Posology : מינונים

4.2   Posology and method of administration

Dosage/Administration
Treatment with Votubia should be initiated by a physician experienced in therapeutic drug monitoring and the treatment of patients with tuberous sclerosis complex (TSC).

Votubia should be taken orally once daily at the same time every day, either consistently with or consistently without food.

The patient should not make up for a missed dose, but should take the next prescribed dose as usual.

Treatment should continue as long as a clinical benefit is observed or until unacceptable toxicity occurs.Votubia dispersible tablets are recommended only for the treatment of TSC patients with refractory epileptic seizures who are undergoing therapeutic drug monitoring.

Votubia dispersible tablets disintegrate quickly in water, forming a suspension that can be prepared in an oral syringe or in a small drinking glass. The suspension may only be prepared with water. The suspension should be administered immediately following preparation. If the suspension cannot be used within 60 minutes of preparation, it must be discarded.

Dosing
Careful titration, with monitoring of everolimus blood concentration using a validated test, is required in order to obtain the optimal therapeutic effect. If possible, the same test method and the same laboratory should be used for therapeutic drug monitoring over the whole course of treatment.

Concomitant anticonvulsant therapy may affect the metabolism of everolimus (see section 4.5 ).

Dosing is individualised based on body surface area (BSA, in m2).

Starting dose and target trough concentration:
The recommended starting daily dose of Votubia dispersible tablets is shown in Table 1. The starting dose should be rounded to the nearest available strength of Votubia dispersible tablets. Different strengths can be combined to attain the desired dose. Dosing should be titrated to attain a trough concentration of 5 to 15 ng/ml.



Table 1       Votubia starting dose in TSC with refractory epileptic seizures 
Age                         Starting dose without                Starting dose with co-administration of                 co-administration of
CYP3A4/P-gp inducers                 CYP3A4/P-gp inducers
<6 years                    6 mg/m2                              9 mg/m2 ≥6 years                    5 mg/m2                              8 mg/m2 

Dose monitoring, titration and long-term dose monitoring
Dose monitoring: The everolimus blood trough concentration should be measured approximately 1 to 2 weeks after the initial dose, after any change in dose or pharmaceutical form, after initiation of or change in concomitant treatment with CYP3A4/P-gp inhibitors, after any change in hepatic status (Child-Pugh) and approximately 2 weeks after initiation of or change in concomitant treatment with CYP3A4/P-gp inducers.

Titration: Individualised dosing should be titrated by increasing the dose by increments of 2 to 4 mg to attain the target trough concentration for optimal clinical response. Efficacy, safety,
concomitant medication and the current trough concentration should be considered when planning dose titration. Individualised dose titration can be based on a simple proportion equation: 
New everolimus dose = current dose × (target concentration/current concentration) 
The trough concentration should be assessed 1 to 2 weeks after a change in dose.

Long-term dose monitoring:
Once a stable target dose is attained, the trough concentration should be checked in patients with a changing body surface area every 3 to 6 months and in patients with an unchanged body surface area every 6 to 12 months for the duration of treatment.



Dose modifications
Adverse effects:
Severe and/or intolerable adverse drug reactions (ADRs) may require temporary interruption of treatment, with or without dose reduction, or discontinuation of treatment with Votubia. If dose reduction is required, a dose approximately 50% lower than the daily dose previously administered is recommended.

If dose reductions cannot be implemented using the lowest dosage strength, alternate-day dosing should be considered (see section 4.4)

Dose reduction, interruption or discontinuation of treatment, as well as any measures to manage adverse effects, should be based on the clinical judgement of the treating physician and an individual benefit-risk assessment.

• For grade 1 adverse reactions, no dose adjustment is normally required.

• For grade 2 adverse reactions, temporary interruption of treatment until the ADR improves to grade ≤1 may be necessary. In most cases treatment may subsequently be resumed at the same dose. In the case of pneumonitis, Votubia treatment should be resumed at a lower dose.

• For grade 3 adverse reactions, temporary interruption of treatment until the ADR improves to grade ≤1 is necessary. Votubia treatment may subsequently be resumed at a lower dose.

