Posology : מינונים

4.2    Posology and method of administration

Posology
Monotherapy for adults and adolescents from 16 years of age
The recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.

Add-on therapy for Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more 
The initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.
Depending upon the clinical response and tolerability, the daily dose can be increased up to 1,500 mg twice daily.
Dose changes can be made in 500 mg twice daily increases or decreases every two to four weeks.


Discontinuation
If levetiracetam has to be discontinued it is recommended to withdraw it gradually (e.g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in children and adolescents weighting less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks; 
Special populations

Elderly (65 years and older)
Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below).

Renal impairment

The daily dose must be individualised according to renal function.
For adult patients, refer to the following table and adjust the dose as indicated. To use this dosing table, an estimate of the patient's creatinine clearance (CLcr) in ml/min is needed. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighing 50 kg or more, the following formula: 
[140-age (years)] x weight (kg)
CLcr (ml/min) =                ---------------------------------------   (x 0.85 for women) 72 x serum creatinine (mg/dl)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (ml/min)
CLcr (ml/min/1.73   m2)   =                     ---------------------------- x 1.73 BSA subject (m2)


Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function: 
Group                                      Creatinine clearance         Dosage and frequency (ml/min/1.73m2)
Normal                                    > 80             500 to 1,500 mg twice daily Mild                                      50-79            500 to 1,000 mg twice daily Moderate                                  30-49            250 to 750 mg twice daily Severe                                    < 30             250 to 500 mg twice daily End-stage renal disease                   -                500 to 1,000 mg once daily (2) patients Undergoing dialysis   (1)

(1) A 750 mg loading dose is recommended on the first day of treatment with levetiracetam.

(2) Following dialysis, a 250 to 500 mg supplemental dose is recommended.


For children with renal impairment, levetiracetam dose needs to be adjusted based on the renal function as levetiracetam clearance is related to renal function. This recommendation is based on a study in adult renally impaired patients.

The CLcr in ml/min/1.73 m2 may be estimated from serum creatinine (mg/dl) determination, for young adolescents and children using the following formula (Schwartz formula):


 ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male 
Dosing adjustment for children and adolescents patients weighing less than 50 kg with impaired renal function: 

Group                   Creatinine clearance                     Dose and frequency(1) (ml/min/1.73 m2)
Normal                  > 80                     10 to 30 mg/kg (0.10 to 0.30 ml/kg) twice daily Mild                    50-79                    10 to 20 mg/kg (0.10 to 0.20 ml/kg) twice daily Moderate                30-49                    5 to 15 mg/kg (0.05 to 0.15 ml/kg) twice daily Severe                  < 30                     5 to 10 mg/kg (0.05 to 0.10 ml/kg) twice daily End-stage renal           --                      10 to 20 mg/kg (0.10 to 0.20 ml/kg) once daily (2) (3) disease patients undergoing dialysis
(1) Keppra oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing  recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.
(2) A 15 mg/kg (0.15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam.
(3) Following dialysis, a 5 to 10 mg/kg (0.05 to 0.10 ml/kg) supplemental dose is recommended.


Hepatic impairment
No dose adjustment is needed in patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the creatinine clearance may underestimate the renal insufficiency. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 60 ml/min/1.73m2.

Paediatric population

The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
The tablet formulation is not adapted for use in children under the age of 6 years.
Keppra oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the administration of doses below 250 mg. In all of the above cases Keppra oral solution should be used.

Monotherapy

The safety and efficacy of Keppra in children and adolescents below 16 years as monotherapy treatment have not been established.
No data are available.

Add-on therapy for children (4 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg 
Keppra oral solution is the preferred formulation for use in children under the age of 6 years.

For children 6 years and above, Keppra oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.
The lowest effective dose should be used. The starting dose for a child or adolescent of 25kg should be 250mg twice daily with a maximum dose of 750mg twice daily.
Dose in children 50 kg or greater is the same as in adults.

The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.

Dosage recommendations for children and adolescents:

Weight                   Starting dose:                          Maximum dose: 10 mg/kg twice daily                    30 mg/kg twice daily

15 kg (1)                150 mg (1.5 ml) twice daily             450 mg (4.5 ml) twice daily     20 kg (1)                200 mg (2 ml) twice daily               600 mg (6ml) twice daily
25 kg                    250 mg twice daily                      750 mg twice daily
From 50 kg (2)           500 mg twice daily                      1500 mg twice daily 

(1) Children weighing less than 25kg should preferably start the treatment with Keppra 100 mg/ml oral solution.
(2) Dosage in children and adolescents 50 kg or more is the same as in adults.


The graduated 10 ml oral syringe contains up to 1,000 mg levetiracetam with a graduation every 0.25 ml (corresponding to 25 mg).

Method of administration
The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. Keppra tablets should not be chewed or crushed.

The oral solution may be diluted in a glass of water and may be taken with or without food. After oral administration the bitter taste of levetiracetam may be experienced

The daily dose is administered in two equally divided doses.