Keppra

Keppra

levetiracetam

Manufacturer:

GlaxoSmithKline Indonesia
Full Prescribing Info
Contents
Levetiracetam.
Description
Levetiracetam is a pyrrolidone derivative [S-enantiomer of α-ethyl-2-oxo-pyrrolidine acetamide], chemically unrelated to existing antiepileptic active substances.
Action
Pharmacology: Mechanism of Action: The mechanism of action of levetiracetam is unknown, but appears to be unrelated to the mechanisms of current drugs. In vitro and in vivo experiments suggest that levetiracetam does not alter basic cell characteristics and normal neurotransmission.
Pharmacodynamic Effects: Levetiracetam induces seizure protection in a broad range of animal models of partial and primarily generalized seizures without having a proconvulsant effect. The primary metabolite is inactive.
In man, activity in both partial and generalised epilepsy conditions (epileptiform discharge/photoparoxysmal response) has confirmed the broad spectrum of the preclinical pharmacological profile.
Pharmacokinetics: Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-subject variability. There is no modification of the clearance after repeated administration. There is no evidence for any relevant gender, race or circadian variability. The pharmacokinetic profile is comparable in healthy volunteers and in patients with epilepsy. Due to its complete and linear absorption, plasma levels can be predicted from the oral dose of levetiracetam expressed as mg/kg body weight. Therefore, there is no need for plasma level monitoring of levetiracetam.
Absorption: Levetiracetam is rapidly absorbed after oral administration. Oral absolute bioavailability is close to 100%. Peak plasma concentrations (Cmax) are achieved at 1.3 hrs after dosing. Steady state is achieved after 2 days of a twice-daily administration schedule. Peak concentrations (Cmax) are typically 31 and 43 mcg/mL following a single 1000-mg dose and repeated 1000 mg twice daily dose, respectively. The extent of absorption is dose-independent and is not altered by food.
Distribution: No tissue distribution data are available in humans. Neither levetiracetam nor its primary metabolite are significantly bound to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5-0.7 L/kg, a value close to the total body water volume.
Biotransformation: Levetiracetam is not extensively metabolised in humans. The major metabolic pathway (24% of the dose) is an enzymatic hydrolysis of the acetamide group. Production of the primary metabolite, ucb L057, is not supported by liver cytochrome P-450 isoforms. Hydrolysis of the acetamide group was measurable in a large number of tissues including blood cells. The metabolite ucb L057 is pharmacologically inactive. Two minor metabolites were also identified. One was obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other one by opening of the pyrrolidone ring (0.9% of the dose). Other unidentified components accounted only for 0.6% of the dose. No enantiomeric interconversion was evidenced in vivo for neither levetiracetam nor its primary metabolite. In vitro, levetiracetam and its primary metabolite have been shown not to inhibit the major human liver cytochrome P-450 isoforms (CYP3A4, 2A6, 2C8/9/10, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase [UGT1*6 and UGT*1 and UGT(p16.2)] and epoxide hydroxylase activities. In addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid. In human hepatocytes in culture, levetiracetam did not cause enzyme induction. Therefore, the interaction of Keppra with other substances, or vice versa, is unlikely.
Elimination:
The plasma t½ in adults was 7±1 hrs and did not vary either with dose, route of administration or repeated administration. The mean total body clearance was 0.96 mL/min/kg. The major route of excretion was via urine, accounting for a mean 95% of the dose (approximately 93% of the dose was excreted within 48 hrs). Excretion via faeces accounted for only 0.3% of the dose. The cumulative urinary excretion of levetiracetam and its primary metabolite accounted for 66% and 24% of the dose, respectively, during the first 48 hrs. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 mL/min/kg, respectively, indicating that levetiracetam is excreted by glomerular filtration with subsequent tubular reabsorption and that the primary metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam elimination is correlated to creatinine clearance.
Elderly: In the elderly, the t½ is increased by about 40% (10-11 hrs). This is related to the decrease in renal function in this population.
Children (6-12 Years): Following single dose administration (20 mg/kg) to epileptic children, the t½ of levetiracetam was 6 hrs. The apparent body weight adjusted clearance was approximately 30% higher than in epileptic adults.
Renal Impairment: The apparent body clearance of both levetiracetam and of its primary metabolite is correlated to the creatinine clearance. It is therefore, recommended to adjust the maintenance daily dose of Keppra based on creatinine clearance in patients with moderate and severe renal impairment. In anuric end-stage renal disease subjects, the t½ was approximately 25 and 3.1 hrs during interdialytic and intradialytic periods, respectively. The fractional removal of levetiracetam was 51% during a typical 4-hr dialysis session. Hepatic Impairment: In subjects with mild and moderate hepatic impairment, there was a relevant modification of the clearance of levetiracetam. In most subjects with severe hepatic impairment, the clearance of levetiracetam was reduced by more than 50% due to a concomitant renal impairment.
Toxicology: Preclinical Safety Data: Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, genotoxicity and carcinogenicity. Although no evidence for carcinogenicity was seen, the potential carcinogenicity has not been fully evaluated due to some shortcomings in the study performed. Adverse effects not observed in clinical studies but seen in the rat and to a lesser extent, in the mouse at exposure levels similar to human exposure levels and with possible relevance for clinical use were liver changes, indicating an adaptive response eg, increased weight and centrilobular hypertrophy, fatty infiltration and increased liver enzymes in serum. In reproductive toxicity studies in the rat, levetiracetam induced developmental toxicity (increase in skeletal variations/minor anomalies, retarded growth, increased pup mortality) at exposure levels similar to or greater than the human exposure. In the rabbit foetal effects (embryonic death, increased skeletal anomalies and increased malformations) were observed in the presence of maternal toxicity. The systemic exposure at the observed no-effect level in the rabbit was about 4-5 times the human exposure.
Indications/Uses
Adjunctive therapy in the treatment of partial onset of seizures with or without secondary generalisation in patient with epilepsy.
Dosage/Direction for Use
Adults and Adolescents >16 Years: Initial Therapeutic Dose: 500 mg twice daily. This dose can be started on the 1st day of treatment. Depending upon the clinical response and tolerance, the daily dose can be increased up to 1500 mg twice daily. Dose changes can be made in 500 mg twice-daily increments or decrements every 2-4 weeks.
Elderly (≥65 Years): Adjustment of the dose is recommended in elderly patients with compromised renal function (see Renal Impairment as follows).
Children: There are insufficient data to recommend the use of levetiracetam in children and adolescents <16 years.
Renal Impairment: The daily dose must be individualised according to renal function. Refer to the table provided and adjust the dose as indicated. To use the dosing table, an estimate of the patient's creatinine clearance (CrCl) in mL/min is needed. (See table.) The CrCl in mL/min may be estimated from serum creatinine (mg/dL) determination using the formula provided. (See equation.)