• For grade 4 adverse reactions, treatment with Votubia should be discontinued, except in the case of thrombocytopenia and neutropenia.

Moderate CYP3A4/P-gp inhibitors
In combination with moderate CYP3A4 or P-gp inhibitors, the Votubia dose should generally be reduced by 50%.

The everolimus trough concentration should be assessed approximately 1 to 2 weeks after co- administration of a moderate CYP3A4/P-gp inhibitor. If the moderate inhibitor is discontinued, the Votubia dose should be returned to that used before initiation of the moderate CYP3A4/P-gp inhibitor, and the trough concentration should be re-assessed approximately 2 weeks later (see section 4.4 and section 4.5.

Strong CYP3A4 inducers
Co-administration of Votubia and a strong inducer of its metabolism should be avoided if possible (see section 4.5). However, enzyme-inducing antiepileptic drugs may become necessary in these patients.

•   Patients with epileptic seizures receiving concomitant strong CYP3A4 inducers (e.g. enzyme- inducing antiepileptics such as carbamazepine, phenobarbital and phenytoin) at the start of treatment with Votubia require an increased everolimus starting dose to attain trough concentrations of 5 to 15 ng/ml (see dosage recommendations in Table 1). The dose should be further adjusted by increments of 2 to 4 mg as necessary to maintain the target trough concentration.

•   For TSC patients with epileptic seizures not receiving concomitant strong CYP3A4 inducers at the start of treatment with Votubia, the addition of a strong inducer may require an increased everolimus dose. The daily dose should be doubled, and tolerability assessed. The everolimus trough concentration should be assessed approximately two weeks after doubling the dose, and the dose further adjusted by increments of 2 to 4 mg as necessary to maintain the target trough concentration.

•   The addition of another strong CYP3A4 inducer may not require additional dose adjustment. The everolimus trough concentration should be assessed approximately two weeks after starting treatment with the additional inducer, and the dose further adjusted by increments of 2 to 4 mg as necessary to maintain the target trough concentration.

•   Discontinuation of one of multiple co-administered strong CYP3A4 inducers may not require additional dose adjustment. The everolimus trough level should be determined approximately two weeks after discontinuation of one of multiple strong CYP3A4 inducers. If discontinuing all strong CYP3A4 inducers, a washout phase of at least 3 to 5 days (reasonable time for significant enzyme de-induction) should be considered before returning to the Votubia dose used before initiation of the strong CYP3A4 inducers. The everolimus trough concentration should be assessed approximately two weeks later (see section 4.4 and section 4.5)

Special dosage instructions

Paediatric patients
Votubia has not been studied in paediatric patients <2 years of age with TSC and refractory epileptic seizures.

Dosage recommendations for paediatric patients with TSC and refractory epileptic seizures are consistent with those for the corresponding adult patient population, with the exception of the starting dose in patients <6 years of age or patients with hepatic impairment.

Treatment with Votubia is not recommended in patients <18 years of age with hepatic impairment and TSC with epileptic seizures.

Elderly patients
No dose adjustment is required (see section 5.2).

Patients with renal impairment
No dose adjustment is required (however, please see section 4.4 and section 5.2).


Patients with hepatic impairment
Dose adjustments for patients with hepatic impairment should be made based on the indication (due to the different dosage recommendations) and hepatic function (Child-Pugh).

Recommended starting dose for patients >18 years of age with hepatic impairment 
• Mild hepatic impairment (Child-Pugh A) – 75% of the dose calculated based on BSA (rounded to the nearest available strength)

• Moderate hepatic impairment (Child-Pugh B) – 50% of the dose calculated based on BSA (rounded to the nearest available strength)

• Severe hepatic impairment (Child-Pugh C) – not recommended. In the event of a positive benefit-risk assessment, 25% of the dose, calculated based on BSA and rounded to the nearest available strength, must not be exceeded.

Everolimus whole blood trough concentrations should be assessed approximately 1 to 2 weeks after commencing treatment or after any change in hepatic status (Child-Pugh). Dosing should be titrated to attain trough concentrations of 5 to 15 ng/ml (see “Dose monitoring”). A dose adjustment should be made if a patient’s hepatic status (Child-Pugh) changes during treatment (see section 5.2).