Chemical formula: C₈H₁₄N₂O₂ Molecular mass: 170.212 g/mol PubChem compound: 5284583
Levetiracetam interacts in the following cases:
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 weighting 50 kg or more, the following formula:
CLcr (ml/min) = {[140-age (years)] x weight (kg) / 72 x serum creatinine (mg/dl)}(x 0,85 for women)
Then CLcr is adjusted for body surface area (BSA) as follows:
CLcr (ml/λεπτό/1,73 m²) = {CLcr (ml/min) / BSA subject (m²)} x 1,73
Dosing adjustment for adult and adolescents patients weighing more than 50 kg with impaired renal function:
| Group | Creatinine clearance (ml/min/1,73 m²) | Dose and frequency |
|---|---|---|
| Normal | >80 | 500-1.500 mg twice daily |
| Mild | 50-79 | 500-1.000 mg twice daily |
| Moderate | 30-49 | 250-750 mg twice daily |
| Severe | <30 | 250-500 mg twice daily |
| End-stage renal disease patients undergoing dialysis (1) | - | 500-1.000 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):
CLcr (ml/min/1,73 m²)= Height (cm) x ks / Serum Creatinine (mg/dl)
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 adolescents patients weighing less than 50 kg with impaired renal function:
| Group | Creatinine clearance(ml/min/1,73 m²) | Dose and frequency1 | |
|---|---|---|---|
| Infants 1 to less than 6 months | Infants 6 to 23 months, children and adolescents weighing less than 50 kg | ||
| Normal | >80 | 7 έως 21 mg/kg (0.07 έως 0.21 ml/kg) δύο φορές την ημέρα | 10 έως 30 mg/kg (0.10 έως 0.30 ml/kg) twice daily |
| Mild | 50-79 | 7 έως 14 mg/kg (0.07 έως 0.14 ml/kg) δύο φορές την ημέρα | 10 έως 20 mg/kg (0.10 έως 0.20 ml/kg) twice daily |
| Moderate | 30-49 | 3,5 έως 10,5 mg/kg (0.035 έως 0.105 ml/kg) δύο φορές την ημέρα | 5 έως 15 mg/kg (0.05 έως 0.15 ml/kg) twice daily |
| Severe | <30 | 3,5 έως 7 mg/kg (0.035 έως 0.07 ml/kg) δύο φορές την ημέρα | 5 έως 10 mg/kg (0.05 έως 0.10 ml/kg) twice daily |
| End-stage renal disease patients undergoing dialysis | -- | 7 έως 14 mg/kg (0.07 έως 0.14 ml/kg) once daily2,4 | 10 έως 20 mg/kg (0.10 έως 0.20 ml/kg) once daily3,5 |
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.
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.
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.
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.
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.
A large amount of postmarketing data on pregnant women exposed to levetiracetam monotherapy (more than 1800, among which in more than 1500 exposure occurred during the 1 st 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 levetiracetam 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.
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.
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.
No impact on fertility was detected in animal studies. 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.
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. Since there was limited exposure for levetiracetam intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of levetiracetam intravenous will rely on levetiracetam oral use.
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 <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).
Very common: Nasopharyngitis
Rare: Infection
Uncommon: Thrombocytopenia, leukopenia
Rare: Drug reaction with eosinophilia and systemic symptoms (DRESS), Hypersensitivity (including angioedema and anaphylaxis)
Common: Anorexia
Uncommon: Weight decreased, weight increase
Rare: Hyponatraemia
Common: Depression, hostility/aggression, anxiety, insomnia, nervousness/irritability
Uncommon: Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation
Rare: Completed suicide, personality disorder, thinking abnormal
Very common: Somnolence, headache
Common: Convulsion, balance disorder, dizziness, lethargy, tremor
Uncommon: Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention
Rare: Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance
Uncommon: Diplopia, vision blurred
Common: Vertigo
Common: Cough
Common: Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea
Rare: Pancreatitis
Uncommon: Liver function test abnormal
Rare: Hepatic failure, hepatitis
Rare: Acute Kidney injury
Common: Rash
Uncommon: Alopecia, eczema, pruritus
Rare: Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
Uncommon: Muscular weakness, myalgia
Rare: Rhabdomyolysis and blood creatine phosphokinase increased*
Common: Asthenia/fatigue
Uncommon: Injury
* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.
Cases of encephalopathy have been rarely observed after levetiracetam administration. These undesirable effects generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.
The risk of anorexia is higher when levetiracetam is coadministered with topiramate. In several cases of alopecia, recovery was observed when levetiracetam was discontinued. Bone marrow suppression was identified in some of the cases of pancytopenia.
In patients aged 1 month to less than 4 years, a total of 190 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. Sixty of these patients were treated with levetiracetam in placebo-controlled studies. In patients aged 4-16 years, a total of 645 patients have been treated with levetiracetam in placebo-controlled and open label extension studies. 233 of these patients were treated with levetiracetam in placebo-controlled studies. In both these paediatric age ranges, these data are supplemented with the post-marketing experience of the use of levetiracetam.
In addition, 101 infants aged less than 12 months have been exposed in a post authorization safety study. No new safety concerns for levetiracetam were identified for infants less than 12 months of age with epilepsy.
The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in paediatric patients in placebo-controlled clinical studies were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse reactions which were more common in children than in adults. In children and adolescents aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), affect lability (common, 1.7%), aggression (common, 8.2%), abnormal behaviour (common, 5.6%), and lethargy (common, 3.9%) were reported more frequently than in other age ranges or in the overall safety profile. In infants and children aged 1 month to less than 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were reported more frequently than in other age groups or in the overall safety profile.
A double-blind, placebo-controlled paediatric safety study with a non-inferiority design has assessed the cognitive and neuropsychological effects of levetiracetam in children 4 to 16 years of age with partial onset seizures. It was concluded that levetiracetam was not different (non inferior) from placebo with regard to the change from baseline of the Leiter-R Attention and Memory, Memory Screen Composite score in the per-protocol population. Results related to behavioural and emotional functioning indicated a worsening in levetiracetamtreated patients on aggressive behaviour as measured in a standardised and systematic way using a validated instrument (CBCL–Achenbach Child Behavior Checklist). However subjects, who took levetiracetam in the long-term open label follow-up study, did not experience a worsening, on average, in their behavioural and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.
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