Levetiracetam

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Levetiracetam is indicated as adjunctive therapy • in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.

• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. • in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

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. 73m2) Dose and frequency Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis (1) ≥ 80 50-79 30-49 < 30 - 500 to 1500 mg twice daily 500 to 1000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1000 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. 20 ml/kg) once daily (3) (5) (1) Levetiracetam oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.

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 tablets are not appropriate for initial treatment in children weighing less than 25 kg, for patients unable to swallow tablets or for the 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 […]

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 3416 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 categoryMedDRA SOC Very common Common Uncommon Rare Very rare Infections and infestations Nasopharyngi tis Infection Blood and lymphatic system disorders Thrombocyto penia, leukopenia Pancytopenia, neutropenia, agranulocytosis Immune system disorders Drug reaction with eosinophilia and systemic symptoms (DRESS),(1) Hypersensitivity (including angioedema and anaphylaxis) Metabolism and nutrition disorders Anorexia Weight decreased, weight increase Hyponatraemia Frequency categoryMedDRA SOC Very common Common Uncommon Rare Very rare 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, thinking abnormal, delirium Obsessive compulsive disorder(2) Nervous system disorders Somnolence , headache Convulsion , balance disorder, dizziness, lethargy, tremor Amnesia, memory impairment, coordination abnormal/ ataxia, paraesthesia, disturbance in attention Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, Seizures aggravated Eye disorders Diplopia, vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Electrocardiogram QT prolonged Respiratory, thoracic and mediastinal disorders Cough Gastrointestin al disorders Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea Pancreatitis Hepatobiliary disorders Liver function test abnormal Hepatic failure, hepatitis Frequency categoryMedDRA SOC Very common Common Uncommon Rare Very rare Skin and Subcutaneous tissue disorders Rash Alopecia, eczema, pruritus, Toxic epidermal necrolysis, Stevens- Johnson syndrome, erythema multiforme Musculoskelet al and connective tissue disorders Muscular weakness, myalgia Rhabdomyolysis and blood creatine phosphokinase increased(3) Renal and Urinary Disorders Acute Kidney injury General disorders and administration site conditions Asthenia/ fatigue Injury, poisoning and procedural complications Injury (1) See Description of selected adverse reactions (2) 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.

(3) 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). Description of selected adverse reactions Multiorgan hypersensitivity reactions Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported rarely in patients treated with levetiracetam.

Clinical manifestations may develop 2 to 8 weeks after starting treatment. These reactions are variable in expression, but typically present with fever, rash, facial oedema, lymphadenopathies, haematologic abnormalities and can be associated with involvement of different organ systems, mostly the liver.

If multiorgan hypersensitivity reaction is suspected, levetiracetam should be discontinued. 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 […]

1.

LEVETIRACETAM (levetiracetam) is indicated as adjunctive therapy in the management of adult (> 18 years of age) patients with epilepsy who are not satisfactorily controlled by conventional therapy. 3 Pharmacokinetics, Special Populations and Conditions, Pediatrics).

3 Pharmacokinetics, Special Populations and Conditions, Geriatrics).

1 Dosing Considerations LEVETIRACETAM is given orally with or without food. After oral administration, the bitter taste of levetiracetam may be experienced. 2 Recommended Dose and Dosage Adjustment Adults Treatment should be initiated at a dose of 1000 mg/day, given as twice daily dosing (500 mg bid).

Depending on clinical response and tolerability, the daily dose may be increased every two weeks by increments of 1000 mg, to a maximum recommended daily dose of 3000 mg. In clinical trials, daily doses of 1000 mg, 2000 mg, and 3000 mg, given as twice a day dosing, were shown to be effective.

Although there was a tendency toward greater response rate with higher dose, a consistent statistically significant increase in response with increased dose has not been shown. There are limited safety data from controlled clinical trials at doses higher than 3000 mg/day (approximately 40 patients), therefore these doses are not recommended.

Patients with Impaired Renal Function PrLEVETIRACETAM (levetiracetam tablets) Page 6 of 36 Renal excretion of unchanged drug accounts for approximately 66% of administered levetiracetam dose. Consistent with this, LEVETIRACETAM dosage should be reduced in patients with impaired renal function (see Table 1 below).

Patients with end stage renal disease should receive supplemental doses following dialysis. To use this dosing table, an estimate of the patient’s creatinine clearance is needed. 73 m2) Dosage 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 twice daily Severe* < 30 250 to 500 mg twice daily End-stage renal disease patients undergoing dialysis (1) – 500 to 1000 mg once daily (1) Following dialysis, a 250 to 500 mg supplemental dose is recommended.

