 

 

Votubia 5 mg dispersible tablets 

 

EU/1/11/710/014-015 

 

 

9. DATE OF FIRST AUTHORISATION/RENEWAL OF THE AUTHORISATION 
 

Date of first authorisation: 02 September 2011 

Date of latest renewal: 28 July 2015 

 

 

10. 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 

 

  

http://www.ema.europa.eu/


60 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX II 

 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO 

THE SAFE AND EFFECTIVE USE OF THE MEDICINAL 

PRODUCT 

 



61 

A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE 

 

Name and address of the manufacturer responsible for batch release 

 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

The printed package leaflet of the medicinal product must state the name and address of the 

manufacturer responsible for the release of the concerned batch. 
 

 

B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE 

 

Medicinal product subject to restricted medical prescription (see Annex I: Summary of Product 

Characteristics, section 4.2). 

 

 

C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING 

AUTHORISATION 

 

 Periodic Safety Update Reports 

The requirements for submission of periodic safety update reports for this medicinal product are set 

out in the list of Union reference dates (EURD list) provided for under Article 107c(7) of Directive 

2001/83/EC and any subsequent updates published on the European medicines web-portal. 

 

 

D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND 

EFFECTIVE USE OF THE MEDICINAL PRODUCT 

 

 Risk Management Plan (RMP) 
The MAH shall perform the required pharmacovigilance activities and interventions detailed in the 

agreed RMP presented in Module 1.8.2 of the Marketing Authorisation and any agreed subsequent 

updates of the RMP. 

 

An updated RMP should be submitted: 

 At the request of the European Medicines Agency; 

 Whenever the risk management system is modified, especially as the result of new information 
being received that may lead to a significant change to the benefit/risk profile or as the result of 

an important (pharmacovigilance or risk minimisation) milestone being reached. 

 
  



62 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

ANNEX III 

 

LABELLING AND PACKAGE LEAFLET 

  



63 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

A. LABELLING 
  



64 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 2.5 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 2.5 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

 

10 x 1 tablets 

30 x 1 tablets 

100 x 1 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



65 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/001 10 x 1 tablets 

EU/1/11/710/002 30 x 1 tablets 

EU/1/11/710/003 100 x 1 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 2.5 mg tablets 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 
 

  



66 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 2.5 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



67 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 5 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 5 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

 

30 x 1 tablets 

100 x 1 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 



68 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/004 30 x 1 tablets 

EU/1/11/710/005 100 x 1 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 5 mg tablets 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 
 

  



69 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 5 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



70 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 10 mg tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each tablet contains 10 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Tablet 

 

10 x 1 tablets 

30 x 1 tablets 

100 x 1 tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



71 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/006 30 x 1 tablets 

EU/1/11/710/007 100 x 1 tablets 

EU/1/11/710/008 10 x 1 tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 10 mg tablets 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 
 

  



72 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 10 mg tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



73 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 1 mg dispersible tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each dispersible tablet contains 1 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersible tablet 

 

30 x 1 dispersible tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

The tablets must be dispersed in water before administration. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 



74 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/016 30 x 1 dispersible tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 1 mg dispersible tablets, abbreviated form accepted, if required for technical reasons 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



75 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 1 mg dispersible tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



76 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 2 mg dispersible tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each dispersible tablet contains 2 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersible tablet 

 

10 x 1 dispersible tablets 

30 x 1 dispersible tablets 

100 x 1 dispersible tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

The tablets must be dispersed in water before administration. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 



77 

9. SPECIAL STORAGE CONDITIONS 

 

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

 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/009 10 x 1 dispersible tablets 

EU/1/11/710/010 30 x 1 dispersible tablets 

EU/1/11/710/011 100 x 1 dispersible tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 2 mg dispersible tablets, abbreviated form accepted, if required for technical reasons 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



78 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 2 mg dispersible tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



79 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 3 mg dispersible tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each dispersible tablet contains 3 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersible tablet 

 

30 x 1 dispersible tablets 

100 x 1 dispersible tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

The tablets must be dispersed in water before administration. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



80 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/012 30 x 1 dispersible tablets 

EU/1/11/710/013 100 x 1 dispersible tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 3 mg dispersible tablets, abbreviated form accepted, if required for technical reasons 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



81 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 3 mg dispersible tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



82 

 

PARTICULARS TO APPEAR ON THE OUTER PACKAGING 

 

CARTON 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 5 mg dispersible tablets 

everolimus 

 

 

2. STATEMENT OF ACTIVE SUBSTANCE(S) 

 

Each dispersible tablet contains 5 mg everolimus. 

 

 

3. LIST OF EXCIPIENTS 

 

Contains lactose. See leaflet for further information. 

 

 

4. PHARMACEUTICAL FORM AND CONTENTS 

 

Dispersible tablet 

 

30 x 1 dispersible tablets 

100 x 1 dispersible tablets 

 

 

5. METHOD AND ROUTE(S) OF ADMINISTRATION 

 

Read the package leaflet before use. 

The tablets must be dispersed in water before administration. 

Oral use. 

 

 

6. SPECIAL WARNING THAT THE MEDICINAL PRODUCT MUST BE STORED OUT 

OF THE SIGHT AND REACH OF CHILDREN 

 

Keep out of the sight and reach of children. 

 

 

7. OTHER SPECIAL WARNING(S), IF NECESSARY 

 

 

8. EXPIRY DATE 

 

EXP 

 

 

9. SPECIAL STORAGE CONDITIONS 

 

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

 



83 

 

10. SPECIAL PRECAUTIONS FOR DISPOSAL OF UNUSED MEDICINAL PRODUCTS 

OR WASTE MATERIALS DERIVED FROM SUCH MEDICINAL PRODUCTS, IF 

APPROPRIATE 

 

 

11. NAME AND ADDRESS OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

 

12. MARKETING AUTHORISATION NUMBER(S) 

 

EU/1/11/710/014 30 x 1 dispersible tablets 

EU/1/11/710/015 100 x 1 dispersible tablets 

 

 

13. BATCH NUMBER 

 

Lot 

 

 

14. GENERAL CLASSIFICATION FOR SUPPLY 

 

 

15. INSTRUCTIONS ON USE 

 

 

16. INFORMATION IN BRAILLE 

 

Votubia 5 mg dispersible tablets, abbreviated form accepted, if required for technical reasons 

 

 

17. UNIQUE IDENTIFIER – 2D BARCODE 

 

2D barcode carrying the unique identifier included. 

