This information is intended for use by health professionals
Keppra 100 mg/ml oral solution
Each ml contains 100 mg levetiracetam
Excipients with known effect:
Each ml contains 2.7 mg of methyl parahydroxybenzoate [E218], 0.3 mg of propyl parahydroxybenzoate [E216] and 300 mg of maltitol liquid.
For the full list of excipients, see section 6.1.
Oral solution.
Clear liquid.
Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
Keppra is indicated as adjunctive therapy
• in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.
• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy.
• in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.
Posology
Partial onset seizures
The recommended dosing for monotherapy [from 16 years of age] and adjunctive therapy is the same; as outlined below.
All indications
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. However, a lower initial dose of 250 mg twice daily may be given based on physician assessment of seizure reduction versus potential side effects. This can be increased to 500 mg twice daily after two weeks.
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 250 mg or 500 mg twice daily increases or decreases every two to four weeks.
Adolescents [12 to 17 years] weighing below 50 kg and children from 1 month of age
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight, age and dose. Refer to Paediatric population section for dosing adjustments based on weight.
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 infants older than 6 months, children and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks; in infants [less than 6 months]: dose decrease should not exceed 7 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:
Then CLcr is adjusted for body surface area [BSA] as follows:
Dosing adjustment for adult and adolescent patients weighing more than 50 kg with impaired renal function:
Group | Creatinine clearance [ml/min/1.73m2] | Dose and frequency |
Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis [1] | ≥ 80 50-79 30-49 < 30 - | 500 to 1,500 mg twice daily 500 to 1,000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1,000 mg once daily [2] |
[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, children and infants, using the following formula [Schwartz formula]:
ks= 0.45 in Term infants to 1 year old; ks= 0.55 in Children to less than 13 years and in adolescent female; ks= 0.7 in adolescent male
Dosing adjustment for infants, children and adolescent patients weighing less than 50 kg with impaired renal function:
Group | Creatinine clearance [ml/min/1.73m2] | Dose and frequency [1] | |
Infants 1 to less than 6 months | Infants 6 to 23 months, children and adolescents weighing less than 50 kg | ||
Normal | ≥80 | 7 to 21 mg/kg [0.07 to 0.21 ml/kg] twice daily | 10 to 30 mg/kg [0.10 to 0.30 ml/kg] twice daily |
Mild | 50-79 | 7 to 14 mg/kg [0.07 to 0.14 ml/kg] twice daily | 10 to 20 mg/kg [0.10 to 0.20 ml/kg] twice daily |
Moderate | 30-49 | 3.5 to 10.5 mg/kg [0.035 to 0.105 ml/kg] twice daily | 5 to 15 mg/kg [0.05 to 0.15 ml/kg] twice daily |
Severe | < 30 | 3.5 to 7 mg/kg [0.035 to 0.07 ml/kg] twice daily | 5 to 10 mg/kg [0.05 to 0.10 ml/kg] twice daily |
End-stage renal disease patients undergoing dialysis | -- | 7 to 14 mg/kg [0.07 to 0.14 ml/kg] once daily [2] [4] | 10 to 20 mg/kg [0.10 to 0.20 ml/kg] once daily [3] [5] |
[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 10.5 mg/kg [0.105 ml/kg] loading dose is recommended on the first day of treatment with levetiracetam.
[3] A 15 mg/kg [0.15 ml/kg] loading dose is recommended on the first day of treatment with levetiracetam.
[4] Following dialysis, a 3.5 to 7 mg/kg [0.035 to 0.07 ml/kg] supplemental dose is recommended.
[5] 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/1.73 m2.
Paediatric population
The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.
Keppra oral solution is the preferred formulation for use in infants and children under the age of 6 years. 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.
Adolescents [16 and 17 years of age] weighing 50 kg or more with partial onset seizures with or without secondary generalisation with newly diagnosed epilepsy
Please refer to the above section on Adults [≥18 years] and adolescents [12 to 17 years] weighing 50 kg or more.
Add-on therapy for infants aged 6 to 23 months, children [2 to 11 years] and adolescents [12 to 17 years] weighing less than 50 kg
The initial therapeutic dose is 10 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased by 10 mg/kg twice daily every 2 weeks 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 for all indications.
Dose in children 50 kg or greater is the same as in adults for all indications.
Please refer to the above section on Adults [≥18 years] and adolescents [12 to 17 years] weighing 50 kg or more for all indications.
Dose recommendations for infants from 6 months of age, children and adolescents:
Weight | Starting dose: 10 mg/kg twice daily | Maximum dose: 30 mg/kg twice daily |
6 kg [1] | 60 mg [0.6 ml] twice daily | 180 mg [1.8 ml] twice daily |
10 kg [1] | 100 mg [1 ml] twice daily | 300 mg [3 ml] 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 [6 ml] twice daily |
25 kg | 250 mg twice daily | 750 mg twice daily |
From 50 kg [2] | 500 mg twice daily | 1,500 mg twice daily |
[1] Children 25 kg or less should preferably start the treatment with Keppra 100 mg/ml oral solution.
[2] Dose in children and adolescents 50 kg or more is the same as in adults.
Add-on therapy for infants aged from 1 month to less than 6 months
The initial therapeutic dose is 7 mg/kg twice daily.
Depending upon the clinical response and tolerability, the dose can be increased by 7 mg/kg twice daily every 2 weeks up to recommended dose of 21 mg/kg twice daily. Dose changes should not exceed increases or decreases of 7 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Infants should start the treatment with Keppra 100 mg/ml oral solution.
