Posology : מינונים

4.2   Posology and method of administration

Posology
Lacosamide therapy can be initiated with either oral or intravenous administration. Solution for infusion is an alternative for patients when oral administration is temporarily not feasible. The overall duration of treatment with intravenous lacosamide is at the physician’s discretion; there is experience from clinical trials with twice daily infusions of lacosamide for up to 5 days in adjunctive therapy. Conversion to or from oral and intravenous administration can be done directly without titration. The total daily dose and twice daily administration should be maintained. Monitor closely patients with known cardiac conduction problems, on concomitant medications that prolong PR interval, or with severe cardiac disease (e.g. myocardial ischemia, heart failure) when lacosamide dose is higher than 400 mg/day (see Method of administration below and section 4.4).
Lacosamide must be taken twice a day (usually once in the morning and once in the evening).

Adolescents and children weighing 50 kg or more, and adults

The following table summarises the recommended posology for adolescents and children weighing 50 kg or more, and for adults. More details are provided in the table below.


Monotherapy                         Adjunctive therapy
Starting dose                       100 mg/day or 200 mg/day            100 mg/day 
Single loading dose                 200 mg                              200 mg (if applicable)
Titration (incremental steps)       50 mg twice a day (100 mg/day) 50 mg twice a day (100 mg/day) at weekly intervals            at weekly intervals
Maximum recommended dose            up to 600 mg/day               up to 400 mg/day 
Monotherapy
The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Lacosamide can also be initiated at the dose of 100 mg twice a day based on the physician's assessment of required seizure reduction versus potential side effects.
Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 300 mg twice a day (600 mg/day).
In patients having reached a dose greater than 400 mg/day and who need an additional antiepileptic medicinal product, the posology that is recommended for adjunctive therapy below should be followed.

Adjunctive therapy
The recommended starting dose is 50 mg twice a day which should be increased to an initial therapeutic dose of 100 mg twice a day after one week.
Depending on response and tolerability, the maintenance dose can be further increased at weekly intervals by 50 mg twice a day (100 mg/day), up to a maximum recommended daily dose of 400 mg (200 mg twice a day).

Initiation of lacosamide treatment with a loading dose
Lacosamide treatment may also be initiated with a single loading dose of 200 mg, followed approximately 12 hours later by a 100 mg twice a day (200 mg/day) maintenance dose regimen. Subsequent dose adjustments should be performed according to individual response and tolerability as described above. A loading dose may be initiated in patients in situations when the physician determines that rapid attainment of lacosamide steady state plasma concentration and therapeutic effect is warranted. It should be administered under medical supervision with consideration of the potential for increased incidence of serious cardiac arrhythmia and central nervous system adverse reactions (see section 4.8). Administration of a loading dose has not been studied in acute conditions such as status epilepticus.

Discontinuation
In accordance with current clinical practice, if lacosamide has to be discontinued, it is recommended this be done gradually (e.g. taper the daily dose by 200 mg/week).
In patients who develop serious cardiac arrhythmia, clinical benefit/risk assessment should be performed and if needed lacosamide should be discontinued.

Special populations

Elderly (over 65 years of age)
No dose reduction is necessary in elderly patients. Age associated decreased renal clearance with an increase in AUC levels should be considered in elderly patients (see following paragraph ‘renal impairment’ and section 5.2). There is limited clinical data in the elderly patients with epilepsy, particularly at doses greater than 400 mg/day (see sections 4.4, 4.8, and 5.1).

Renal impairment
No dose adjustment is necessary in mildly and moderately renally impaired adult and paediatric patients (CLCR > 30 ml/min). In paediatric patients weighing 50 kg or more and in adult patients with mild or moderate renal impairment a loading dose of 200 mg may be considered, but further dose titration (> 200 mg daily) should be performed with caution. In paediatric patients weighing 50 kg or more and in adult patients with severe renal impairment (CLCR ≤ 30 ml/min) or with end-stage renal disease, a maximum dose of 250 mg/day is recommended and the dose titration should be performed with caution. If a loading dose is indicated, an initial dose of 100 mg followed by a 50 mg twice daily regimen for the first week should be used. In paediatric patients weighing less than 50 kg with severe renal impairment (CLCR ≤ 30 ml/min) and in those with end-stage renal disease, a reduction of 25 % of the maximum dose is recommended. For all patients requiring haemodialysis a supplement of up to 50 % of the divided daily dose directly after the end of haemodialysis is recommended.
Treatment of patients with end-stage renal disease should be made with caution as there is little clinical experience and accumulation of a metabolite (with no known pharmacological activity).

