Source: European Medicines Agency (EU) Revision Year: 2022 Publisher: Novartis Europharm Limited, Vista Building, Elm Park, Merrion Road, Dublin 4, Ireland
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.
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.
Treatment with Votubia should be initiated by a physician experienced in the treatment of patients with TSC and therapeutic drug monitoring.
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.
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.
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.
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. | |
| 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
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.
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 with renal angiomyolipoma associated with TSC:
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment.
Patients with SEGA associated with TSC:
Patients <18 years of age:
Votubia is not recommended for patients <18 years of age with SEGA and hepatic impairment.
Patients ≥18 years of age:
Everolimus whole blood trough concentrations should be assessed at least 1 week after any change in hepatic status (Child-Pugh).
The safety and efficacy of Votubia in children aged 0 to 18 years with renal angiomyolipoma associated with TSC in the absence of SEGA have not been established. No data are available.
The safety, 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.
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).
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.
3 years.
Do not store above 25°C.
Store in the original package in order to protect from light and moisture.
Aluminium/polyamide/aluminium/PVC perforated unit-dose blister containing 10 × 1 tablets.
Votubia 2.5 mg tablets:
Packs containing 10 × 1, 30 × 1 or 100 × 1 tablets.
Votubia 5 mg tablets:
Packs containing 30 × 1 or 100 × 1 tablets.
Votubia 10 mg tablets:
Packs containing 10 × 1, 30 × 1 or 100 × 1 tablets.
Not all pack sizes may be marketed.
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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