* or according to best clinical judgment Patients with Impaired Hepatic Function 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.

73m2. 3 Pediatrics). Geriatrics (≥ 65 years of age) Dose selection and titration should proceed cautiously in elderly patients, as renal function decreases with age. 4 Administration The film-coated tablets must be taken orally, swallowed with liquid.

The daily dose is administered in two equally divided doses. 5 Missed Dose If the patient misses a dose by a few hours, they should be instructed to take LEVETIRACETAM as soon as they remember. If it is close to their next dose, they should be instructed to take their medication at the next regular time.

Patients should not take two doses at the same time.

). Seizure Worsening A paradoxical reaction of worsening of seizure may be observed especially when starting treatment or at increase in dose. Lack of efficacy or seizure worsening has also been reported in patients with epilepsy associated with sodium voltage-gated channel alpha subunit 8 (SCN8A) mutations.

In the case of lack of efficacy or worsening seizures, use of LEVETIRACETAM should be re-evaluated. Psychiatric Suicidal Ideation and Behaviour Suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents in several indications.

All patients treated with antiepileptic drugs, irrespective of indication, should be monitored for signs of depression and/or suicidal ideation and behaviour and appropriate treatment should be considered. Patients (and caregivers of patients) should be advised to seek medical advice should signs of suicidal ideation or behaviour emerge.

An FDA meta-analysis of randomized placebo-controlled trials, in which antiepileptic drugs were used for various indications, has shown a small increased risk of suicidal ideation and behaviour in patients treated with these drugs.

The mechanism of this risk is not known. There were 43892 patients in the placebo controlled clinical trials that were included in the meta- analysis. Approximately 75% of patients in these clinical trials were treated for indications other than epilepsy and, for the majority of non-epilepsy indications the treatment (antiepileptic drug or placebo) was administered as monotherapy.

, patients in both treatment arms were being treated with one or more antiepileptic drug). 24% for patients on placebo) is based largely on patients that received monotherapy treatment (antiepileptic drug or placebo) for non-epilepsy indications.

The study design does not allow an estimation of the risk of suicidal ideation and behaviour for patients with epilepsy that are taking antiepileptic drugs, due both to this population being the minority in the study, and the drug- placebo comparison in this population being confounded by the presence of adjunct antiepileptic drug treatment in both arms.

Psychiatric Reactions and Changes in Behaviour LEVETIRACETAM may cause behavioural abnormalities and psychotic symptoms. Behavioural adverse reactions reported with levetiracetam include affect liability, aggression, agitation, anger, anxiety, apathy, depression, hostility, irritability, personality change, paranoia and obsessive-compulsive disorder (OCD).

Closely monitor patients treated with LEVETIRACETAM for psychiatric signs and symptoms. Renal Renal excretion of unchanged drug accounts for approximately 66% of administered levetiracetam dose. 3 Pharmacokinetics, Special Populations and Conditions, Renal Insufficiency).

In patients with renal impairment LEVETIRACETAM dosage should be appropriately reduced. e. 2 Recommended Dose and Dosage Adjustment, Patients with Impaired Renal Function).

Reproductive Health:

Female and Male Potential • Fertility The effect of this medication on human fertility is unknown. No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology) • Teratogenic Risk There is non-clinical evidence suggesting that levetiracetam is embryotoxic and teratogenic (see 16 NON-CLINICAL TOXICOLOGY, Reproductive and Developmental Toxicology).

1 Pregnant Women). 1 Pregnant Women Levetiracetam Blood Levels May Decrease During Pregnancy: As with other antiepileptic drugs, physiological changes during pregnancy may affect levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy.

This decrease is more pronounced during the third trimester (up to 60% of baseline concentration before pregnancy). It is recommended that clinical response should be monitored carefully in women receiving LEVETIRACETAM treatment during pregnancy, and determination of changes in plasma concentrations should be considered to ensure that adequate seizure control is maintained throughout pregnancy.

In the event that PrLEVETIRACETAM (levetiracetam tablets) Page 12 of 36 medication is increased during pregnancy, the dose may need to be adjusted postpartum).

Risk to the Unborn Child:

In reproductive toxicity studies in rats and rabbits, levetiracetam induced developmental toxicity at exposure levels similar to or greater than the human exposure. There was evidence of increased skeletal variations/minor anomalies, retarded growth, embryonic death, and increased pup mortality.

In the rat, fetal abnormalities occurred in the absence of overt maternal toxicity. The systemic exposure at the observed no effect level in the rabbit was about 4 to 5 times the human exposure. There are no adequate and well-controlled studies on the use of levetiracetam in pregnant women.

