Drug Class Description
Pyrrolidone derivatives (anti- epileptics /anticonvulsants).

Generic Name
Levetiracetam

Drug Description
Tablets:Each film-coated tablet contains 250 mg levetiracetam, 500 mg levetiracetam, 750 mg levetiracetam & excipient colouring agent E110 or 1000 mg levetiracetam.Oral solution:Each ml contains 100 mg levetiracetam.Excipients: methyl parahydroxybenzoate (E218), propyl parahydroxybenzoate (E216) and 300 mg maltitol.Concentrate for solution for infusion:Each ml contains 100 mg of levetiracetam.The 5 ml vial contains 500 mg of levetiracetam.

Presentation
Film-coated tablet.Blue, oblong, scored and debossed with the code “ucb” and “250” on one side. Yellow, oblong, scored and debossed with the code “ucb 500” on one side. Orange, oblong, scored and debossed with the code “ucb 750” on one side. White, oblong, scored and debossed with the code “ucb 1000” on one side.Oral solution:Clear liquid.Concentrate for solution for infusion:Keppra concentrate is a clear, colourless, sterile solution

Indications
Keppra is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalisation in patients 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 and children from 4 years 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. Keppra concentrate is an alternative for patients when oral administration is temporarily not feasible.

Adult Dosage
Tablets:The film-coated tablets must be taken orally, swallowed with a sufficient quantity of liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.Oral solution:The oral solution may be diluted in a glass of water and may be taken with or without food. A graduated oral syringe and instruction for use in the package leaflet are provided with Keppra. The daily dose is administered in two equally divided doses.Concentrate for solution for infusion:Keppra therapy can be initiated with either intravenous or oral administration.Conversion to or from oral to intravenous administration can be done directly without titration. The total daily dose and frequency of administration should be maintained.Keppra concentrate is for intravenous use only and the recommended dose must be diluted in at least 100 ml of a compatible diluent and administered intravenously as a 15-minute intravenous infusion.There is no experience with administration of intravenous levetiracetam for longer period than 4 days.• MonotherapyAdults and adolescents from 16 years of ageThe recommended starting dose is 250 mg twice daily which should be increased to an initial therapeutic dose of 500 mg twice daily after two weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1500 mg twice daily.• Add-on therapyAdults (18 years) and adolescents (12 to 17 years) weighing 50 kg or moreThe initial therapeutic dose is 500 mg twice daily. This dose can be started on the first day of treatment.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 500 mg twice daily increases or decreases every two to four weeks.Elderly (65 years and older)Adjustment of the dose is recommended in elderly patients with compromised renal functionChildren aged 4 to 11 years and adolescents (12 to 17 years) weighing less than 50 kgThe initial therapeutic dose is 10 mg/kg twice daily.Depending upon the clinical response and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose changes should not exceed increases or decreases of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.Dosage in children 50 kg or greater is the same as in adults.The physician should prescribe the most appropriate pharmaceutical form and strength according to weight and dose.Dosage recommendations for children and adolescents:WeightStarting dose: 10 mg/kg twice dailyMaximum dose: 30 mg/kg twice daily15 kg (1)150 mg twice daily450 mg twice daily20 kg (1)200 mg twice daily600 mg twice daily25 kg250 mg twice daily750 mg twice dailyFrom 50 kg (2)500 mg twice daily1500 mg twice daily(1) Children 20 kg or less should preferably start the treatment with Keppra 100 mg/ml oral solution.(2) Dosage in children and adolescents 50 kg or more is the same as in adults.The graduated oral syringe contains up to 1,000 mg levetiracetam (corresponding to 10 ml) with a graduation every 25 mg (corresponding to 0.25 ml).A Keppra concentrate vial contains 500 mg levetiracetam in 5 ml (corresponding to 100 mg/ml).Infants and children less than 4 years Keppra is not recommended for use in children below 4 years of age due to insufficient data on safety and efficacy.Patients with renal impairmentThe 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. The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination using the following formula:Then CLcr is adjusted for body surface area (BSA) as follows:Dosing adjustment for adult patients with impaired renal functionGroupCreatinine clearance (ml/min/1.73 m2 )Dosage and frequencyNormal 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.Patients with 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. Therefore a 50 % reduction of the daily maintenance dose is recommended when the creatinine clearance is < 70 ml/min.

Child Dosage
Under 16 years, not recommended; Under 16 years, not recommended; over 16 years, as for adults.

Contra Indications
Hypersensitivity to levetiracetam or other pyrrolidone derivatives or any of the excipients.

Special Precautions
In accordance with current clinical practice, if Keppra has to be discontinued it is recommended to withdraw it gradually (e.g. in adults: 500 mg decreases twice daily every two to four weeks; in children: dose decrease should not exceed 10 mg/kg twice daily every two weeks).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.An increase in seizure frequency of more than 25 % was reported in 14 % of levetiracetam treated adult and paediatric patients with partial onset seizures, whereas it was reported in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.When Keppra was used to treat primary generalised tonic-clonic seizures in adults and adolescents with idiopathic generalised epilepsy, there was no effect on the frequency of absences.The administration of Keppra to patients with renal impairment may require dose adjustment. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.Suicide, suicide attempt and suicidal ideation and behaviour have been reported in patients treated with antiepileptic agents (including levetiracetam). A meta-analysis of randomized placebo controlled trials of epileptic drugs 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.Keppra 100 mg/ml oral solution includes methyl parahydroxybenzoate (E218) and propyl parahydroxybenzoate (E216) which may cause allergic reactions (possibly delayed).It also includes maltitol; patients with rare hereditary problems of fructose intolerance should not take this medicine.Keppra 100 mg/ml concentrate for solution for infusion:This medicinal product contains 0.313 mmol (or 7.196 mg) of sodium per vial. To be taken into consideration by patients on a controlled sodium diet.

