LEVETIRACETAM NEURAXPHARM

Posology Partial onset seizures The recommended dosing for monotherapy (from 16 years of age) and adjunctive therapy is the same; as outlined below. All indications Adults (≥18 years) and adolescents (12 to 17 years) weighing 50 kg or more The initial therapeutic dose is 500 mg twice daily.

This dose can be started on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be given based on physician assessment of seizure reduction versus potential side effects. This can be increased to 500 mg twice daily after two weeks.

Depending upon the clinical response and tolerability, the daily dose can be increased up to 1500 mg twice daily. Dose changes can be made in 250 mg or 500 mg twice daily increases or decreases every two to four weeks. Adolescents (12 to 17 years) weighing below 50 kg and children from 1 month of age The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to weight, age and dose.

Refer to Paediatric population section for dosing adjustments based on weight. g. in adults and adolescents weighing more than 50 kg: 500 mg decreases twice daily every two to four weeks; in infants older than 6 months, children and adolescents weighing less than 50 kg: dose decrease should not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months): dose decrease should not exceed 7 mg/kg twice daily every two weeks).

Special populations Elderly (65 years and older) Adjustment of the dose is recommended in elderly patients with compromised renal function (see “Renal impairment” below). Renal impairment 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. 73 m²) Dose and frequency Normal ≥ 80 500 to 1500 mg twice daily Mild 50-79 500 to 1000 mg twice daily Moderate 30-49 250 to 750 mg twice daily Severe < 30 250 to 500 mg twice daily End-stage renal disease - 500 to 1000 mg once daily (2) patients undergoing dialysis (1) (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. 20 ml/kg) once daily (3) (5) (1) Levetiracetam oral solution should be used for doses under 250 mg and for doses not multiple of 250 mg when dosing recommendation is not achievable with granules for oral solution in sachet.

105 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam. 15 ml/kg) loading dose is recommended on the first day of treatment with levetiracetam. 07 ml/kg) supplemental dose is recommended. 10 ml/kg) supplemental dose is recommended.

Hepatic impairment 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. 73 m2. Paediatric population The physician should prescribe the most appropriate pharmaceutical form, presentation and strength according to age, weight and dose.

Levetiracetam oral solution is the preferred formulation for use in infants and children under the age of 6 years. In addition, the available dose strengths of the granules for oral solution are not appropriate for initial treatment in children weighing less than 25 kg or for administration of doses below 250 mg.

In all of the above cases Levetiracetam oral solution should be used. Monotherapy The safety and efficacy of levetiracetam in children and adolescents below 16 years as monotherapy treatment have not been established. No data are available.

Adolescents (16 and 17 years of age) weighing 50 kg or more with partial onset seizures with or without secondary […]

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

Frequency category MedDRA system organ class Very common Common Uncommon Rare Infections and infestations Nasopharyngitis Infection Blood and lymphatic system disorders Thrombocytopenia, leukopenia Pancytopenia, neutropenia, agranulocytosi Immune system disorders Drug reaction with eosinophi and systemic symptoms (DRESS), Hypersensitivi (including angioedema an anaphylaxis) Metabolism and nutrition disorders Anorexia Weight decreased, weight increase Hyponatraemia Psychiatric disorders Depression, hostility/ aggression, anxiety, insomnia, nervousness/irritability Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation Completed suicide, personality disorder, think abnormal, delirium Nervous system disorders Somnolence, headache Convulsion, balance disorder, dizziness, lethargy, tremor Amnesia, memory impairment, coordination abnormal/ataxia, paraesthesia, disturbance in attention Choreoathetos dyskinesia, hyperkinesia, g disturbance, encephalopath seizures aggravated Eye disorders Diplopia, vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Electrocardiog QT prolonged Respiratory, thoracic and mediastinal disorders Cough Gastrointestinal disorders Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea Pancreatitis Hepatobiliary disorders Liver function test abnormal Hepatic failure hepatitis Renal and Urinary Disorders Acute Kidney injury Skin and subcutaneous tissue disorders Rash Alopecia, eczema, pruritus, Toxic epiderm necrolysis, Stevens-Johns syndrome, erythema multiforme Musculoskeletal and connective tissue disorders Muscular weakness, myalgia Rhabdomyolys and blood crea phosphokinase increased* General disorders and administration site conditions Asthenia/fatigue Injury, poisoning and procedural complications Injury * Prevalence is significantly higher in Japanese patients when compared to non- Japanese patients.

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.

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.

9 %) were reported more frequently than in other age ranges or in the overall safety profile. 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 […]

Renal impairment The administration of levetiracetam to patients with renal impairment may require dose adjustment. 2). Acute Kidney injury The use of levetiracetam has been very rarely associated with acute kidney injury, with a time to onset ranging from a few days to several months.

Blood cell counts Rare cases of decreased blood cell counts (neutropenia, agranulocytosis, leucopenia, thrombocytopenia and pancytopenia) have been described in association with levetiracetam administration, generally at the beginning of the treatment.

8). Suicide Suicide, suicide attempt, suicidal ideation and behaviour have been reported in patients treated with anti-epileptic agents (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anti-epileptic medicinal products has shown a small increased risk of suicidal thoughts and behaviour.

The mechanism of this risk is not known. Therefore, patients should be monitored for signs of depression and/or suicidal ideation and behaviours and appropriate treatment should be considered. Patients (and Weight Starting dose: 10 mg/kg twice daily Maximum dose: 30 mg/kg twice daily 25 kg 250 mg twice daily 750 mg twice daily From 50 kg (1) 500 mg twice daily 1500 mg twice daily caregivers of patients) should be advised to seek medical advice should signs of depression and/or suicidal ideation or behaviour emerge.

Abnormal and aggressive behaviours Levetiracetam may cause psychotic symptoms and behavioural abnormalities including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for developing psychiatric signs suggesting important mood and/or personality changes.

If such behaviours are noticed, treatment adaptation or gradual discontinuation should be considered. 2. Worsening of seizures As with other types of antiepileptic drugs, levetiracetam may rarely exacerbate seizure frequency or severity.

This paradoxical effect was mostly reported within the first month after levetiracetam initiation or increase of the dose, and was reversible upon drug discontinuation or dose decrease. Patients should be advised to consult their physician immediately in case of aggravation of epilepsy.

Electrocardiogram QT interval prolongation Rare cases of ECG QT interval prolongation have been observed during post- marketing surveillance. Levetiracetam should be used with caution in patients with QTc-interval prolongation, in patients concomitantly treated with drugs affecting the QTc-interval, or in patients with relevant pre-existing cardiac disease or electrolyte disturbances.

Paediatric population Available data in children did not suggest impact on growth and puberty. However, long term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.

Excipients This medicinal product contains isomalt (E 953). Patients with rare hereditary problems of fructose intolerance should not take this medicine. This medicinal product contains sucrose. Patients with rare hereditary problems of fructose intolerance, glucose-galactose malabsorption or sucrase-isomaltase insufficiency should not take this medicine.

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