 

 

18. UNIQUE IDENTIFIER - HUMAN READABLE DATA 

 

PC: 

SN: 

NN: 

  



84 

 

MINIMUM PARTICULARS TO APPEAR ON BLISTERS OR STRIPS 

 

BLISTER 

 

 

1. NAME OF THE MEDICINAL PRODUCT 

 

Votubia 5 mg dispersible tablets 

everolimus 

 

 

2. NAME OF THE MARKETING AUTHORISATION HOLDER 

 

Novartis Europharm Limited 

 

 

3. EXPIRY DATE 

 

EXP 

 

 

4. BATCH NUMBER 

 

Lot 

 

 

5. OTHER 

 

  



85 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

B. PACKAGE LEAFLET 



86 

Package leaflet: Information for the user 

 

Votubia 2.5 mg tablets 

Votubia 5 mg tablets 

Votubia 10 mg tablets 

everolimus 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Votubia is and what it is used for 

2. What you need to know before you take Votubia 

3. How to take Votubia 

4. Possible side effects 

5. How to store Votubia 

6. Contents of the pack and other information 

 

 

1. What Votubia is and what it is used for 

 

Votubia is an anti-tumour medicine which can block certain cells in the body from growing. It 

contains an active substance called everolimus which may reduce the size of kidney tumours called 

renal angiomyolipomas and brain tumours called subependymal giant cell astrocytomas (SEGA). 

These tumours are caused by a genetic disorder called tuberous sclerosis complex (TSC). 

 

Votubia tablets are used to treat: 

 TSC with angiomyolipoma of the kidney in adults who do not require immediate surgery. 

 SEGA associated with TSC in adults and children for whom surgery is not appropriate. 
 

 

2. What you need to know before you take Votubia 

 

If you are being treated for TSC with angiomyolipoma of the kidney, Votubia will only be prescribed 

for you by a doctor with experience in treating patients with TSC. 

 

If you are being treated for SEGA associated with TSC, Votubia will only be prescribed by a doctor 

with experience in treating patients with SEGA and with access to blood tests which will measure how 

much Votubia is in your blood. 

 

Follow all the doctor’s instructions carefully. They may differ from the general information contained 

in this leaflet. If you have any questions about Votubia or why it has been prescribed for you, ask your 

doctor. 

 

Do not take Votubia 

 if you are allergic to everolimus, to related substances such as sirolimus or temsirolimus, or to 
any of the other ingredients of this medicine (listed in section 6). 

If you had allergic reactions before, please ask your doctor for advice. 

 



87 

Warnings and precautions 

Talk to your doctor before taking Votubia: 

 if you have any problems with your liver or if you have ever had any disease which may have 
affected your liver. If this is the case, your doctor may need to prescribe a different dose of 

Votubia or stop treatment, either for a short time or permanently. 

 if you have diabetes (high level of sugar in your blood). Votubia may increase blood sugar 
levels and worsen diabetes mellitus. This may result in the need for insulin and/or oral 

antidiabetic agent therapy. Tell your doctor if you experience any excessive thirst or increased 

frequency of urination. 

 if you need to receive a vaccine while taking Votubia as vaccination may be less effective. For 
children with SEGA, it is important to have a discussion with the doctor about the childhood 

vaccination program before treatment with Votubia. 

 if you have high cholesterol. Votubia may elevate cholesterol and/or other blood fats. 

 if you have had recent major surgery, or if you still have an unhealed wound following surgery. 
Votubia may increase the risk of problems with wound healing. 

 if you have an infection. It may be necessary to treat your infection before starting Votubia. 

 if you have previously had hepatitis B, because this may occur again during treatment with 
Votubia (see section 4 ‘Possible side effects’). 

 

Votubia may also: 

 cause mouth sores (oral ulcerations). 

 weaken your immune system. Therefore, you may be at risk of getting an infection while you 
are taking Votubia. If you have fever or other signs of an infection, consult with your doctor. 

Some infections may be severe and may have fatal consequences in adults and children. 

 impact your kidney function. Therefore, your doctor will monitor your kidney function while 
you are taking Votubia. 

 cause shortness of breath, cough and fever (see section 4 ‘Possible side effects’). 
Tell your doctor immediately if you experience these symptoms. 

 

You will have blood tests before and periodically during treatment. These will check the amount of 

blood cells (white blood cells, red blood cells and platelets) in your body to see if Votubia is having an 

unwanted effect on these cells. Blood tests will also be carried out to check your kidney function 

(levels of creatinine, blood urea nitrogen or urinary protein), liver function (level of transaminases) 

and your blood sugar and lipid levels. This is because these can also be affected by Votubia. 

 

If you receive Votubia for the treatment of SEGA associated with TSC, regular blood tests are also 

necessary to measure how much Votubia is in your blood since this will help your doctor decide how 

much Votubia you need to take. 

 

Children and adolescents 

Votubia can be used in children and adolescents SEGA associated with TSC. 

 

Votubia is not to be used in children or adolescents with TSC who have angiomyolipoma of the 

kidney in the absence of SEGA, as it has not been studied in such patients. 

 

Other medicines and Votubia 
Votubia may affect the way some other medicines work. If you are taking other medicines at the same 

time as Votubia, your doctor may need to change the dose of Votubia or the other medicines. 

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

  



88 

The following may increase the risk of side effects with Votubia: 

 ketoconazole, itraconazole, voriconazole, or fluconazole and other antifungals used to treat 
fungal infections. 

 clarithromycin, telithromycin or erythromycin, antibiotics used to treat bacterial infections. 

 ritonavir, and other medicines used to treat HIV infection/AIDS. 

 verapamil or diltiazem, used to treat heart conditions or high blood pressure. 

 dronedarone, a medicine used to help regulate your heart beat. 

 ciclosporin, a medicine used to stop the body from rejecting organ transplants. 

 imatinib, used to inhibit the growth of abnormal cells. 

 angiotensin-converting enzyme (ACE) inhibitors (such as ramipril) used to treat high blood 
pressure or other cardiovascular problems. 

 

The following may reduce the effectiveness of Votubia: 

 rifampicin, used to treat tuberculosis (TB). 

 efavirenz or nevirapine, used to treat HIV infection/AIDS. 

 St. John’s wort (Hypericum perforatum), a herbal product used to treat depression and other 
conditions. 

 dexamethasone, a corticosteroid used to treat a wide variety of conditions including 
inflammatory or immune problems. 

 phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to stop seizures or fits. 
 

All medicines listed above should be avoided during your treatment with Votubia. If you are taking 

any of them, your doctor may switch you to a different medicine, or may change your dose of Votubia. 

 

If you are taking an anti-seizure medicine, a change in the dose of the anti-seizure medicine (increase 

or decrease) may make a change in the Votubia dose necessary. Your doctor will decide this. If the 

dose of your anti-seizure medicine changes, please inform your doctor. 

 

Votubia with food and drink 

Avoid grapefruit and grapefruit juice while you are on Votubia. It may increase the amount of Votubia 

in the blood, possibly to a harmful level. 

 

Pregnancy, breast-feeding and fertility 

Pregnancy 

Votubia could harm an unborn baby and is not recommended during pregnancy. Tell your doctor if 

you are pregnant or think that you may be pregnant. 

 

Women who could potentially become pregnant must use highly effective contraception during 

treatment, and for up to 8 weeks after ending treatment. If, despite these measures, you think you may 

have become pregnant, ask your doctor for advice before taking any more Votubia. 

