Posology : מינונים

4.2    Posology and method of administration


Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of
anticancer therapies or in the treatment of patients with TSC and therapeutic drug monitoring.

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

Posology
For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets.

Oncology patients
The recommended dose is 10 mg everolimus once daily.

Renal angiomyolipoma associated with TSC
The recommended dose is 10 mg of everolimus once daily.

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 individualized based on Body Surface Area (BSA, in m2) using the Dubois formula, where
weight (W) is in kilograms and height (H) is in centimeters:
BSA = (W0.425 x H0.725) x 0.007184

The recommended starting daily dose for Afinitor for the treatment of patients with TSC who have
SEGA is 4.5 mg/m2. Different strengths of Afinitor tablets can be combined to attain the desired dose.

Everolimus whole blood trough concentrations should be assessed at least 1 week after commencing
treatment for patients <3 years of age and approximately 2 weeks after commencing treatment for
patients ≥3 years of age. 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.

Dosing recommendations for paediatric patients with SEGA are consistent with those for the adult
SEGA population, except for patients with hepatic impairment (see “Hepatic impairment” below and
section 5.2).

SEGA volume should be evaluated approximately 3 months after commencing Afinitor 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.



AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022
 For all indications:

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 drug reactions
Management of severe and/or intolerable suspected adverse drug reactions may require dose reduction
and/or temporary interruption of Afinitor therapy. For adverse reaction of Grade 1, dose adjustment is
usually not required. If dose reduction is required for oncology patients, the recommended dose is 5 mg
daily and must not be lower than 5 mg daily.
If dose reduction is required for TSC patients 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 the dose adjustment recommendations for specific adverse reactions (see also
section 4.4).


Table 1             Afinitor dose adjustment recommendations

Adverse Drug                 Severity1      Afinitor dose adjustment
reaction
Non-infectious                Grade 2       Consider interruption of therapy, until symptoms improve to
pneumonitis                                 Grade≤ 1.
Re-initiate Afinitor (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).
Discontinue treatment if failure to recover within 4 weeks.
Grade 3       Interrupt treatment until symptoms resolve to Grade ≤1.
Consider re-initiating Afinitor (5 mg daily for oncology
patients and approximately 50% lower than the daily dose
previously administered for TSC patients).
If toxicity recurs at Grade 3, consider discontinuation.
Grade 4       Discontinue treatment.
Stomatitis                    Grade 2       Temporary dose interruption until recovery to Grade ≤1.
Re-initiate treatment at same dose.
If stomatitis recurs at Grade 2, interrupt dose until recovery to
Grade ≤1.
Re-initiate Afinitor (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).
Grade 3       Temporary dose interruption until recovery to Grade ≤1.
Re-initiate treatment (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).
AFI API SEP22 V11                                              REF: Afinitor SmPC August 2022, Votubia SmPC August 2022
Adverse Drug              Severity1       Afinitor dose adjustment
reaction
Grade 4        Discontinue treatment.

Other non-                 Grade 2        If toxicity is tolerable, no dose adjustment required.
hematologic                               If toxicity becomes intolerable, temporary dose interruption
toxicities                                until recovery to Grade ≤1. Re-initiate Afinitor at same dose.
(excluding metabolic                      If toxicity recurs at Grade 2, interrupt Afinitor until recovery
events)                                   to Grade ≤1.
Re-initiate Afinitor (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).
Grade 3        Temporary dose interruption until recovery to Grade ≤1.
Consider re-initiating Afinitor (5 mg daily for oncology
patients and approximately 50% lower than the daily dose
previously administered for TSC patients). If toxicity recurs
at Grade 3, consider discontinuation.
Grade 4        Discontinue Afinitor treatment.
Metabolic events           Grade 2        No dose adjustment required.
(e.g.
hyperglycemia,             Grade 3        Temporary dose interruption.
dyslipidemia)                             Re-initiate Afinitor (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).
Grade 4         Discontinue Afinitor treatment.
Thrombocytopenia           Grade 2        Temporary dose interruption until recovery to Grade ≤1
(<75, ≥50x109/l)   (≥75x109/l). Re-initiate treatment at same dose.

Grade 3 & 4      Temporary dose interruption until recovery to Grade ≤1
(<50x109/l)      (≥75x109/l). Re-initiate treatment (5 mg daily for oncology
patients and approximately 50% lower than the daily dose
previously administered for TSC patients).
Neutropenia                Grade 2        No dose adjustment required.
(≥1x109/l)

Grade 3        Temporary dose interruption until recovery to Grade ≤2
(<1, ≥0.5x109/l)   (≥1x109/l). Re-initiate treatment at same dose.

Grade 4        Temporary dose interruption until recovery to Grade ≤2
(<0.5x109/l)     (≥1x109/l). Re-initiate treatment (5 mg daily for oncology
patients and approximately 50% lower than the daily dose
previously administered for TSC patients).



AFI API SEP22 V11                                           REF: Afinitor SmPC August 2022, Votubia SmPC August 2022
Adverse Drug                  Severity1       Afinitor dose adjustment
reaction
Febrile neutropenia            Grade 3        Temporary dose interruption until recovery to Grade ≤2
(≥1.25x109/l) and no fever.
Re-initiate treatment (5 mg daily for oncology patients and
approximately 50% lower than the daily dose previously
administered for TSC patients).

Grade 4       Discontinue Afinitor treatment.
1
Grading based on National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events
(CTCAE) v3.0

Therapeutic drug monitoring for patients treated for TSC
Therapeutic drug monitoring of everolimus blood concentrations, using a validated assay, is required
for patients treated for SEGA. Trough concentrations should be assessed approximately 2 weeks after
the initial dose, after any change in dose or pharmaceutical form, 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 “Hepatic impairment” below and section 5.2). For patients <3 years of
age, trough concentrations should be monitored at least 1 week after start of treatment or after any
change in dose or pharmaceutical form (see section 5.2).

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 “Hepatic impairment” below and
section 5.2).

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

Special populations – For all indications
Elderly patients (≥65 years)
No dose adjustment is required (see section 5.2).

Renal impairment
No dose adjustment is required (see section 5.2).

Hepatic impairment
For Oncology patients and patients treated for TSC with renal angiomyolipoma:
- 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) – Afinitor is only recommended if the desired benefit
outweighs the risk. In this case, a dose of 2.5 mg daily must not be exceeded.
Dose adjustments should be made if a patient’s hepatic (Child-Pugh) status changes during treatment
(see also sections 4.4 and 5.2).



AFI API SEP22 V11                                             REF: Afinitor SmPC August 2022, Votubia SmPC August 2022
Patients with SEGA associated with TSC:
Patients <18 years of age:
Afinitor is not recommended for patients <18 years of age with SEGA 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): 25% of the recommended starting dose
calculated based on BSA (rounded to the nearest strength)
•     Severe hepatic impairment (Child-Pugh C): not recommended
Everolimus whole blood trough concentrations should be assessed approximately 2 weeks after any
change in hepatic status (Child-Pugh).

Paediatric population
The safety and efficacy of Afinitor in children aged 0 to 18 years who are oncology patients have not
been established. No data are available.

The safety and efficacy of Afinitor 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 Afinitor 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 Afinitor on growth and pubertal development.

Method of administration
Afinitor must be administered orally once daily at the same time every day, consistently either with or
without food (see section 5.2). Afinitor tablets should be swallowed whole with a glass of water.
No information is available for tablets crushed, split or chewed.

For patients with TSC who have SEGA and are unable to swallow tablets, Afinitor Tablet(s) can be
dispersed completely in a glass with approximately 30 mL of water by gently stirring until the tablet(s)
is 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).