Interactions
Pre-marketing data from clinical studies conducted in adults indicate that Keppra did not influence the serum concentrations of existing antiepileptic medicinal products (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these antiepileptic medicinal products did not influence the pharmacokinetics of Keppra.As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.A retrospective assessment of pharmacokinetic interactions in children and adolescents with epilepsy (4 to 17 years) confirmed that adjunctive therapy with orally administered levetiracetam did not influence the steady-state serum concentrations of concomitantly administered carbamazepine and valproate. However, data suggested a 22% higher levetiracetam clearance in children taking enzyme-inducing antiepileptic medicinal products. Dosage adjustment is not required.Probenecid (500 mg four times daily), a renal tubular secretion blocking agent, has been shown to inhibit the renal clearance of the primary metabolite but not of levetiracetam. Nevertheless, the concentration of this metabolite remains low. It is expected that other medicinal products excreted by active tubular secretion could also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid was not studied and the effect of levetiracetam on other actively secreted medicinal products, e.g. NSAIDs, sulfonamides and methotrexate, is unknown.Levetiracetam 1,000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl-estradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified. Levetiracetam 2,000 mg daily did not influence the pharmacokinetics of digoxin and warfarin; prothrombin times were not modified. Co-administration with digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.No data on the influence of antacids on the absorption of levetiracetam are available.The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.No data on the interaction of levetiracetam with alcohol are available.

Adverse Reactions
Undesirable effects that resulted from Keppra intravenous use are similar to those associated with Keppra oral use. The most frequently reported adverse reactions were dizziness, somnolence, headache and postural dizziness. Since there was limited exposure for Keppra intravenous use and since oral and intravenous formulations are bioequivalent, the safety information of Keppra intravenous will rely on Keppra oral use.Pooled safety data from clinical studies conducted with Keppra oral formulations in adult patients with partial onset seizures showed that 46.4 % of the patients in the Keppra group and 42.2 % of the patients in the placebo group experienced undesirable effects. Serious undesirable effects were experienced in 2.4% of the patients in the Keppra and 2.0% of the patients in the placebo groups. The most commonly reported undesirable effects were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the central nervous system related undesirable effects decreased over time.In monotherapy 49.8 % of the subjects experienced at least one drug related undesirable effect. The most frequently reported undesirable effects were fatigue and somnolence.A study conducted in paediatric patients (4 to 16 years) with partial onset seizures showed that 55.4 % of the patients in the Keppra group and 40.2 % of the patients in the placebo group experienced undesirable effects. Serious undesirable effects were experienced in 0.0 % of the patients in the Keppra group and 1.0 % of the patients in the placebo group. The most commonly reported undesirable effects were somnolence, hostility, nervousness, emotional lability, agitation, anorexia, asthenia and headache in the paediatric population. Safety results in paediatric patients were consistent with the safety profile of levetiracetam in adults except for behavioural and psychiatric adverse events which were more common in children than in adults (38.6% versus 18.6%). However, the relative risk was similar in children as compared to adults.A study conducted in adults and adolescents with myoclonic seizures (12 to 65 years) showed that 33.3% of the patients in the Keppra group and 30.0% of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported undesirable effects were headache and somnolence. The incidence of undesirable effects in patients with myoclonic seizures was lower than that in adult patients with partial onset seizures (33.3% versus 46.4%).A study conducted in adults and children (4 to 65 years) with idiopathic generalised epilepsy with primary generalised tonic-clonic seizures showed that 39.2 % of the patients in the Keppra group and 29.8 % of the patients in the placebo group experienced undesirable effects that were judged to be related to treatment. The most commonly reported undesirable effect was fatigue.Undesirable effects reported in clinical studies (adults and children) or from post-marketing experience are listed in the following table per System Organ Class and per frequency. For clinical trials, the frequency is defined as follows: very common (1/10); common (1/100,<1/10); uncommon (1/1,000, <1/100); rare (1/10,000, <1/1,000); very rare (<1/10,000), including isolated reports. Data from post-marketing experience are insufficient to support an estimate of their incidence in the population to be treated.- General disorders and administration site conditionsVery common: asthenia/fatigue- Nervous system disordersVery common: somnolenceCommon: amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, balance disorder, disturbance in attention, memory impairment.Post-marketing experience: paraesthesia- Psychiatric disordersCommon: agitation, depression, emotional lability/mood swings, hostility/aggression, insomnia, nervousness/irritability, personality disorders, thinking abnormalPost-marketing experience: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicidal ideation- Gastrointestinal disordersCommon: abdominal pain, diarrhoea, dyspepsia, nausea, vomitingPost-marketing experience: pancreatitis- Hepatobiliary disorders:Post-marketing experience: hepatic failure, hepatitis, liver function test abnormal- Metabolism and nutrition disordersCommon: anorexia, weight increase.The risk of anorexia is higher when topiramate is coadministered with levetiracetam.Post-marketing experience: weight loss- Ear and labyrinth disordersCommon: vertigo- Eye disordersCommon: diplopia, vision blurred- Musculoskeletal and connective tissue disordersCommon: myalgia- Injury, poisoning and procedural complicationsCommon: accidental injury- Infections and infestationsCommon: infection, nasopharyngitis- Respiratory, thoracic and mediastinal disordersCommon: cough increased- Skin and subcutaneous tissue disordersCommon: rash, eczema, pruritusPost-marketing experience: alopecia: in several cases, recovery was observed when Keppra was discontinued.- Blood and lymphatic system disordersCommon: thrombocytopeniaPost-marketing experience: leukopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of the cases)

Manufacturer
UCB

Drug Availability
(POM)

Updated
18 October 2010