 

Breast-feeding 

Votubia could harm a breast-fed baby. You should not breast-feed during treatment and for 2 weeks 

after the last dose of Votubia. Tell your doctor if you are breast-feeding. 

 

Fertility 

Votubia may affect male and female fertility. Talk to your doctor if you wish to have children. 

 

Driving and using machines 

If you feel unusually tired (fatigue is a common side effect), take special care when driving or using 

machines. 

 

Votubia contains lactose 

Votubia contains lactose (milk sugar). If you have been told by your doctor that you have an 

intolerance to some sugars, contact your doctor before taking this medicine. 

 



89 

 

3. How to take Votubia 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Votubia exists as tablets 

and dispersible tablets. Consistently take only the tablets or only the dispersible tablets, and never a 

combination of both. Check with your doctor or pharmacist if you are not sure. 

 

How much Votubia to take 

If you receive Votubia for the treatment of TSC with angiomyolipoma of the kidney, the usual dose is 

10 mg, to be taken once daily. 

 

A higher or lower dose may be recommended by your doctor based on your individual treatment 

needs, for example if you have problems with your liver or if you are taking certain other medicines in 

addition to Votubia. 

 

If you receive Votubia for the treatment of TSC with SEGA, your doctor will determine the dose of 

Votubia you need to take depending on: 

 your age 

 your body size 

 the health of your liver 

 other medicines you are taking. 
 

You will have blood tests during treatment with Votubia. This is to measure the amount of Votubia in 

your blood and find the best daily dose for you. 

 

If you experience certain side effects (see section 4) while you are taking Votubia, your doctor may 

lower your dose or stop treatment, either for a short time or permanently. 

 

How to take this medicine 

 Take Votubia tablets once a day. 

 Take them at the same time every day. 

 You can take them either with or without food, but you need to do this in the same way each 
day. 

 

Swallow the tablets whole with a glass of water. Do not chew or crush the tablets. If you are taking 

Votubia tablets for the treatment of TSC with SEGA and if you are unable to swallow the tablets, you 

can stir them into a glass of water: 

 Put the required number of tablets into a glass of water (approximately 30 ml). 

 Gently stir the contents of the glass until the tablets break apart (approximately 7 minutes) and 
then drink the contents immediately. 

 Refill the glass with the same amount of water (approximately 30 ml), gently stir the remaining 
content and drink the whole amount to make sure that you get the full dose of Votubia tablets. 

 If necessary, drink additional water to wash out any residues in your mouth. 
 

Special information for caregivers 

Caregivers are advised to avoid contact with suspensions of Votubia tablets. Wash hands thoroughly 

before and after preparation of the suspension. 

 

If you take more Votubia than you should 

 If you have taken too much Votubia, or if someone else accidentally takes your tablets, see a 
doctor or go to a hospital immediately. Urgent treatment may be necessary. 

 Take the carton and this leaflet, so that the doctor knows what has been taken. 
 

  



90 

If you forget to take Votubia 

If you miss a dose, take your next dose as scheduled. Do not take a double dose to make up for the 

forgotten tablets. 

 

If you stop taking Votubia 

Do not stop taking Votubia tablets unless your doctor tells you to. 

 

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

 

 

4. Possible side effects 
 

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

 

STOP taking Votubia and seek medical help immediately if you or your child experiences any of the 

following signs of an allergic reaction: 

 difficulty breathing or swallowing 

 swelling of the face, lips, tongue or throat (signs of angioedema) 

 severe itching of the skin, with a red rash or raised bumps 
 

Serious side effects of Votubia include: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Fever, cough, difficulty breathing, wheezing (signs of inflammation of the lung due to infection, 
also known as pneumonia) 

 

Common side effects (may affect up to 1 in 10 people) 

 Swelling, feeling of heaviness or tightness, pain, limited mobility of body parts (this could occur 
anywhere in the body and is a potential sign of an abnormal build-up of fluid in soft tissue due 

to a blockage in the lymphatic system, also known as lymphoedema) 

 Rash, itching, hives, difficulty breathing or swallowing, dizziness (signs of serious allergic 
reaction, also known as hypersensitivity) 

 Fever, cough, difficulty breathing, wheezing (signs of inflammation of the lung, also known as 
pneumonitis) 

 

Uncommon side effects (may affect up to 1 in 100 people) 

 Rash of small fluid-filled blisters, appearing on reddened skin (signs of viral infection that can 
be potentially severe, also known as herpes zoster) 

 Fever, chills, rapid breathing and heart rate, rash, and possibly confusion and disorientation 
(signs of serious infection, also known as sepsis) 

 

If you experience any of these side effects, tell your doctor immediately as this might have 

life-threatening consequences. 

 

Other possible side effects of Votubia include: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Upper respiratory tract infection 

 Sore throat and runny nose (nasopharyngitis) 

 Headache, pressure in the eyes, nose or cheek area (signs of inflammation of the sinuses and 
nasal passages, also known as sinusitis) 

 Urinary tract infection 

 High level of lipids (fats) in the blood (hypercholesterolaemia) 

 Decreased appetite 

 Headache 

 Cough 



91 

 Mouth ulcers 

 Diarrhoea 

 Being sick (vomiting) 

 Acne 

 Skin rash 

 Feeling tired 

 Fever 

 Menstruation disorders such as absence of periods (amenorrhoea) or irregular periods 

 Sore throat (pharyngitis) 

 Headache, dizziness, signs of high blood pressure (hypertension) 
 

Common side effects (may affect up to 1 in 10 people) 

 Middle ear infection 

 Swollen, bleeding gums (signs of gum inflammation, also known as gingivitis) 

 Skin inflammation (cellulitis) 

 High level of lipids (fats) in the blood (hyperlipidaemia, raised triglycerides) 

 Low level of phosphate in the blood (hypophosphataemia) 

 High level of sugar in the blood (hyperglycaemia) 

 Tiredness, breathlessness, dizziness, pale skin (signs of low level of red blood cells, also known 
as anaemia) 

 Fever, sore throat or mouth ulcers due to infections (signs of low level of white blood cells, also 
known as leucopenia, lymphopenia, neutropenia) 

 Spontaneous bleeding or bruising (signs of low level of platelets, also known as 
thrombocytopenia) 

 Mouth pain 

 Nose bleeds (epistaxis) 

 Stomach upset like feeling sick (nausea) 

 Abdominal pain 

 Severe pain in the lower abdomen and pelvic area that may be sharp, with menstrual 
irregularities (ovarian cyst) 

 Excess amount of gas in the bowels (flatulence) 

 Constipation 

 Abdominal pain, nausea, vomiting, diarrhoea, swelling and bloating of the abdomen (signs of 
inflammation of the stomach lining, also known as gastritis or gastroenteritis viral) 

 Dry skin, itching (pruritus) 

 An inflammatory condition of the skin characterised by redness, itching, and oozing 
liquid-filled cysts which become scaly, crusted, or hardened (dermatitis acneiform) 

 Loss of hair (alopecia) 

 Protein in the urine 

 Menstruation disorders such as heavy periods (menorrhagia) or vaginal bleeding 

 Trouble sleeping (insomnia) 

 Irritability 

 Aggression 

 High level of an enzyme called blood lactate dehydrogenase that gives information about the 
health of certain organs 

 High level of the hormone that triggers ovulation (blood luteinising hormone increased) 
 Weight loss 
 

  



92 

Uncommon side effects (may affect up to 1 in 100 people) 

 Muscle spasms, fever, red-brown urine which may be symptoms of a muscle disorder 
(rhabdomyolysis) 

 Cough with phlegm, chest pain, fever (signs of inflammation of airways, also known as 
bronchitis viral) 

 Disturbed taste (dysgeusia) 

 Menstruation disorders such as delayed periods 

 Higher level of female reproductive hormone (blood follicle stimulating hormone increased) 
 

If these side effects get severe please tell your doctor and/or pharmacist. Most of the side effects 

are mild to moderate and will generally disappear if your treatment is interrupted for a few 

days. 

