Clinical Trial Data and Post-Marketing Data: Summary of the safety profile:
The adverse event profile presented as follows 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 most frequently reported adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The safety profile of levetiracetam is generally similar across age groups (adult and paediatric patients) and across the approved epilepsy indications.
Adverse drug reactions (ADRs) are listed as follows by MedDRA system organ class and by frequency.
Frequencies are defined as: Very common ≥1/10; Common ≥1/100 to <1/10; Uncommon ≥1/1000 to <1/100; Rare ≥1/10000 to <1/1000; Very rare <1/10000; Not known (cannot be estimated from the available data).
Infections and infestations:
Very common: nasopharyngitis. Rare: infection.
Blood and lymphatic system disorders:
Uncommon: thrombocytopenia, leukopenia. Rare: neutropenia, pancytopenia, agranulocytosis.
Immune system disorders:
Rare: drug reaction with eosinophilia and systemic symptoms (DRESS), hypersensitivity (including angioedema and anaphylaxis).
Metabolism and nutrition disorders:
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.
Nervous system disorders:
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, encephalopathy, seizures aggravated.
Uncommon: diplopia, vision blurred.
Ear and labyrinth disorders:
Rare: electrocardiogram QT prolonged.
Respiratory, thoracic and mediastinal disorders:
Common: abdominal pain, diarrhoea, dyspepsia, nausea, vomiting. Rare: pancreatitis.
Uncommon: liver function test abnormal. Rare: hepatic failure, hepatitis.
Renal and urinary disorders:
Rare: acute kidney injury.
Skin and subcutaneous tissue disorders:
Common: rash. Uncommon: alopecia, eczema, pruritus. Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
Musculoskeletal and connective tissue disorders:
Uncommon: muscular weakness, myalgia. Rare: rhabdomyolysis and blood creatine phosphokinase increased*.
General disorders and administration site conditions:
Injury, poisoning and procedural complications:
*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.
Description of selected adverse reactions:
The risk of anorexia is higher when levetiracetam is co-administered 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.
Case of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation.
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.
The adverse event 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 levetiracetam-treated 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.