Keppra Tablets 250 mg/500 mg/750 mg/1 000 mg Tablets

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 u2022 in the treatment of partial onset seizures with or without secondary generalisation in adults and children over 16 years of age with epilepsy u2022 in the treatment of myoclonic seizures in adults and adolescents from 12 years of age with Juvenile Myoclonic Epilepsy u2022 in the treatment of primary generalised tonic-clonic seizures in adults and children from 16 years of age with idiopathic generalised epilepsy.

The film-coated tablets must be taken orally, swallowed with liquid and may be taken with or without food. The daily dose is administered in two equally divided doses.

Monotherapy: Adults and adolescents from 16 years of age: The 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 daily dose is 1 500 mg twice daily.

Add-on therapy: Adults (u2265 18 years) and adolescents (12 to 17 years) weighing 50 kg or more, when indicated (see INDICATIONS): The initial therapeutic dose is 500 mg twice daily. The 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. The maximum daily dose is 3 000 mg.

Elderly (65 years and older): Adjustment of the dose is recommended in elderly patients with compromised renal function (see u2018 Patients with renal impairment u2019 below).

Adolescents (12 to 17 years) weighing less than 50 kg, when indicated (see INDICATIONS): The initial therapeutic dose is 10 mg/kg twice daily. This dose can be started on the first day of treatment. 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.

Recommended dosage for children and adolescents with normal renal function: Weight Starting dose Maximum dose 10 mg/kg twice daily 30 mg/kg twice daily 15 kg (1) 150 mg twice daily 450 mg twice daily 20 kg (1) 200 mg twice daily 600 mg twice daily 25 kg 250 mg twice daily 750 mg twice daily From 50 kg (2) 500 mg twice daily 1500 mg twice daily (1) Children 20 kg or less should preferably start 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 syringe contains up to 1000 mg levetiracetam (corresponding to 10 ml) with a graduation every 25 mg (corresponding to 0,25 ml).

Infants and children less than 12 years: There are insufficient data to recommend the use of KEPPRA tablets in children under 12 years of age.

Patients with renal impairment: The KEPPRA 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 patientu2019s creatinine clearance (CLcr) in ml/min is needed. The CLcr may be estimated from serum creatinine (mg/dl) determination using the following formula: [140 u2013 age (years) x weight (kg)] CLcr = ------------------------------------------ (x 0,85 for women) serum creatinine (u03bcmol/l)

Dosing adjustment for adult patients with impaired renal function. Group Creatinine clearance (ml/min) 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 mg twice daily Severe < 30 250 to 500 mg twice daily End-stage renal disease patients undergoing dialysis (1) -- 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 mg to 500 mg supplemental dose is recommended.

Hypersensitivity to levetiracetam or other pyrrolidone derivatives or any of the excipients. The use of KEPPRA is contra-indicated in pregnancy and lactation (see PREGNANCY AND LACTATION).

Discontinuation: If KEPPRA has to be discontinued, it is recommended to withdraw it gradually (e.g. 500 mg twice daily decrements every two to four weeks) in adults: 10 mg/kg twice daily decrements every two weeks in children).

Seizure frequency: An increase in seizure frequency of more than 25 % was reported in 14 % of KEPPRA treated adult and paediatric patients, whereas it was reported in 26 % and 21 % of placebo treated adult and paediatric patients, respectively.

Renal insufficiency: The administration of KEPPRA to patients with renal impairment may require dose adaptation. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection (see DOSAGE AND DIRECTIONS FOR USE).

Suicide: Suicide, suicide attempt and suicidal ideation have been reported in patients treated with KEPPRA. Patients should be advised to immediately report any symptoms of depression and/or suicidal ideation to their prescribing physician.

Monitoring: Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg bodyweight. Therefore there is no need for plasma level monitoring of levetiracetam.

Effects on ability to drive and use machines: No studies on the effect on the ability to drive and use machines have been performed. Patients might experience, at the beginning of treatment or following a dosage increase, somnolence or other CNS related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks, e.g. driving vehicles, or operating machinery.