 

The following side effects have been reported in patients taking everolimus for the treatment of 

conditions other than TSC: 
 Kidney disorders: altered frequency or absence of urination may be symptoms of kidney failure 

and have been observed in some patients receiving everolimus. Other symptoms may include 
altered kidney function test (increase in creatinine). 

 Symptoms of heart failure such as breathlessness, difficulty breathing when lying down, 
swelling of the feet or legs 

 Blockage or obstruction of a blood vessel (vein) in the leg (deep vein thrombosis). Symptoms 
may include swelling and/or pain in one of your legs, usually in the calf, redness or warm skin 
in the affected area 

 Problems with wound healing 

 High levels of sugar in the blood (hyperglycaemia) 
 

Hepatitis B reactivation has been observed in some patients taking everolimus. Tell your doctor if you 

experience symptoms of hepatitis B during treatment with everolimus. The first symptoms may 

include fever, skin rash, joint pain and inflammation. Other symptoms may include fatigue, loss of 

appetite, nausea, jaundice (yellowing of the skin), and pain in the upper right abdomen. Pale stools or 

dark urine may also be signs of hepatitis. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Votubia 
 

 Keep this medicine out of the sight and reach of children. 

 Do not use this medicine after the expiry date which is stated on the carton and blister foil. The 
expiry date refers to the last day of that month. 

 Do not store above 25°C. 

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

 Open the blister just before taking the Votubia tablets. 

 Do not use this medicine if the pack is damaged or shows signs of tampering. 
 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 

  

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


93 

6. Contents of the pack and other information 

 

What Votubia tablets contain 

 The active substance is everolimus. 
Each Votubia 2.5 mg tablet contains 2.5 mg of everolimus. 

Each Votubia 5 mg tablet contains 5 mg of everolimus. 

Each Votubia 10 mg tablet contains 10 mg of everolimus. 

 The other ingredients are butylated hydroxytoluene (E321), magnesium stearate, lactose 
monohydrate, hypromellose, crospovidone type A and lactose anhydrous (see section 2 “Votubia 

contains lactose”). 

 

What Votubia tablets looks like and contents of the pack 

Votubia 2.5 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with 

“LCL” on one side and “NVR” on the other. 

Votubia 5 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with “5” on 

one side and “NVR” on the other. 

Votubia 10 mg tablets are white to slightly yellowish, elongated tablets. They are engraved with 

“UHE” on one side and “NVR” on the other. 

 

Votubia 2.5 mg tablets are available in packs containing 10 x 1, 30 x 1 or 100 x 1 tablets in perforated 

unit-dose blisters of 10 x 1 tablets each. 

Votubia 5 mg tablets are available in packs containing 30 x 1 or 100 x 1 tablets in perforated unit-dose 

blisters of 10 x 1 tablets each. 

Votubia 10 mg tablets are available in packs containing 10 x 1, 30 x 1 or 100 x 1 tablets in perforated 

unit-dose blisters of 10 x 1 tablets each. 

 

Not all pack sizes or strengths may be marketed in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

  



94 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 
SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 
Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 
Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 
Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 
Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 
Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 
Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 
Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 
Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 
Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



95 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 

 

http://www.ema.europa.eu/


96 

Package leaflet: Information for the user 

 

Votubia 1 mg dispersible tablets 

Votubia 2 mg dispersible tablets 

Votubia 3 mg dispersible tablets 

Votubia 5 mg dispersible tablets 

everolimus 

 

Read all of this leaflet carefully before you start taking this medicine because it contains 

important information for you. 
- Keep this leaflet. You may need to read it again. 
- If you have any further questions, ask your doctor or pharmacist. 
- This medicine has been prescribed for you only. Do not pass it on to others. It may harm them, 

even if their signs of illness are the same as yours. 

- If you get any side effects, talk to your doctor or pharmacist. This includes any possible side 
effects not listed in this leaflet. See section 4. 

 

What is in this leaflet 
 

1. What Votubia is and what it is used for 

2. What you need to know before you take Votubia 

3. How to take Votubia 

4. Possible side effects 

5. How to store Votubia 

6. Contents of the pack and other information 

 

 

1. What Votubia is and what it is used for 

 

Votubia dispersible tablets contain an active substance called everolimus. It is used to treat children 

aged 2 years and above and adults with partial seizures with or without secondary generalisation 

(epilepsy) associated with a genetic disorder called tuberous sclerosis complex (TSC) and which are 

not controlled by other antiepileptic medicines. Partial seizures start by only affecting one side of the 

brain but can spread and extend to larger areas on both sides of the brain (called a “secondary 

generalisation”). Votubia dispersible tablets are given together with other medicines for epilepsy. 

 

Votubia is also an anti-tumour medicine which can block certain cells in the body from growing. It 

may reduce the size of brain tumours called subependymal giant cell astrocytomas (SEGA) which are 

also caused by TSC. 

 

Votubia dispersible tablets are used to treat SEGA associated with TSC in adults and children for 

whom surgery is not appropriate. 

 

 

2. What you need to know before you take Votubia 

 

Votubia will only be prescribed by a doctor with experience in treating patients with SEGA or seizures 

and with access to blood tests which will measure how much Votubia is in your blood. 

 

Follow all the doctor’s instructions carefully. They may differ from the general information contained 

in this leaflet. If you have any questions about Votubia or why it has been prescribed for you, ask your 

doctor. 

 

Do not take Votubia 

 if you are allergic to everolimus, to related substances such as sirolimus or temsirolimus, or to 
any of the other ingredients of this medicine (listed in section 6). 

If you had allergic reactions before, please ask your doctor for advice. 