Hepatic impairment
A maximum dose of 300 mg/day is recommended for paediatric patients weighing 50 kg or more and for adult patients with mild to moderate hepatic impairment.
The dose titration in these patients should be performed with caution considering co-existing renal impairment.
In adolescents and adults weighing 50 kg or more, a loading dose of 200 mg may be considered, but further dose titration (> 200 mg daily) should be performed with caution. Based on data in adults, in paediatric patients weighing less than 50 kg with mild to moderate hepatic impairment a reduction of 25% of the maximum dose should be applied. The pharmacokinetics of lacosamide has not been evaluated in severely hepatic impaired patients (see section 5.2). Lacosamide should be administered to adult and paediatric patients with severe hepatic impairment only when the expected therapeutic benefits are anticipated to outweigh the possible risks. The dose may need to be adjusted while carefully observing disease activity and potential side effects in the patient.

Paediatric population

The physician should prescribe the most appropriate formulation and strength according to weight and dose.
Adolescents and children weighing 50 kg or more

Dosage in adolescents and children weighing 50 kg or more is the same as in adults (see above).

Children (from 4 years of age) and adolescents weighing less than 50 kg 
Monotherapy
The recommended starting dose is 2 mg/kg/day which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 2 mg/kg/day every week. The dose should be gradually increased until the optimum response is obtained. In children weighing less than 40 kg, a maximum dose of up to 12 mg/kg/day is recommended. In children weighing from 40 to under 50 kg, a maximum dose of 10 mg/kg/day is recommended.

The following table below summarises the recommended posology in monotherapy for children and adolescents weighing less than 50 kg.
Starting dose                                       2 mg/kg/day

Single loading dose                                        Not recommended Titration (incremental steps)                              2 mg/kg/day every week Maximum recommended dose in patients < 40 kg               up to 12 mg/kg/day Maximum recommended dose in patients ≥ 40 kg to            up to 10 mg/kg/day < 50 kg

The tables below provide examples of volumes of solution for infusion per administration depending on prescribed dose and body weight. The precise volume of solution for infusion is to be calculated according to the exact body weight of the child.


Monotherapy doses to be taken twice daily for children from 4 years of age weighing less than 40 kg: Weight   0.1 ml/kg       0.2 ml/kg      0.3 ml/kg        0.4 ml/kg      0.5 ml/kg      0.6 ml/kg (1 mg/kg)       (2 mg/kg)      (3 mg/kg)        (4 mg/kg)      (5 mg/kg)      (6 mg/kg) Starting dose                                                                 Maximum recommended dose
10 kg    1 ml            2 ml           3 ml             4 ml           5 ml           6 ml (10 mg)         (20 mg)        (30 mg)          (40 mg)        (50 mg)        (60 mg) 15 kg    1.5 ml          3 ml           4.5 ml           6 ml           7.5 ml         9 ml (15 mg)         (30 mg)        (45 mg)          (60 mg)        (75 mg)        (90 mg)  20 kg    2 ml            4 ml           6 ml             8 ml           10 ml          12 ml
(20 mg)         (40 mg)        (60 mg)          (80 mg)        (100 mg)       (120 mg)  25 kg    2.5 ml          5 ml           7.5 ml           10 ml          12.5 ml        15 ml
(25 mg)         (50 mg)        (75 mg)          (100 mg)       (125 mg)       (150 mg) 30 kg    3 ml            6 ml           9 ml             12 ml          15 ml          18 ml (30 mg)         (60 mg)        (90 mg)          (120 mg)       (150 mg)       (180 mg) 35 kg    3.5 ml          7 ml           10.5 ml          14 ml          17.5 ml        21 ml (35 mg)         (70 mg)        (105 mg)         (140 mg)       (175 mg)       (210 mg) 
Monotherapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 40 kg to under 50 kg(1):
Weight     0.1 ml/kg         0.2 ml/kg           0.3 ml/kg          0.4 ml/kg          0.5 ml/kg (1 mg/kg)         (2 mg/kg)           (3 mg/kg)          (4 mg/kg)          (5 mg/kg) Starting dose                                                               Maximum recommended dose
40 kg      4 ml              8 ml                12 ml              16 ml              20 ml
(40 mg)           (80 mg)             (120 mg)           (160 mg)           (200 mg)  45 kg      4.5 ml            9 ml                13.5 ml            18 ml              22.5 ml
(45 mg)           (90 mg)             (135 mg)           (180 mg)           (225 mg) (1)
Dosage in adolescents 50 kg or more is the same as in adults.