Levetiracetam and/or its metabolites cross the placental barrier in animal species and in humans. Information about the […]

LEVETIRACETAM is contraindicated in patients who are hypersensitive to: • this drug or to any ingredient in the formulation, including any non-medicinal ingredient, or component of the container. For a complete listing, see 6 DOSAGE FORMS, STRENGTHS, COMPOSITION AND PACKAGING.

1 Partial Onset Seizures Levetiracetam tablets USP are indicated for treatment of partial-onset seizures in patients 1 month of age and older. 2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam tablets USP are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.

3 Primary Generalized Tonic-Clonic Seizures Levetiracetam tablets USP are indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

1 ). 1 Important Administration Instructions Levetiracetam tablets USP are given orally with or without food. The levetiracetam dosing regimen depends on the indication, age group, dosage form (tablets), and renal function. Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg.

Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon).

Levetiracetam tablets should be swallowed whole. Levetiracetam tablets should not be chewed or crushed. 2 Dosing for Partial Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.

Adults 16 Years of Age and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg.

There is no evidence that doses greater than 3000 mg/day confer additional benefit.

Pediatric Patients 1 Month to < 6 Months:

Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group.

6 Months to <4 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily).

If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group. 4 Years to < 16 Years: Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg.

The maximum daily dose was 3000 mg/day. For levetiracetam tablet dosing in pediatric patients weighing 20 to 40 kg, initiate treatment with a daily dose of 500 mg given as twice daily dosing (250 mg twice daily). Increase the daily dose every 2 weeks by increments of 500 mg to a maximum recommended daily dose of 1500 mg (750 mg twice daily).

For levetiracetam tablet dosing in pediatric patients weighing more than 40 kg, initiate treatment with a daily dose of 1000 mg/day given as twice daily dosing (500 mg twice daily). Increase the daily dose every 2 weeks by increments of 1000 mg/day to a maximum recommended daily dose of 3000 mg (1500 mg twice daily).

3 Dosing for Myoclonic Seizures in Patients 12 Years of Age and Older with Juvenile Myoclonic Epilepsy Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg.

The effectiveness of doses lower than 3000 mg/day has not been studied. 4 Dosing for Primary Generalized Tonic-Clonic Seizures Adults 16 Years of Age and Older Initiate treatment with a dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily).

Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses lower than 3000 mg/day has not been adequately studied. Pediatric Patients 6 to <16 Years of Age Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily).

Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied. Patients with body weight ≤20 kg should be dosed with oral solution.

1 )] . Only whole tablets should be administered. 5 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam tablets dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1.

In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. 73 m 2 ) Dosage (mg) Frequency Normal >80 500 to 1,500 Every 12 hours Mild 50 to 80 500 to 1,000 Every 12 hours Moderate 30 to 50 250 to 750 Every 12 hours Severe <30 250 to 500 Every 12 hours ESRD patients using dialysis ----- 500 to 1,000 Following dialysis, a 250 to 500 mg supplemental dose is recommended.

8 )] figure 1 figure 2

1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceutical Inc. gov/medwatch . 1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

1 ) ], the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Of the most common adverse reactions in adults experiencing partial - onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam.

Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy.

Levetiracetam (N = 769) % Placebo (N=439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

Table 4 lists the most common (>1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients. Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Pediatric Patients 4 Years to <16 Years: The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies in pediatric patients 4 to 16 years of age with partial onset seizures.

The most common adverse reactions in pediatric patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo.

In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Levetiracetam (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Cough 9 5 Nasal Congestion 9 2 Upper Abdominal Pain 9 8 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Altered Mood 3 1 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In the controlled pooled pediatric clinical studies in patients 4 to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction.

Pediatric Patients 1 Month to < 4 Years:

In the 7-day, controlled pediatric clinical study in children 1 month to less than 4 years of age with partial - onset seizures, the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability.

Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients. Therefore, other controlled pediatric data, presented above, should also be considered to apply to this age group.

Table 6 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with levetiracetam in the placebo-controlled study and were numerically more common than in patients treated with placebo.

In this study, either levetiracetam or placebo was added to concurrent AED therapy. Levetiracetam (N=60) % Placebo (N=56) % Somnolence 13 2 Irritability 12 0 In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

There was no adverse reaction that resulted in discontinuation for more than one patient. Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies.

The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. 2 )], the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo.

In this study, either levetiracetam or placebo was added to concurrent AED therapy. Levetiracetam (N=60) % Placebo (N=60) % Somnolence 12 2 Neck Pain 8 2 Pharyngitis 7 0 Depression 5 2 Influenza 5 2 Vertigo 5 3 In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction.