Click on icon to see table/diagram/image




Click on icon to see table/diagram/image


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 CrCl is <70 mL/min.
Administration: Keppra 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 2 equally divided doses.
Overdosage
Symptoms: Somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with Keppra overdoses.
Treatment: After an acute overdose, the stomach may be emptied by gastric lavage or by induction of emesis.
There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include haemodialysis. The dialyser extraction efficiency is 60% for levetiracetam and 74% for the primary metabolite.
Contraindications
Hypersensitivity to levetiracetam or other pyrrolidone derivatives or to any of the excipients of Keppra.
Special Precautions
In accordance with current clinical practice, if Keppra has to be discontinued, it is recommended to withdraw it gradually (eg, 500 mg twice-daily decrements every 2-4 weeks). There are insufficient data for the withdrawal of concomitant antiepileptic medicinal products, once seizure control with levetiracetam in the add-on situation has been reached, in order to reach monotherapy on levetiracetam.
An increase in seizure frequency of >25% has been reported in 14% and 26% of the levetiracetam and placebo-treated patients, respectively. 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.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed. Due to possible different individual sensitivity, some patients might experience somnolence or other central nervous system-related symptoms, at the beginning of treatment or following a dose increase. Therefore, caution is recommended in those patients when performing skilled tasks eg, driving vehicles or operating machinery.
Use in pregnancy & lactation: There are no adequate data from the use of Keppra in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Keppra should not be used during pregnancy unless clearly necessary. Discontinuation of antiepileptic treatments may result in exacerbation of the disease, which could be harmful to the mother and the foetus.
Animal data show that levetiracetam is excreted in human breast milk. No data are available on the presence of levetiracetam in human breast milk. Therefore, breastfeeding is not recommended.
Use In Pregnancy & Lactation
There are no adequate data from the use of Keppra in pregnant women. Studies in animals have shown reproductive toxicity. The potential risk for humans is unknown. Keppra should not be used during pregnancy unless clearly necessary. Discontinuation of antiepileptic treatments may result in exacerbation of the disease, which could be harmful to the mother and the foetus.
Animal data show that levetiracetam is excreted in human breast milk. No data are available on the presence of levetiracetam in human breast milk. Therefore, breastfeeding is not recommended.
Adverse Reactions
Pooled safety data from clinical studies showed that 46.4% and 42.2% of the patients experienced adverse reactions in the Keppra and placebo groups, respectively, and that 2.4% and 2% of the patients experienced serious undesirable effects in the Keppra and placebo groups, respectively. The most commonly reported adverse reactions were somnolence, asthenia and dizziness. In the pooled safety analysis, there was no clear dose-response relationship but incidence and severity of the CNS-related adverse reactions decreased over time.
Undesirable effects reported in clinical studies or from post-marketing experience are listed as follows by system organ class and frequency. For clinical trials, the frequency is defined as follows: Very common (>10%); common (>1-10%); uncommon (>0.1-1%); rare (0.01-0.1%); very rare (<0.01%), 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 Conditions: Very Common: Asthenia.
Nervous System Disorders: Very Common: Somnolence. Common: Amnesia, ataxia, convulsion, dizziness, headache, tremor.
Psychiatric Disorders: Common: Depression, emotional lability, hostility, insomnia, nervousness. Post-Marketing Experience: Abnormal behaviour, aggression, anger, anxiety, confusion, hallucination, irritability, psychotic disorder.
Gastrointestinal Disorders: Common: Diarrhoea, dyspepsia, nausea.
Metabolism and Nutrition Disorders: Common: Anorexia.
Ear and Labyrinth Disorders: Common: Vertigo.
Eye Disorders: Common: Diplopia.
Injury, Poisoning and Procedural Complications: Common: Accidental injury.
Skin and Subcutaneous Tissue Disorders: Common: Rash.
Blood and Lymphatic System Disorders: Post-Marketing Experience: Leukopenia, neutropenia, pancytopenia, thrombocytopenia.
Drug Interactions
Premarketing data from clinical studies 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.
Probenecid (500 mg 4 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 eg, NSAIDs, sulphonamides and methotrexate is unknown.
Levetiracetam 1000 mg daily did not influence the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were not modified.
Levetiracetam 2000 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.
Storage
Do not store above 30°C.
MIMS Class
ATC Classification
N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.
Presentation/Packing
FC tab 250 mg x 30's. 500 mg x 20's. 1000 mg x 20's.
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