Adjunctive therapy
The recommended starting dose is 2 mg/kg/day which should be increased to an initial therapeutic dose of 4 mg/kg/day after one week.
Depending on response and tolerability, the maintenance dose can be further increased by 2 mg/kg/day every week. The dose should be gradually adjusted until the optimum response is obtained. In children weighing less than 20 kg, due to an increased clearance compared to adults, a maximum dose of up to 12 mg/kg/day is recommended. In children weighing from 20 to under 30 kg, a maximum dose of 10 mg/kg/day is recommended and in children weighing from 30 to under 50 kg a maximum dose of 8 mg/kg/day is recommended, although in open-label studies (see sections 4.8 and 5.2), a dose up to 12 mg/kg/day has been used by a small number of these children.

The following table below summarises the recommended posology in adjunctive therapy for children and adolescents weighing less than 50 kg.
Starting dose                                    2 mg/kg/day

Single loading dose                             Not recommended
Titration (incremental steps)                   2 mg/kg/day every week Maximum recommended dose in patients < 20 kg    up to 12 mg/kg/day
Maximum recommended dose in patients ≥ 20 kg to up to 10 mg/kg/day
< 30 kg
Maximum recommended dose in patients ≥ 30 kg to up to 8 mg/kg/day
< 50 kg

The tables below provide guidance on the volume of solution for infusion per administration depending on prescribed dose and body weight. The precise volume of solution for infusion is to be calculated according to the exact body weight of the child.

Adjunctive therapy doses to be taken twice daily for children from 4 years of age weighing less than 20 kg: Weight      0.1 ml/kg       0.2 ml/kg      0.3 ml/kg       0.4 ml/kg       0.5 ml/kg     0.6 ml/kg (1 mg/kg)       (2 mg/kg)      (3 mg/kg)       (4 mg/kg)       (5 mg/kg)     (6 mg/kg) Starting dose                                                                Maximum recommended dose
10 kg       1 ml            2 ml           3 ml            4 ml            5 ml          6 ml (10 mg)         (20 mg)        (30 mg)         (40 mg)         (50 mg)       (60 mg) 15 kg       1.5 ml          3 ml           4.5 ml          6 ml            7.5 ml        9 ml (15 mg)         (30 mg)        (45 mg)         (60 mg)         (75 mg)       (90 mg) 

Adjunctive therapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 20 kg to under 30 kg:
Weight       0.1 ml/kg          0.2 ml/kg         0.3 ml/kg          0.4 ml/kg          0.5 ml/kg (1 mg/kg)          (2 mg/kg)         (3 mg/kg)          (4 mg/kg)          (5 mg/kg) Starting dose                                                              Maximum recommended dose
20 kg        2 ml               4 ml              6 ml               8 ml               10 ml
(20 mg)            (40 mg)           (60 mg)            (80 mg)            (100 mg)  25 kg        2.5 ml             5 ml              7.5 ml             10 ml              12.5 ml
(25 mg)            (50 mg)           (75 mg)            (100 mg)           (125 mg) .


Adjunctive therapy doses to be taken twice daily for children and adolescents from 4 years of age weighing 30 kg to under 50 kg:
Weight     0.1 ml/kg              0.2 ml/kg                0.3 ml/kg               0.4 ml/kg (1 mg/kg)              (2 mg/kg)                (3 mg/kg)               (4 mg/kg) Starting dose                                                           Maximum recommended dose
30 kg      3 ml (30 mg)           6 ml (60 mg)             9 ml (90 mg)            12 ml (120 mg) 35 kg      3.5 ml (35 mg)         7 ml (70 mg)             10.5 ml (105 mg)        14 ml (140 mg)  40 kg      4 ml (40 mg)           8 ml (80 mg)             12 ml (120 mg)          16 ml (160 mg)
45 kg      4.5 ml (45 mg)         9 ml (90 mg)             13.5 ml (135 mg)        18 ml (180 mg)


Loading dose
Administration of a loading dose has not been studied in children. Use of a loading dose is not recommended in adolescents and children weighing less than 50 kg.

Children less than 4 years
The safety and efficacy of lacosamide in children aged below 4 years have not yet been established. No data are available.

Method of administration

The solution for infusion is infused over a period of 15 to 60 minutes twice a day. An infusion duration of at least 30 minutes for administration > 200 mg per infusion (i.e. > 400 mg/day) is preferred.
Vimpat solution for infusion can be administered intravenously without further dilution or can be diluted with sodium chloride 9 mg/ml (0.9 %) solution for injection, glucose 50 mg/ml (5 %) solution for injection or lactated Ringer’s solution for injection.