The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 8. Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies.

The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures. 3 )], the most common adverse reaction in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 9 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy.

Levetiracetam (N=79) % Placebo (N=84) % Nasopharyngitis 14 5 Fatigue 10 8 Diarrhea 8 7 Irritability 6 2 Mood swings 5 1 In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.

This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Tables 4 and 8).

In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision. Comparison of Gender, Age and Race The overall adverse reaction profile of levetiracetam was similar between females and males.

There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race. 2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levetiracetam.

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been reported in patients receiving marketed levetiracetam worldwide.

The listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorder (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss and worsening of seizures including in patients with SCN8A mutations.

Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

4 ) Levetiracetam is contraindicated in patients with a hypersensitivity to levetiracetam. 4 )] .

Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in adults and adolescents from 16 years of age with newly diagnosed epilepsy. Keppra is indicated as adjunctive therapy • in the treatment of partial onset seizures with or without secondary generalisation in adults, adolescents, children and infants from 1 month of age with epilepsy.

• in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy. • in the treatment of primary generalised tonic-clonic seizures in adults and adolescents from 12 years of age with Idiopathic Generalised Epilepsy.

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. 3 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. 73m2) Dose and frequency Normal Mild Moderate Severe End-stage renal disease patients undergoing dialysis (1) ≥ 80 50-79 30-49 < 30 - 500 to 1500 mg twice daily 500 to 1000 mg twice daily 250 to 750 mg twice daily 250 to 500 mg twice daily 500 to 1000 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. 20 ml/kg) once daily (3) (5) (1) Keppra oral solution should be used for doses under 250 mg, for doses not multiple of 250 mg when dosing recommendation is not achievable by taking multiple tablets and for patients unable to swallow tablets.

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.

The tablet formulation is not adapted for use in infants and children under the age of 6 years. Keppra oral solution is the preferred formulation for use in this population. In addition, the available dose strengths of the tablets are not appropriate for initial treatment in children weighing less than 25 kg, for […]

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 pooledplacebo- controlled clinical trials with all indications studied, with a total of 3416 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 (≥1/10000 to <1/1000) and very rare (<1/10000).

9 MedDRA SOC Frequency category Very common Common Uncommon Rare Very rare Infections and infestations Nasopharyngit is Infection Blood and lymphatic system disorders Thrombocytop enia, leukopenia Pancytopenia, neutropenia, agranulocytosis Immune system disorders Drug reaction with eosinophilia and systemic symptoms (DRESS)(1), Hypersensitivity (including angioedema and 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, thinking abnormal, delirium Obsessive compulsive disorder(2) Nervous system disorders Somnolence, headache Convulsion, balance disorder, dizziness, lethargy, tremor Amnesia, memory impairment, coordination abnormal/ataxi a, paraesthesia, disturbance in attention Choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, seizures aggravated, Neuroleptic malignant syndrome(3) Eye disorders Diplopia, vision blurred Ear and labyrinth disorders Vertigo Cardiac disorders Electrocardiogra m QT prolonged 10 MedDRA SOC Frequency category Very common Common Uncommon Rare Very rare Respiratory, thoracic and mediastinal disorders Cough Gastrointestin al disorders Abdominal pain, diarrhoea, dyspepsia, vomiting, nausea Pancreatitis Hepatobiliary disorders Liver function test abnormal Hepatic failure, hepatitis Skin and subcutaneous tissue disorders Rash Alopecia, eczema, pruritus, Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme Musculoskelet al and connective tissue disorders Muscular weakness, myalgia Rhabdomyolysis and blood creatine phosphokinase increased(3) Renal and urinary disorders Acute kidney injury General disorders and administration site conditions Asthenia/ fatigue Injury, poisoning and procedural complications Injury (1) See Description of selected adverse reactions.

(2) 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. (3) Prevalence is significantly higher in Japanese patients when compared to non-Japanese patients.

Description of selected adverse reactions Multiorgan hypersensitivity reactions Multiorgan hypersensitivity reactions (also known as Drug Reaction with Eosinophilia and Systemic Symptoms, DRESS) have been reported rarely in patients treated with levetiracetam.

Clinical manifestations may develop 2 to 8 weeks after starting treatment. These reactions are variable in expression, but typically present with fever, rash, facial oedema, lymphadenopathies, haematologic abnormalities and can be associated with involvement of different organ systems, mostly the liver.

If multiorgan hypersensitivity reaction is suspected, levetiracetam should be discontinued. 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. 11 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.

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