97 

 

Warnings and precautions 

Talk to your doctor before taking Votubia: 

 if you have any problems with your liver or if you have ever had any disease which may have 
affected your liver. If this is the case, your doctor may need to prescribe a different dose of 

Votubia or stop treatment, either for a short time or permanently. 

 if you have diabetes (high level of sugar in your blood). Votubia may increase blood sugar 
levels and worsen diabetes mellitus. This may result in the need for insulin and/or oral 

antidiabetic agent therapy. Tell your doctor if you experience any excessive thirst or increased 

frequency of urination. 

 if you need to receive a vaccine while taking Votubia as vaccination may be less effective. For 
children with SEGA or seizures, it is important to have a discussion with the doctor about the 

childhood vaccination program before treatment with Votubia. 

 if you have high cholesterol. Votubia may elevate cholesterol and/or other blood fats. 

 if you have had recent major surgery, or if you still have an unhealed wound following surgery. 
Votubia may increase the risk of problems with wound healing. 

 if you have an infection. It may be necessary to treat your infection before starting Votubia. 

 if you have previously had hepatitis B, because this may occur again during treatment with 
Votubia (see section 4 ‘Possible side effects’). 

 

Votubia may also: 

 cause mouth sores (oral ulcerations). 

 cause mouth sores (oral ulcerations). 

 weaken your immune system. Therefore, you may be at risk of getting an infection while you 
are taking Votubia. If you have fever or other signs of an infection, consult with your doctor. 

Some infections may be severe and may have fatal consequences in adults and children. 

 impact your kidney function. Therefore, your doctor will monitor your kidney function while 
you are taking Votubia. 

 cause shortness of breath, cough and fever (see section 4 ‘Possible side effects’). 
Tell your doctor immediately if you experience these symptoms. 

 

You will have blood tests before and periodically during treatment. These will check the amount of 

blood cells (white blood cells, red blood cells and platelets) in your body to see if Votubia is having an 

unwanted effect on these cells. Blood tests will also be carried out to check your kidney function 

(levels of creatinine, blood urea nitrogen or urinary protein), liver function (level of transaminases) 

and your blood sugar and lipid levels. This is because these can also be affected by Votubia. 

 

Regular blood tests are also necessary to measure how much Votubia is in your blood since this will 

help your doctor decide how much Votubia you need to take. 

 

Children and adolescents 

Votubia can be used in children and adolescents with SEGA associated with TSC. 

 

Votubia is not to be used in children below the age of 2 years with TSC and seizures. 

 

Other medicines and Votubia 
Votubia may affect the way some other medicines work. If you are taking other medicines at the same 

time as Votubia, your doctor may need to change the dose of Votubia or the other medicines. 

 

Tell your doctor or pharmacist if you are taking, have recently taken or might take any other 

medicines. 

 

  



98 

The following may increase the risk of side effects with Votubia: 

 ketoconazole, itraconazole, voriconazole, or fluconazole and other antifungals used to treat 
fungal infections. 

 clarithromycin, telithromycin or erythromycin, antibiotics used to treat bacterial infections. 

 ritonavir, and other medicines used to treat HIV infection/AIDS. 

 verapamil or diltiazem, used to treat heart conditions or high blood pressure. 

 dronedarone, a medicine used to help regulate your heart beat. 

 ciclosporin, a medicine used to stop the body from rejecting organ transplants. 

 imatinib, used to inhibit the growth of abnormal cells. 

 angiotensin-converting enzyme (ACE) inhibitors (such as ramipril) used to treat high blood 
pressure or other cardiovascular problems. 

 

The following may reduce the effectiveness of Votubia: 

 rifampicin, used to treat tuberculosis (TB). 

 efavirenz or nevirapine, used to treat HIV infection/AIDS. 

 St. John’s wort (Hypericum perforatum), a herbal product used to treat depression and other 
conditions. 

 dexamethasone, a corticosteroid used to treat a wide variety of conditions including 
inflammatory or immune problems. 

 phenytoin, carbamazepine or phenobarbital and other anti-epileptics used to stop seizures or fits. 
 

All medicines listed above should be avoided during your treatment with Votubia. If you are taking 

any of them, your doctor may switch you to a different medicine, or may change your dose of Votubia. 

 

If you are taking an anti-seizure medicine, a change in the dose of the anti-seizure medicine (increase 

or decrease) may make a change in the Votubia dose necessary. Your doctor will decide this. If the 

dose of your anti-seizure medicine changes, please inform your doctor. 

 

If you are following a specific diet to reduce the frequency of your seizures, please inform your doctor 

before taking Votubia. 

 

Votubia with food and drink 

Avoid grapefruit and grapefruit juice while you are on Votubia. It may increase the amount of Votubia 

in the blood, possibly to a harmful level. 

 

Pregnancy, breast-feeding and fertility 

Pregnancy 

Votubia could harm an unborn baby and is not recommended during pregnancy. Tell your doctor if 

you are pregnant or think that you may be pregnant. 

 

Women who could potentially become pregnant must use highly effective contraception during 

treatment, and for up to 8 weeks after ending treatment. If, despite these measures, you think you may 

have become pregnant, ask your doctor for advice before taking any more Votubia. 

 

Breast-feeding 

Votubia could harm a breast-fed baby. You should not breast-feed during treatment and for 2 weeks 

after the last dose of Votubia. Tell your doctor if you are breast-feeding. 

 

Fertility 

Votubia may affect male and female fertility. Talk to your doctor if you wish to have children. 

 

  



99 

Driving and using machines 

If you feel unusually tired (fatigue is a common side effect), take special care when driving or using 

machines. 

 

Votubia contains lactose 

Votubia contains lactose (milk sugar). If you have been told by your doctor that you have an 

intolerance to some sugars, contact your doctor before taking this medicine. 

 

 

3. How to take Votubia 

 

Always take this medicine exactly as your doctor or pharmacist has told you. Votubia exists as tablets 

and dispersible tablets. Consistently take only the tablets or only the dispersible tablets, and never a 

combination of both. Check with your doctor or pharmacist if you are not sure. 

 

How much Votubia to take 

Your doctor will determine the dose of Votubia you need to take depending on: 

 your age 

 your body size 

 the health of your liver 

 other medicines you are taking. 
 

You will have blood tests during treatment with Votubia. This is to measure the amount of Votubia in 

your blood and find the best daily dose for you. 

 

If you experience certain side effects (see section 4) while you are taking Votubia, your doctor may 

lower your dose or stop treatment, either for a short time or permanently. 

 

How to take this medicine 

 Take Votubia dispersible tablets once a day. 

 Take them at the same time every day. 

 You can take them either with or without food, but you need to do this in the same way each 
day. 

 

Take Votubia dispersible tablets as an oral suspension only 

Do not chew or crush the dispersible tablets. Do not swallow them whole. You must mix the 

dispersible tablets with water to create a cloudy liquid (known as an oral suspension). 

 

How to prepare and take the oral suspension 

Prepare the oral suspension by mixing the dispersible tablets with water either in an oral syringe or in 

a small glass. You must drink the suspension immediately after preparing it. If you do not drink it 

within 30 minutes when using an oral syringe or within 60 minutes when using a small glass, throw it 

away and prepare a new suspension. Please read the detailed instructions at the end of this leaflet to 

find out how to do this. Ask your doctor or pharmacist if you are not sure. 

 

Special information for caregivers 

Caregivers are advised to avoid contact with suspensions of Votubia dispersible tablets. Wash hands 

thoroughly before and after preparation of the suspension. 

