Adverse reactions : תופעות לוואי

4.8 Undesirable effects
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. Since there was limited exposure for Levetiracetam 100 mg/ml intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Levebon 100 mg/ml intravenous will rely on Levetiracetam oral use.

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 <1/10); uncommon (≥1/1,000 to <1/100); rare (≥1/10,000 to <1/1,000) and very rare (<1/10,000).

MedDRA                                        Frequency category
SOC               Very            Common               Uncommon                Rare                 Very rare common
Infections and    Nasopharyn                                                   Infection infestations      gitis
Blood and                                                Thrombocytopeni       Pancytopenia, lymphatic                                                a, leukopenia         neutropenia, system                                                                         agranulocytosi disorders                                                                      s Immune                                                                         Drug reaction system                                                                         with disorders                                                                      eosinophilia and systemic symptoms
(DRESS),
Hypersensitivi ty (including angioedema and anaphylaxis)
Metabolism                    Anorexia               Weight decrease,       Hyponatraemi and nutrition                                        weight increase        a disorders
Psychiatric                   Depression,            Suicide attempt,       Completed        Obsessive disorders                     hostility/             suicidal ideation,     suicide,         compulsive aggression, anxiety,   psychotic              personality      disorder** insomnia,              disorder,              disorder,
nervousness/irritabi   abnormal               thinking lity                   behaviour,             abnormal,
hallucination,         delirium anger, confusional state, panic attack,
affect lability/mood swings, agitation
Nervous          Somnolence   Convulsion,            Amnesia, memory        Choreoathetosi system           , headache   balance disorder,      impairment,            s, dyskinesia, disorders                     dizziness, lethargy,   coordination           hyperkinesia, tremor                 abnormal/ataxia,       gait paraesthesia,          disturbance,
disturbance in         encephalopath attention              y, seizures aggravated
Eye disorders                                        Diplopia, vision blurred
Ear and                       Vertigo labyrinth disorders
Cardiac                                                                     Electrocardiog disorders                                                                   ram QT prolonged
Respiratory,                  Cough thoracic and mediastinal disorders
Gastrointestin                Abdominal pain,                               Pancreatitis al disorders                  diarrhoea,
dyspepsia,
vomiting, nausea
Hepatobiliary                                        Liver function test Hepatic disorders                                            abnormal            failure, hepatitis
Renal and                                                                Acute kidney Urinary                                                                  injury Disorders
Skin and                      Rash                   Alopecia, eczema,      Toxic subcutaneous                                         pruritus,              epidermal tissue                                                                      necrolysis, disorders                                                                   Stevens- Johnson syndrome,
erythema multiforme
Musculoskelet                                          Muscular             Rhabdomyolys al and                                                 weakness,            is and blood connective                                             myalgia              creatine tissue                                                                      phosphokinase disorders                                                                   increased* General                         Asthenia/fatigue disorders and administration site conditions
Injury,                                                Injury poisoning and procedural complications


* Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.
Evidence also suggests a possible predisposition of the Japanese population to neuroleptic malignant syndrome (NMS).
**Very rare cases of development of obsessive-compulsive disorders (OCD) in patients with underlying history of OCD or psychiatric disorders have been observed in post-marketing surveillance.


Description of selected adverse reactions
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.
Cases of encephalopathy generally occurred at the beginning of the treatment (few days to a few months) and were reversible after treatment discontinuation

Paediatric 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 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 100 mg/ml 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.

Reporting of suspected adverse reactions
Reporting suspected adverse reactions after authorisation of the medicinal product is important.
It allows continued monitoring of the benefit/risk balance of the medicinal product.
Any suspected adverse events should be reported to the Ministry of Health according to the National Regulation by using an online form https://sideeffects.health.gov.il