Afinitor Dosage/Direction for Use

Treatment with Afinitor should be initiated and supervised by a physician experienced in the use of anticancer therapies and in the treatment of patients with TSC and therapeutic drug monitoring.
Posology: Tablet (Oncology Indications): For the different dose regimens Afinitor is available as 2.5 mg, 5 mg and 10 mg tablets.
The recommended dose is 10 mg 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 next prescribed dose as usual.
Dose adjustment due to adverse reactions: Management of severe and/or intolerable suspected adverse reactions may require dose reduction and/or temporary interruption of Afinitor therapy. For adverse reactions of Grade 1, dose adjustment is usually not required. If dose reduction is required, the recommended dose is 5 mg daily and must not be lower than 5 mg daily.
Table 11 summarises the dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 11.)

Click on icon to see table/diagram/image

Tablet (Tuberous Sclerosis Complex-Related Indications): 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 Interactions).
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 = (W^0.425 x H^0.725) x 0.007184.
The recommended starting dose for Afinitor 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 Pharmacology: Pharmacokinetics under Actions). 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. 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 C_min 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 "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
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.
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 Afinitor 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 12 summarises dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 12.)

Click on icon to see table/diagram/image

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 Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions). Trough concentrations should be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see Precautions and Interactions) 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 Pharmacology: Pharmacodynamics under Actions) after initiation of or change in co-administration of CYP3A4 inducers or inhibitors (see Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
When possible, the same assay and laboratory for therapeutic drug monitoring should be used throughout the treatment.
Switching pharmaceutical forms: Afinitor is available in two pharmaceutical forms: tablets and dispersible tablets. Afinitor tablets and Afinitor 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 "Therapeutic drug monitoring" as previously mentioned).
Dispersible tablet: 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 Interactions).
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 = (W^0.425 x H^0.725) x 0.007184.
Starting dose and target trough concentrations in SEGA associated with TSC: The recommended starting dose for Afinitor 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 Pharmacology: Pharmacokinetics under Actions). Different strengths of Afinitor 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 "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
Starting dose and target trough concentrations in TSC with refractory seizures: The recommended starting dose for Afinitor for the treatment of patients with seizures is shown in Table 13. Different strengths of Afinitor dispersible tablets can be combined to attain the desired dose. (See Table 13.)

Click on icon to see table/diagram/image

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 (see Table 13 as previously mentioned), and those with hepatic impairment (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions).
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 C_min 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 Afinitor 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 Afinitor 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 12 summarises dose adjustment recommendations for specific adverse reactions (see also Precautions). (See Table 12 as previously mentioned).
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 Precautions and Interactions) or after any change in hepatic status (Child-Pugh) (see "Hepatic impairment" as follows and Pharmacology: Pharmacokinetics under Actions). Trough concentrations should be assessed 2 to 4 weeks after initiation of or change in co-administration of CYP3A4 inducers (see Precautions and Interactions) 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: Afinitor is available in two pharmaceutical forms: tablets and dispersible tablets. Afinitor tablets and Afinitor 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 "Therapeutic drug monitoring" as previously mentioned).
Special populations: Elderly patients (≥65 years): No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Renal impairment: No dose adjustment is required (see Pharmacology: Pharmacokinetics under Actions).
Hepatic impairment: Tablet (Oncology Indications): 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 Precautions and Pharmacology: Pharmacokinetics under Actions).
Tablet (Tuberous Sclerosis Complex-Related Indications): 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): 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 (see Precautions and Pharmacology: Pharmacokinetics under Actions).
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: 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): 50% of the recommended starting dose calculated based on BSA (rounded to the nearest strength).
Severe hepatic impairment (Child-Pugh C): Afinitor 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).
Dispersible tablet: Patients <18 years of age: Afinitor 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).
Paediatric population: Tablet (Oncology Indications): The safety and efficacy of Afinitor in children aged 0 to 18 years have not been established. No data are available.
Tablet (Tuberous Sclerosis Complex-Related Indications): 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 Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
Clinical study results did not show an impact of Afinitor on growth and pubertal development.
Dispersible tablet: 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 Pharmacology: Pharmacodynamics and Pharmacokinetics under Actions).
The safety, efficacy and pharmacokinetic profile of Afinitor has not been established in children below the age of 2 years with TSC and refractory seizures. Currently available data are described in Pharmacology: Pharmacokinetics under Actions, but no recommendation on a posology can be made.
Clinical study results did not show an impact of Afinitor on growth and pubertal development.
Method of administration: Tablet (Oncology Indications): Afinitor should be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions). Afinitor tablets should be swallowed whole with a glass of water. The tablets should not be chewed or crushed.
Tablet (Tuberous Sclerosis Complex-Related Indications): Afinitor must be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions). Afinitor 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, Afinitor 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 Pharmacology: Pharmacokinetics under Actions).
Dispersible tablet: Afinitor must be administered orally once daily at the same time every day, consistently either with or without food (see Pharmacology: Pharmacokinetics under Actions).
Afinitor 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 Shelf life under Storage). Only water should be used as the vehicle.
For further details on handling, see Special precautions for disposal and other handling under Cautions for Usage.