 

If you take more Votubia than you should 

 If you have taken too much Votubia, or if someone else accidentally takes your dispersible 
tablets, see a doctor or go to a hospital immediately. Urgent treatment may be necessary. 

 Take the carton and this leaflet, so that the doctor knows what has been taken. 
 

  



100 

If you forget to take Votubia 

If you miss a dose, take your next dose as scheduled. Do not take a double dose to make up for the 

forgotten dispersible tablets. 

 

If you stop taking Votubia 

Do not stop taking Votubia dispersible tablets unless your doctor tells you to. 

 

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

 

 

4. Possible side effects 
 

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

 

STOP taking Votubia and seek medical help immediately if you or your child experiences any of the 

following signs of an allergic reaction: 

 difficulty breathing or swallowing 

 swelling of the face, lips, tongue or throat (signs of angioedema) 

 severe itching of the skin, with a red rash or raised bumps 
 

Serious side effects of Votubia include: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Fever, cough, difficulty breathing, wheezing (signs of inflammation of the lung due to infection, 
also known as pneumonia) 

 

Common side effects (may affect up to 1 in 10 people) 

 Swelling, feeling of heaviness or tightness, pain, limited mobility of body parts (this could occur 
anywhere in the body and is a potential sign of an abnormal build-up of fluid in soft tissue due 

to a blockage in the lymphatic system, also known as lymphoedema) 

 Rash, itching, hives, difficulty breathing or swallowing, dizziness (signs of serious allergic 
reaction, also known as hypersensitivity) 

 Fever, cough, difficulty breathing, wheezing (signs of inflammation of the lung, also known as 
pneumonitis) 

 

Uncommon side effects (may affect up to 1 in 100 people) 

 Rash of small fluid-filled blisters, appearing on reddened skin (signs of viral infection that can 
be potentially severe, also known as herpes zoster) 

 Fever, chills, rapid breathing and heart rate, rash, and possibly confusion and disorientation 
(signs of serious infection, also known as sepsis) 

 

If you experience any of these side effects, tell your doctor immediately as this might have 

life-threatening consequences. 

 

Other possible side effects of Votubia include: 

 

Very common side effects (may affect more than 1 in 10 people) 

 Upper respiratory tract infection 

 Sore throat and runny nose (nasopharyngitis) 

 Headache, pressure in the eyes, nose or cheek area (signs of inflammation of the sinuses and 
nasal passages, also known as sinusitis) 

 Urinary tract infection 

 High level of lipids (fats) in the blood (hypercholesterolaemia) 

 Decreased appetite 

 Headache 

 Cough 



101 

 Mouth ulcers 

 Diarrhoea 

 Being sick (vomiting) 

 Acne 

 Skin rash 

 Feeling tired 

 Fever 

 Menstruation disorders such as absence of periods (amenorrhoea) or irregular periods 

 Sore throat (pharyngitis) 

 Headache, dizziness, signs of high blood pressure (hypertension) 
 

Common side effects (may affect up to 1 in 10 people) 

 Middle ear infection 

 Swollen, bleeding gums (signs of gum inflammation, also known as gingivitis) 

 Skin inflammation (cellulitis) 

 High level of lipids (fats) in the blood (hyperlipidaemia, raised triglycerides) 

 Low level of phosphate in the blood (hypophosphataemia) 

 High level of sugar in the blood (hyperglycaemia) 

 Tiredness, breathlessness, dizziness, pale skin (signs of low level of red blood cells, also known 
as anaemia) 

 Fever, sore throat or mouth ulcers due to infections (signs of low level of white blood cells, also 
known as leucopenia, lymphopenia, neutropenia) 

 Spontaneous bleeding or bruising (signs of low level of platelets, also known as 
thrombocytopenia) 

 Mouth pain 

 Nose bleeds (epistaxis) 

 Stomach upset like feeling sick (nausea) 

 Abdominal pain 

 Severe pain in the lower abdomen and pelvic area that may be sharp, with menstrual 
irregularities (ovarian cyst) 

 Excess amount of gas in the bowels (flatulence) 

 Constipation 

 Abdominal pain, nausea, vomiting, diarrhoea, swelling and bloating of the abdomen (signs of 
inflammation of the stomach lining, also known as gastritis or gastroenteritis viral) 

 Dry skin, itching (pruritus) 

 An inflammatory condition of the skin characterised by redness, itching, and oozing 
liquid-filled cysts which become scaly, crusted, or hardened (dermatitis acneiform) 

 Loss of hair (alopecia) 

 Protein in the urine 

 Menstruation disorders such as heavy periods (menorrhagia) or vaginal bleeding 

 Trouble sleeping (insomnia) 

 Irritability 

 Aggression 

 High level of an enzyme called blood lactate dehydrogenase that gives information about the 
health of certain organs 

 High level of the hormone that triggers ovulation (blood luteinising hormone increased) 
 Weight loss 
 

  



102 

Uncommon side effects (may affect up to 1 in 100 people) 

 Muscle spasms, fever, red-brown urine which may be symptoms of a muscle disorder 
(rhabdomyolysis) 

 Cough with phlegm, chest pain, fever (signs of inflammation of airways, also known as 
bronchitis viral) 

 Disturbed taste (dysgeusia) 

 Menstruation disorders such as delayed periods 

 Higher level of female reproductive hormone (blood follicle stimulating hormone increased) 
 

If these side effects get severe please tell your doctor and/or pharmacist. Most of the side effects 

are mild to moderate and will generally disappear if your treatment is interrupted for a few 

days. 

 

The following side effects have been reported in patients taking everolimus for the treatment of 

conditions other than TSC: 
 Kidney disorders: altered frequency or absence of urination may be symptoms of kidney failure 

and have been observed in some patients receiving everolimus. Other symptoms may include 
altered kidney function test (increase in creatinine). 

 Symptoms of heart failure such as breathlessness, difficulty breathing when lying down, 
swelling of the feet or legs 

 Blockage or obstruction of a blood vessel (vein) in the leg (deep vein thrombosis). Symptoms 
may include swelling and/or pain in one of your legs, usually in the calf, redness or warm skin 
in the affected area 

 Problems with wound healing 

 High levels of sugar in the blood (hyperglycaemia) 
 

Hepatitis B reactivation has been observed in some patients taking everolimus. Tell your doctor if you 

experience symptoms of hepatitis B during treatment with everolimus. The first symptoms may 

include fever, skin rash, joint pain and inflammation. Other symptoms may include fatigue, loss of 

appetite, nausea, jaundice (yellowing of the skin), and pain in the upper right abdomen. Pale stools or 

dark urine may also be signs of hepatitis. 

 

Reporting of side effects 

If you get any side effects, talk to your doctor or pharmacist. This includes any possible side effects 

not listed in this leaflet. You can also report side effects directly via the national reporting system 

listed in Appendix V. By reporting side effects you can help provide more information on the safety of 

this medicine. 

 

 

5. How to store Votubia 
 

 Keep this medicine out of the sight and reach of children. 