Dose recommendations for infants aged from 1 month to less than 6 months:
Weight | Starting dose: 7 mg/kg twice daily | Maximum dose: 21 mg/kg twice daily |
4 kg | 28 mg [0.3 ml] twice daily | 84 mg [0.85 ml] twice daily |
5 kg | 35 mg [0.35 ml] twice daily | 105 mg [1.05 ml] twice daily |
7 kg | 49 mg [0.5 ml]twice daily | 147 mg [1.5 ml] twice daily |
Three presentations are available:
- A 300 ml bottle with a 10 ml oral syringe [delivering up to 1000 mg levetiracetam] graduated every 0.25 ml [corresponding to 25 mg].
This presentation should be prescribed for children aged 4 years and older, adolescents and adults.
- A 150 ml bottle with a 3 ml oral syringe [delivering up to 300 mg levetiracetam] graduated every 0.1 ml [corresponding to 10 mg]
In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants and young children aged from 6 months to less than 4 years.
- A 150 ml bottle with a 1 ml oral syringe [delivering up to 100 mg levetiracetam] graduated every 0.05 ml [corresponding to 5 mg]
In order to ensure the accuracy of the dosing, this presentation should be prescribed for infants aged 1 month to less than 6 months.
Method of administration
The oral solution may be diluted in a glass of water or baby's bottle and may be taken with or without food. After oral administration the bitter taste of levetiracetam may be experienced.
Hypersensitivity to the active substance or other pyrrolidone derivatives or to any of the excipients listed in section 6.1.
Renal impairment
The administration of levetiracetam to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection [see section 4.2].
Acute Kidney injury
The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.
Blood cell counts
Rare cases of decreased blood cell counts [neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia] have been described in association with levetiracetam administration, generally at the beginning of the treatment. Complete blood cell counts are advised in patients experiencing important weakness, pyrexia, recurrent infections or coagulation disorders [section 4.8].
Suicide
Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents [including levetiracetam]. A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour. The mechanism of this risk is not known.
Therefore, patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients [and caregivers of patients] should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.
Abnormal and aggressive behaviours
Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes. If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. If discontinuation is considered, please refer to section 4.2.
Worsening of seizures
As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity. This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy.
Electrocardiogram QT interval prolongation
Rare cases of ECG QT interval prolongation have been observed during the post-marketing surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.
Paediatric population
Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
Excipients
Keppra 100 mg/ml oral solution contains methyl parahydroxybenzoate [E218] and propyl parahydroxybenzoate [E216] which may cause allergic reactions [possibly delayed].
It also contains maltitol liquid; patients with rare hereditary problems of fructose intolerance should not take this medicinal product.
Antiepileptic medicinal products
Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam did not influence the serum concentrations of existing antiepileptic medicinal products [phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone] and that these antiepileptic medicinal products did not influence the pharmacokinetics of levetiracetam.
As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.
A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy [4 to 17 years] confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 20 % higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dose adjustment is not required.
Probenecid
Probenecid [500 mg four times daily], a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low.
Methotrexate
Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.
Oral contraceptives and other pharmacokinetics interactions
Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives [ethinyl-estradiol and levonorgestrel]; endocrine parameters [luteinizing hormone and progesterone] were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
Laxatives
There have been isolated reports of decreased levetiracetam efficacy when the osmotic laxative macrogol has been concomitantly administered with oral levetiracetam. Therefore, macrogol should not be taken orally for one hour before and for one hour after taking levetiracetam.
Food and alcohol
The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.
No data on the interaction of levetiracetam with alcohol are available.
Women of child bearing potential
Specialist advice should be given to women who are of childbearing potential. Treatment with levetiracetam should be reviewed when a woman is planning to become pregnant. As with all antiepileptic medicines, sudden discontinuation of levetiracetam should be avoided as this may lead to breakthrough seizures that could have serious consequences for the woman and the unborn child. Monotherapy should be preferred whenever possible because therapy with multiple antiepileptic medicines AEDs could be associated with a higher risk of congenital malformations than monotherapy, depending on the associated antiepileptics.
Pregnancy
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy [more than 1,800, among which in more than 1,500 exposure occurred during the 1st trimester] do not suggest an increase in the risk for major congenital malformations. Only limited evidence is available on the neurodevelopment of children exposed to Keppra monotherapy in utero. However, current epidemiological studies [on about 100 children] do not suggest an increased risk of neurodevelopmental disorders or delays.
Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed. In such case, the lowest effective dose is recommended.
Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester [up to 60% of baseline concentration before pregnancy]. Appropriate clinical management of pregnant women treated with levetiracetam should be ensured.
Breastfeeding
Levetiracetam is excreted in human breast milk. Therefore, breast-feeding is not recommended.
However, if levetiracetam treatment is needed during breastfeeding, the benefit/risk of the treatment should be weighed considering the importance of breastfeeding.
Fertility
No impact on fertility was detected in animal studies [see section 5.3]. No clinical data are available, potential risk for human is unknown.
Levetiracetam has minor or moderate influence on the ability to drive and use machines. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system related symptoms, especially at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles or operating machinery. Patients are advised not to drive or use machines until it is established that their ability to perform such activities is not affected.
Summary of the safety profile
The most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The adverse reaction profile presented below is based on the analysis of pooled placebo-controlled clinical trials with all indications studied, with a total of 3,416 patients treated with levetiracetam. These data are supplemented with the use of levetiracetam in corresponding open-label extension studies, as well as post-marketing experience. The safety profile of levetiracetam is generally similar across age groups [adult and paediatric patients] and across the approved epilepsy indications.
Tabulated list of adverse reactions
Adverse reactions reported in clinical studies [adults, adolescents, children and infants > 1 month] and from post-marketing experience are listed in the following table per System Organ Class and per frequency. Adverse reactions are presented in the order of decreasing seriousness and their frequency is defined as follows: very common [≥1/10]; common [≥1/100 to