Data indicate that KEPPRA did not influence the serum concentrations of existing antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone) and that these anti-epileptic medicines did not influence the pharmacokinetics of KEPPRA.

Probenecid: 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 medicines 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 drugs, e.g. NSAIDs, sulphonamides and methotrexate is unknown.

Oral contraceptives and other pharmacokinetic interactions: KEPPRA 1 000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinyl oestradiol and levonorgestrel); endocrine parameters (luteinising hormone (LH) and progesterone) were not modified. KEPPRA 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.

Antacids: No data on the influence of antacids on the absorption of levetiracetam are available.

Food and alcohol: The extent of absorption of levetiracetam was not altered by food, but the rate of absorption was slightly reduced.

There is no adequate information on the use of KEPPRA during pregnancy. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown (see CONTRA - INDICATIONS).

Physiological changes during pregnancy may affect KEPPRA levetiracetam concentration. There have been reports of decreased levetiracetam concentration during pregnancy. KEPPRA is contra - indicated in pregnancy.

Levetiracetam is excreted in human breast milk. Patients using KEPPRA should not breast-feed. Safety in breast-feeding has not been established (see CONTRA - INDICATIONS).

The most commonly reported side effects are somnolence, asthenia and dizziness. 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 KEPPRA in adults.

Clinical trial data: Undesirable effects reported in clinical studies (adults and children), the frequency is defined as follows: Very common (u2265 /10) Common (u2265 1/100 to < 1/10) Uncommon (u2265 1/1 000 to < 1/100) Rare (u2265 1/10 000 to < 1/1 000) Very rare (< 1/ 10 000), including isolated reports, not known (cannot be estimated on available data).

System Organ Class Frequency: Side effect Infections and infestations Common: infection, nasopharyngitis. Blood and lymphatic system disorders Common: thrombocytopenia Metabolism and nutrition disorders Common: anorexia, weight increase. The risk of anorexia is higher when topiramate is co-administered with KEPPRA.

Psychiatric disorders Common: agitation, depression, emotional instability/mood swings, hostility/aggression, insomnia, nervousness/irritability, personality disorders, thinking abnormal.

Nervous system disorders Very common: somnolence Common: Amnesia, ataxia, convulsions, dizziness, headache, hyperkinesias, tremor, balance disorder, disturbance in attention, memory impairment.

Eye disorders Common: diplopia, blurred vision. Ear and labyrinth disorders Common: vertigo. Respiratory, thoracic and mediastinal disorders Common: increased cough. Gastrointestinal disorders Common: diarrhoea, abdominal pain, dyspepsia, nausea, vomiting. Skin and subcutaneous tissue disorders Common: rash, eczema, pruritus. Musculoskeletal, connective tissue and bone disorders Common: myalgia. General disorders and administrative site conditions Very common: asthenia/fatigue Injury and poisoning Common: accidental injury.

Post marketing data: In addition to adverse events reported during clinical studies, and listed above, the following adverse events have been reported in post-marketing experience. Data are insufficient to support an estimate of their incidence in the population to be treated. Nervous system disorders: paraesthesia Psychiatric disorders: abnormal behaviour, anger, anxiety, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicide ideation Gastrointestinal disorders: pancreatitis Hepatobiliary disorders: hepatic failure, hepatitis, liver function test abnormal Metabolism and nutritional disorders: weight loss Skin and subcutaneous tissue disorders: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme and alopecia Blood and lymphatic system disorders: leucopenia, neutropenia, pancytopenia (with bone marrow suppression identified in some of the cases), thrombocytopenia.

There is no experience with doses greater than 5 000 mg/day orally. No serious adverse events were reported by healthy volunteers at single doses up to and including 5 000 mg orally. Symptoms of overdosage: somnolence, agitation, depressed level of consciousness, respiratory depression and coma. In acute, significant overdosage, the stomach may be emptied by gastric lavage or by induction of emesis. There is no specific antidote for levetiracetam. Treatment for an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60 % for levetiracetam and 74 % for the metabolite ucb L057.