 Do not use this medicine after the expiry date which is stated on the carton and blister foil. The 
expiry date refers to the last day of that month. 

 This medicine does not require any special temperature storage conditions. 

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

 Open the blister just before taking Votubia dispersible tablets. 

 The stability of the ready to use suspension has been demonstrated for 60 minutes. After 
preparation the suspension must be taken straight away. If you do not use it within 60 minutes, 

throw it away and prepare a new suspension. 

 Do not use this medicine if the pack is damaged or shows signs of tampering. 
 

Do not throw away any medicines via wastewater or household waste. Ask your pharmacist how to 

throw away medicines you no longer use. These measures will help to protect the environment. 

 

 

http://www.ema.europa.eu/docs/en_GB/document_library/Template_or_form/2013/03/WC500139752.doc


103 

6. Contents of the pack and other information 

 

What Votubia dispersible tablets contain 

 The active substance is everolimus. 
Each Votubia 1 mg dispersible tablet contains 1 mg of everolimus. 

Each Votubia 2 mg dispersible tablet contains 2 mg of everolimus. 

Each Votubia 3 mg dispersible tablet contains 3 mg of everolimus. 

Each Votubia 5 mg dispersible tablet contains 5 mg of everolimus. 

 The other ingredients are butylated hydroxytoluene (E321), magnesium stearate, lactose 
monohydrate, hypromellose, crospovidone type A, mannitol, cellulose microcrystalline and 

silica colloidal anhydrous (see section 2 “Votubia contains lactose”). 

 

What Votubia dispersible tablets looks like and contents of the pack 

Votubia 1 mg dispersible tablets are white to slightly yellowish, round, flat tablets with a bevelled 

edge and no score. They are engraved with “D1” on one side and “NVR” on the other. 

Votubia 2 mg dispersible tablets are white to slightly yellowish, round, flat tablets with a bevelled 

edge and no score. They are engraved with “D2” on one side and “NVR” on the other. 

Votubia 3 mg dispersible tablets are white to slightly yellowish, round, flat tablets with a bevelled 

edge and no score. They are engraved with “D3” on one side and “NVR” on the other. 

Votubia 5 mg dispersible tablets are white to slightly yellowish, round, flat tablets with a bevelled 

edge and no score. They are engraved with “D5” on one side and “NVR” on the other. 

 

Votubia 1 mg dispersible tablets are available in packs containing 30 dispersible tablets in perforated 

unit-dose blisters of 10 x 1 tablets each. 

Votubia 2 mg dispersible tablets are available in packs containing 10 x 1, 30 x 1 or 100 x 1 dispersible 

tablets in perforated unit-dose blisters of 10 x 1 tablets each. 

Votubia 3 mg and Votubia 5 mg dispersible tablets are available in packs containing 30 x 1 or 

100 x1 dispersible tablets in perforated unit-dose blisters of 10 x 1 tablets each. 

 

Not all pack sizes or strengths may be marketed in your country. 

 

Marketing Authorisation Holder 

Novartis Europharm Limited 

Vista Building 

Elm Park, Merrion Road 

Dublin 4 

Ireland 

 

Manufacturer 

Novartis Farmacéutica SA 

Ronda de Santa Maria 158 

08210 Barberà del Vallès, Barcelona 

Spain 

 

Novartis Pharma GmbH 

Roonstrasse 25 

D-90429 Nuremberg 

Germany 

 

  



104 

For any information about this medicine, please contact the local representative of the Marketing 

Authorisation Holder: 

 

België/Belgique/Belgien 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Lietuva 
SIA Novartis Baltics Lietuvos filialas 

Tel: +370 5 269 16 50 

 

България 

Novartis Bulgaria EOOD 

Тел.: +359 2 489 98 28 

 

Luxembourg/Luxemburg 
Novartis Pharma N.V. 

Tél/Tel: +32 2 246 16 11 

 

Česká republika 
Novartis s.r.o. 

Tel: +420 225 775 111 

 

Magyarország 

Novartis Hungária Kft. 

Tel.: +36 1 457 65 00 

Danmark 
Novartis Healthcare A/S 

Tlf: +45 39 16 84 00 

 

Malta 

Novartis Pharma Services Inc. 

Tel: +356 2122 2872 

Deutschland 
Novartis Pharma GmbH 

Tel: +49 911 273 0 

 

Nederland 
Novartis Pharma B.V. 

Tel: +31 88 04 52 555 

Eesti 

SIA Novartis Baltics Eesti filiaal 

Tel: +372 66 30 810 

 

Norge 
Novartis Norge AS 

Tlf: +47 23 05 20 00 

Ελλάδα 
Novartis (Hellas) A.E.B.E. 

Τηλ: +30 210 281 17 12 

 

Österreich 
Novartis Pharma GmbH 

Tel: +43 1 86 6570 

España 

Novartis Farmacéutica, S.A. 

Tel: +34 93 306 42 00 

 

Polska 

Novartis Poland Sp. z o.o. 

Tel.: +48 22 375 4888 

France 

Novartis Pharma S.A.S. 

Tél: +33 1 55 47 66 00 

 

Portugal 
Novartis Farma - Produtos Farmacêuticos, S.A. 

Tel: +351 21 000 8600 

Hrvatska 

Novartis Hrvatska d.o.o. 

Tel. +385 1 6274 220 

 

România 

Novartis Pharma Services Romania SRL 

Tel: +40 21 31299 01 

Ireland 
Novartis Ireland Limited 

Tel: +353 1 260 12 55 

 

Slovenija 
Novartis Pharma Services Inc. 

Tel: +386 1 300 75 50 

Ísland 

Vistor hf. 

Sími: +354 535 7000 

 

Slovenská republika 

Novartis Slovakia s.r.o. 

Tel: +421 2 5542 5439 

 

Italia 
Novartis Farma S.p.A. 

Tel: +39 02 96 54 1 

Suomi/Finland 
Novartis Finland Oy 

Puh/Tel: +358 (0)10 6133 200 

 



105 

Κύπρος 

Novartis Pharma Services Inc. 

Τηλ: +357 22 690 690 

 

Sverige 

Novartis Sverige AB 

Tel: +46 8 732 32 00 

 

Latvija 

SIA Novartis Baltics 

Tel: +371 67 887 070 

 

United Kingdom 

Novartis Pharmaceuticals UK Ltd. 

Tel: +44 1276 698370 

 

 

This leaflet was last revised in 

 

Other sources of information 

Detailed information on this medicine is available on the European Medicines Agency website: 

http://www.ema.europa.eu 



106 

INSTRUCTIONS FOR USE 

 

Read and follow these instructions carefully so that you know how to correctly prepare the 

medicine. This will look like a cloudy liquid (known as an oral suspension). 

 

Use an oral syringe or a small glass for preparing and taking the Votubia suspension only – do 

not use it for anything else. 

 

Important information: 

 

Take Votubia dispersible tablets as a suspension only. 

 

These instructions are for taking a dose between 1 mg and 10 mg. 

