Source: European Medicines Agency (EU) Revision Year: 2018 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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 tuberous sclerosis complex (TSC).
Votubia is indicated for the treatment of adult and paediatric patients with subependymal giant cell astrocytoma (SEGA) associated with tuberous sclerosis complex (TSC) who require therapeutic intervention but are not amenable to surgery.
The evidence is based on analysis of change in SEGA volume. Further clinical benefit, such as improvement in disease-related symptoms, has not been demonstrated.
Treatment with Votubia should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring.
Careful titration may be required to obtain the optimal therapeutic effect. Doses that will be tolerated and effective vary between patients. Concomitant antiepileptic therapy may affect the metabolism of everolimus and may contribute to this variance (see section 4.5).
Dosing is individualised based on Body Surface Area (BSA) using the Dubois formula, where weight (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 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).
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).
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.
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).
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 body surface area, or every 6 to 12 months in patients with stable body surface area, 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.
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).
Table 2 Votubia dose adjustment recommendations:
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.
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).
No dose adjustment is required (see section 5.2).
No dose adjustment is required (see section 5.2).
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:
Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).
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.
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.
Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been given with acceptable acute tolerability in the adult population.
It is essential to assess everolimus blood levels in cases of suspected overdose. General supportive measures should be initiated in all cases of overdose. Everolimus is not considered dialysable to any relevant degree (less than 10% was removed within 6 hours of haemodialysis).
A limited number of paediatric patients have been exposed to doses higher than 10 mg/m²/day. No signs of acute toxicity have been reported in these cases.
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.
This medicinal product does not require any special temperature storage conditions. Store in the original package in order to protect from light and moisture.
Aluminium/polyamide/aluminium/PVC perforated unit-dose blister containing 10 × 1 dispersible tablets.
Votubia 1 mg dispersible tablets: Packs containing 30 × 1 dispersible tablets.
Votubia 2 mg dispersible tablets: Packs containing 10 × 1, 30 × 1 or 100 × 1 dispersible tablets.
Votubia 3 mg dispersible tablets: Packs containing 30 × 1 or 100 × 1 dispersible tablets.
Votubia 5 mg dispersible tablets: Packs containing 30 × 1 or 100 × 1 dispersible tablets.
Not all pack sizes may be marketed.
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.
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”.
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.
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