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.
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 ≥1/1000 to <1/100; Rare ≥1/10,000 to <1/1000; Very rare <1/10,000 
Frequency category
MedDRA SOC                                                                                                Very rare Very common       Common                     Uncommon               Rare Infections and   Nasopharyngitis                                                     infection infestations
Blood and                                                     Thrombocytopenia,      Pancytopenia lymphatic                                                     leukopenia             neutropenia, system                                                                               agranulocytosis disorders
Immune system                                                                        Drug reaction with disorders                                                                            eosinophilia and systemic symptoms
(DRESS),
Hypersensitivity
(including angioedema and anaphylaxis)


Metabolism and                     Anorexia                   Weight decreased,      Hyponatraemia.
nutrition                                                     weight increase disorders

Psychiatric                        Depression,                Suicide attempt,       Completed            Obsessive disorders                          hostility/aggression,      suicidal ideation,     suicide,             compulsive anxiety, insomnia,         psychotic disorder,    personality          disorder** nervousness/irritability   abnormal               disorder, thinking behaviour,             abnormal,
hallucination,         delirium anger, confusional state, panic attack,
affect lability/mood swings, agitation.

Nervous          Somnolence,       Convulsion, balance        Amnesia, memory        Choreoathetosis, system           headache          disorder, dizziness,       impairment,            dyskinesia, disorders                          lethargy, tremor           coordination           hyperkinesia, abnormal/ataxia,       gait disturbance,
paraesthesia,          encephalopathy,
disturbance in         seizures attention.             aggravated,

Neuroleptic malignant syndrome*
Eye disorders                                             Diplopia,
vision blurred

Ear and                           Vertigo labyrinth disorders
Cardiac                                                                         Electrocardiogram Disorders                                                                       QT prolonged Respiratory,                      Cough thoracic and mediastinal disorders


Gastrointestinal                  Abdominal pain,                               Pancreatitis disorders                         diarrhoea, dyspepsia,
vomiting, nausea

Hepatobiliary                                             Liver function test   Hepatic failure, disorders                                                 abnormal              hepatitis Renal and                                                                       Acute Kidney Urinary                                                                         Injury disorders
Skin and                          Rash                    Alopecia, eczema,     Toxic epidermal subcutaneous                                              pruritus              necrolysis, tissue disorders                                                                Stevens-Jonson syndrome,
erythema multiforme

Musculoskeletal                                           Muscular              Rhabdomyolysis and connective                                            weakness, myalgia     and blood tissue disorders                                                                creatine phosphokinase 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.
**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 administered with topiramate.
In several cases of alopecia, recovery was observed when levetiracetam was discontinued.
Bone marrow suppression was identified in some 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 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. This data is supplemented with the post-marketing experience of the use of levetiracetam.

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.

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 Keppra 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 behavioral and emotional functioning indicated a worsening in levetiracetam treated patients on aggressive behavior 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 behavioral and emotional functioning; in particular measures of aggressive behaviour were not worse than baseline.

Reporting of suspected adverse reactions:
Reporting of 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/