 The most you can take at one time using the oral syringe or small glass is 10 mg, using a 
maximum of 5 dispersible tablets. 

 If you need to take a higher dose or need to use more than 5 dispersible tablets, split the dose 
and repeat the steps using the same oral syringe or small glass. 

 Ask your doctor or pharmacist about how to split the dose if you are not sure. 
 

Caregivers should try to avoid skin contact with the oral suspension. Keep the medicine out of the 

reach of children. 

 

Only use water (drinkable tap water or non-sparkling bottled water) to prepare the oral suspension. Do 

not use juice or any other liquids. 

 

The patient must drink the suspension immediately after it is prepared. If the patient does not drink it 

within 30 minutes if an oral syringe has been used or within 60 minutes if a small glass has been used, 

throw it away and prepare a new suspension. 

 

Instructions for caregivers preparing the suspension using an oral syringe: 

 

You will need: 

 The blister with Votubia dispersible tablets 

 Scissors to open the blister 

 10 ml oral syringe with 1 ml increments (for single use): see figure below 
 2 clean glasses 

 Approximately 30 ml of water 
 

 
 

Plunger 
Barrel 

Volume 

indicators 

Tip 



107 

Getting ready 

 

1. Wash and dry your hands. 

 

 

 

 

 

2. Take the 10 ml oral syringe and pull out the plunger, 

removing it completely from the barrel of the syringe. 

 

 
 

Adding the dispersible tablets 

 

3. Use scissors to open the blister along the dotted line. Remove 

the dispersible tablets from the blister. Place them into the 

barrel of the oral syringe straight away. 

 

 

 

 
 

 

4. Re-insert the plunger into the barrel of the oral syringe. Push 

the plunger in until it touches the dispersible tablets. 

 

 
 

Adding water 

 

5. Fill a small glass with water (drinkable tap water or 

non-sparkling bottled water). Put the tip of the syringe into 

the water. Draw up about 5 ml of water by slowly pulling the 

plunger out until it is at the 5 ml mark on the syringe. 

 

Note: The amount of water in the oral syringe does not need 

to be exact but all the tablets should be covered. If any 

tablets get stuck in the dry upper part of the oral syringe, 

gently tap the oral syringe until they fall down into the water. 

 

 

 

 

Mixing the medicine 

 

6. Hold the oral syringe with the tip pointing up. Pull the 

plunger slowly down to draw in air until it is at the 9 ml 

mark on the syringe. 

 

 

 
 

7. Put the filled oral syringe in the clean, empty glass with the 

tip pointing up. Wait for 3 minutes – until the dispersible 

tablets have completely broken apart. 

 

 

 
 

3 Min 



108 

 

8. Mix the medicine by slowly turning the oral syringe upside 

down and back again five times just before using the dose. 

Do not shake it. Use the oral suspension immediately. If you 

do not use it within 30 minutes, throw it away and prepare a 

new suspension. 

 

 
 

Removing air 

 

9. Hold the oral syringe with the tip pointing upwards. Push the 

plunger up slowly to remove most of the air (it is okay for a 

small amount of air to remain around the tip). 

 

 

 
 

Taking the medicine 

 

10. Put the oral syringe into the patient’s mouth. Push the 

plunger in slowly to release the full contents of the oral 

syringe. 

 

 

 

 
 

11. Carefully remove the oral syringe from the patient’s mouth. 

 

 

Making sure all of the medicine has been taken 

 

12. Insert the tip of the oral syringe into the glass filled with 

water. Draw up 5 ml of water by slowly pulling the plunger 

up. 

 

 

 

 
 

 

13. Hold the oral syringe with the tip pointing up. Pull the 

plunger slowly down to draw in air until it is at the 9 ml 

mark on the syringe. 

 

 

 
 

 

14. With the tip of the oral syringe pointing upwards, swirl the 

water around to collect any medicine that is left inside. 

 

 
 

 

15. Hold the oral syringe with the tip pointing upward. Push the 

plunger up slowly to remove most of the air. 

 

 
 

5x 
 



109 

16. Put the oral syringe into the patient’s mouth. Push the 

plunger in slowly to release the full contents of the oral 

syringe. 

 

 
 

17. Carefully remove the oral syringe from the patient’s mouth. 

 

If the total prescribed dose is more than 10 mg or has to 

be prepared using more than 5 dispersible tablets, repeat 

steps 2 to 17 to finish giving the dose. 

 

 

Cleaning up 

 

18. Ask your pharmacist how to throw away the oral syringe. 

 

 

 

 

 

 

19. Wash and dry your hands. 

 

 

 

Instructions for patients or caregivers preparing the suspension using a small glass: 

 

You will need: 

 Blister with Votubia dispersible tablets 

 Scissors to open the blister 

 1 small glass (maximum size 100 ml) 

 30 ml dose cup for measuring water 

 Approximately 50 ml of water to prepare the suspension 

 Spoon for stirring 
 

Getting ready 

 

1. Wash and dry your hands. 

 

 

 

Adding water 

 

2. Add about 25 ml of water to the 30 ml dose cup. The amount 

of water added does not need to be exact. 

 

 
 

3. Pour the water from the dose cup into the small glass. 

 
Adding the dispersible tablets 

 

4. Use scissors to open the blister along the dotted line. Remove 

the dispersible tablets from the blister. 

 

5. Add the dispersible tablets into the water. 

 

25 ml 

of water 



110 

Mixing the medicine 

 

6. Wait for 3 minutes until the dispersible tablets have 

completely broken apart. 

 

 
 

7. Gently stir the contents of the glass with a spoon and then 

proceed immediately to step 8. 

 
 

Taking the medicine 

 

8. The patient must immediately drink all of the oral suspension 

from the glass. If the suspension is not used within 

60 minutes, throw it away and prepare a new suspension. 

 

 
 

Making sure all of the medicine has been taken 

 

9. Refill the glass with the same amount of water (about 25 ml). 

Stir the contents with the spoon to remove any medicine left 

on the glass and spoon. 

 

 
 

10 The patient must drink all of the oral suspension from the 

glass. 

If the total prescribed dose is more than 10 mg or has to 

be prepared using more than 5 dispersible tablets, repeat 

steps 2 to 10 to finish taking the dose. 

 

 
 

Cleaning up 

 

11. Wash the glass and the spoon thoroughly with clean water. 

Wipe the glass and spoon with a clean paper towel. Store 

them in a dry and clean place until next time. 

 

 
 

12. Wash and dry your hands.  
 

3 Min 
 


	SUMMARY OF PRODUCT CHARACTERISTICS
	A. MANUFACTURER RESPONSIBLE FOR BATCH RELEASE
	B. CONDITIONS OR RESTRICTIONS REGARDING SUPPLY AND USE
	C. OTHER CONDITIONS AND REQUIREMENTS OF THE MARKETING AUTHORISATION
	D. CONDITIONS OR RESTRICTIONS WITH REGARD TO THE SAFE AND EFFECTIVE USE OF THE MEDICINAL PRODUCT
	A. LABELLING
	B. PACKAGE LEAFLET