LEVETIRACETAM SANDOZ

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 1,500 mg twice daily. Dose changes can be made in 250 mg or500 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. 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.

73m2) Dose and frequency Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis (1) ≥ 80 50-79 30-49 < 30 - 500 to 1,500 mg twice daily 500 to 1,000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1,000 mg once daily (2) (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. 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.

Summary of the safety profile The adverse event 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 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.

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.

The 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 categoryMedDRA SOC Very common Common Uncommon Rare Very rare Infections and infestation s Nasopharyngi tis Infection Blood and lymphatic system disorders Thrombocytope nia, leukopenia Pancytope nia, neutropeni a agranulocy tosis Immune system disorders Drug reaction with eosinophili a and systemic symptoms (DRESS) Metabolis m and nutrition disorders Anorexia Weight decreased, weight increase Hyponatra emia Psychiatric disorders Depressio n, hostility/ aggressio n, anxiety, insomnia, nervousne ss/irritabil ity Suicide attempt, suicidal ideation, psychotic disorder, abnormal behaviour, hallucination, anger, confusional state, panic attack, affect lability/mood swings, agitation Completed suicide, personality disorder, thinking abnormal, delerium Obsessive compulsive disorder** Nervous system disorders Somnolence, headache Convulsio n, balance disorder, dizziness, lethargy, tremor Amnesia, memory impairment, coordination abnormal/ataxia , paraesthesia, disturbance in attention Choreoathe tosis, dyskinesia, hyperkines ia, gait disturbance , encephalop athy, seizures aggravated, neuroleptic malignant syndrome* Eye disorders Diplopia, vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Electrocard iogram QT prolonged Respirator y, thoracic and mediastina l disorders Cough Gastrointe stinal disorders Abdomin al pain, diarrhoea, dyspepsia , vomiting, nausea Pancreatiti s Hepatobili Liver function Hepatic ary disorders test abnormal failure, hepatitis Skin and subcutane ous tissue disorders Rash Alopecia, eczema, pruitus, Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme Musculosk eletal and connective tissue disorders Muscular weakness, myalgia General disorders and administra tion site conditions Asthenia/ fatigue Injury, poisoning and procedural complicati ons Injury **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.

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 weighting 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).

Renal insufficiency The administration of levetiracetam to patients with renal impairment may require dose adjustment. 2). 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 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.

1.