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Dermatologic: Pruritus, skin discoloration, vesiculobullous rash (2%); alopecia.
ENT: Nasopharyngitis (14%); rhinitis (13%); pharyngitis (10%); conjunctivitis (3%); amblyopia, diplopia, ear pain (2%).
GI: Vomiting (15%); anorexia (13%); diarrhea (8%); gastroenteritis (4%); constipation (3%); pancreatitis.
Genitourinary: Albuminuria (4%); urine abnormality (2%).
Hematologic-Lymphatic: Ecchymosis (4%); leukopenia, neutropenia, pancytopenia, thrombocytopenia.
Hepatic: Hepatic failure, hepatitis.
Metabolic-Nutritional: Dehydration (2%); weight loss.
Musculoskeletal: Neck pain (8%).
Respiratory: Increased cough (11%); asthma, sinusitis (2%).
Miscellaneous: Accidental injury (17%); asthenia (15%); infection (13%); pain (7%); influenza (5%); flu syndrome (3%); face edema, viral infection (2%).
Summary of the safety profile: Julitam: Oral solution: Pooled safety data from clinical studies conducted with Levetiracetam Oral Solution oral formulations in adult patients with partial onset seizures showed that 46.4% of the patients in the Levetiracetam Oral Solution group and 42.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in 2.4% of the patients in the Levetiracetam Oral Solution and 2.0% of the patients in the placebo groups.
The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the central nervous system related adverse reactions decreased over time.
In monotherapy 49.8% of the subjects experienced at least one drug related adverse reaction. The most frequently reported adverse reactions were fatigue and somnolence.
A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3% of the patients in the Levetiracetam Oral Solution group and 30.0% of the patients in the placebo group experienced adverse reactions that were judged to be related to treatment. The most commonly reported adverse reactions were headache and somnolence. The incidence of adverse reactions in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% versus 46.4%).
A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2% of the patients in the Levetiracetam Oral Solution group and 29.% of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported adverse reaction was fatigue.
An increase in seizure frequency of more than 25% was reported in 14% of levetiracetam treated adult and paediatric patients (4 to 16 years of age) with partial onset seizures, whereas it was reported in 26% and 21% of placebo treated adult and paediatric patients, respectively.
When Levetiracetam Oral Solution was used to treat primary generalised tonic clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.
Adverse reactions that resulted from Levetiracetam Oral Solution intravenous use are similar to those associated with Levetiracetam Oral Solution oral use. The most frequently reported adverse reactions were dizziness, somnolence, headache and postural dizziness. Since there was limited exposure for Levetiracetam Oral Solution intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Levetiracetam Oral Solution intravenous will rely on Levetiracetam Oral Solution oral use.
Julitam I.V.: The adverse reaction 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 pediatric patients) and across the approved epilepsy indications.
Adverse reactions reported in clinical studies (adults, adolescents and children >1 month) and from postmarketing experience are listed in the following table per System and per Frequency.
Very common (≥ 1/10); Common (≥1/100, <1/10); Uncommon (≥1/1000; <1/100); Rare (≥1/10000, <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.
Diseases of the immune system: Infrequent: Drug reaction (DRESS), hypersensitivity (including angioedema and anaphylaxis) with eosinophilia and systemic symptoms.
Metabolism and nutrition disorders: Common: Anorexia. Uncommon: Weight increase, weight decrease, agranulocytosis. Rare: Hyponatremia.
Psychiatric disorders: 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, difficulty in walking.
Eye disorders: Uncommon: Diplopia, vision blurred.
Ear and Labyrinth Disorders: Common: Vertigo.
Respiratory, thoracic and mediastinal disorders: Common: Cough.
Gastrointestinal disorders: Common: Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea. Rare: Pancreatitis.
Hepatobiliary disorders: Uncommon: Liver function test abnormal. Rare: Hepatic failure, hepatitis.
Kidney and urinary tract diseases: 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.
General disorders and administration site disorders: Common: Asthenia/fatigue.
Injury, poisoning and procedural complications: Uncommon: Injury.
Encephalopathy has rarely been seen after levetiracetam administration. These undesirable effects usually occur at the beginning of treatment (several days to several months) and resolve after discontinuation of treatment.
* In Japanese patients, the prevalence is significantly higher than in non-Japanese patients.
Description of selected adverse reactions: Julitam: Oral solution: The risk of anorexia is higher when topiramate is coadministered with levetiracetam. In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Julitam I.V.: 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.
Pediatric population: 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 groups, these data are supplemented with the post-marketing experience.
In addition, 101 infants under 12 months of age were included in the post-registration safety study. No new safety concerns were found in infants with epilepsy younger than 12 months.
The adverse reaction profile of levetiracetam is generally similar across age groups and across the approved epilepsy indications. Safety results in pediatric 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 pediatric 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 standardized 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.
Paediatric population: Julitam: Oral solution: A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4% of the patients in the Levetiracetam Oral Solution group and 40.2% of the patients in the placebo group experienced adverse reactions. Serious adverse reactions were experienced in none of the patients in the Levetiracetam Oral Solution group and 1.0% of the patients in the placebo group. The most commonly reported adverse reactions were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients 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 (38.6% versus 18.6%). However, the relative risk was similar in children as compared to adults.
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