Epitam 500

Yellow, oval, biconvex film-coated tablet. One side has incision, letter "L" and "T" on each side. Another side has the figure "500".
Each film-coated tablet contains Levetiracetam 500 mg.

Pharmacology: Pharmacodynamics: Mechanism of action: Levetiracetam, a pyrrolidine derivative, is an anticonvulsant agent that is structurally unrelated to other currently available anticonvulsants. The mechanism of anticonvulsants action of levetiracetam is unknown.
In vitro studies show that levetiracetam affects intraneuronal Ca²⁺ levels by partial inhibition of N-type Ca²⁺ currents and by reducing the release of Ca²⁺ from intraneuronal stores. In addition, it partially reverses the reductions in GABA- and glycine-gated currents induced by zinc and β-carbolines. Furthermore, levetiracetam has been shown in in vitro studies to bind to a specific site in rodent brain tissue. This binding site is the synaptic vesicle protein 2A, believed to be involved in vesicle fusion and neurotransmitter release. Levetiracetam and related analogs show a rank order of affinity for binding to the synaptic vesicle protein 2A which correlates with the potency of their anti-seizure protection in the mouse audiogenic model of epilepsy. This finding suggests that the interaction between levetiracetam and the synaptic vesicle protein 2A seems to contribute to the antiepileptic mechanism of action of the drug.
Pharmacokinetics: Levetiracetam is readily absorbed from the gastrointestinal tract with a bioavailability of almost 100%, peak plasma concentrations usually occur within 1.3 hours of oral doses and steady state after 2 days. Plasma protein binding is minimal at less than 10%. Levetiracetam is not extensively metabolised; about 25% of a dose is metabolised by hydroxylation to inactive metabolites. Around 95% of a dose is excreted as unchanged drug and metabolites in the urine. The plasma elimination half-life has been reported to be about 7 hours in adults and children aged 12 years and over; the half-life may be shorter in younger children. Levetiracetam is distributed into breast milk.

Levetiracetam is indicated as monotherapy in the treatment of partial onset seizures with or without secondary generalization in adults and adolescents from 16 years of age with newly diagnosed epilepsy.
Levetiracetam is indication as adjunctive therapy in the treatment of: partial onset seizures with or without secondary generalization in adults, adolescents and children from 4 years of age with epilepsy; myoclonic seizures in adults and adolescents from 12 years of age with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures in adults, adolescents and children from 6 years of age with idiopathic generalized epilepsy.

Recommended Dose: Adult: 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 2 weeks. The dose can be further increased by 250 mg twice daily every two weeks depending upon the clinical response. The maximum dose is 1,500 mg twice daily.
Add-on therapy: 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. Depending upon the clinical response and tolerance, the daily dose can be increased up to 1,500 mg twice daily. Dose changes can be made in 500 mg twice daily increases every two to four weeks.
Children: 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 children under the age of 6 years. Levetiracetam oral solution is preferred formulation for use in this population.
In additional, 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 previously mentioned 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.
There are no data available.
Add-on therapy for children (4 to 11 years) and adolescents (12 to 17 years) weighing less than 50 kg: Levetiracetam oral solution is the preferred formulation for use in children under the age of 6 years.
For children 6 years and above, 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.
The 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 increments or decrements of 10 mg/kg twice daily every two weeks. The lowest effective dose should be used.
Dose in children 50 kg or greater is the same as in adults.
Dose recommendations for children and adolescents: See Table 1.

Click on icon to see table/diagram/image

Adequate presentation must be used to ensure the accuracy of the dosing.
Elderly: Adjustment of the dose is recommended in elderly patients with compromised renal function.
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.
The CLcr in ml/min may be estimated from serum creatinine (mg/dl) determination, for adults and adolescents weighing 50 kg or more, using the following formula: See Equation 1 and Table 2.

Click on icon to see table/diagram/image


Click on icon to see table/diagram/image

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.
The CLcr in ml/min/1.73 m² may be estimated from serum creatinine (mg/dl) determination using, for young adolescents and children using the following formula (Schwartz formula): See Equation 2 and Table 3.

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 creatinine clearance is <60 ml/min/1.73 m².
Mode of Administration: EPITAM 500 is administered orally without regard to food.^{[1, 4]}

Symptom and signs: somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with levetiracetam overdoses.
Treatment: There is no specific antidote for levetiracetam. Treatment of an overdose will be symptomatic and may include heamodialysis. The dialyser extraction efficiency is 60% for levetiracetam and 74% for the primary metabolite. Further management should be as clinically indicated or as recommended by the national poisons centre, where available.

Levetiracetam is contraindicated in patients with known hypersensitivity to the drug or other pyrrolidone derivatives.

Psychiatric symptoms: Psychosis, paranoia, hallucinations and behavioral symptoms (including aggression, agitation, anger, anxiety, apathy, confusion, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder) may occur; dose reduction or discontinuation may be required.
Suicidal ideation: Pooled analysis of trials involving various antiepileptics (regardless of indication) showed an increased risk of suicidal thoughts/behavior (incidence rate: 0.43% treated patients compared to 0.24% of patients receiving placebo); risk observed as early as 1 week after initiation and continued through duration of trials (most trials 24 weeks or less). Monitor all patients for notable changes in behavior that might indicate suicidal thoughts or depression; notify health care provider immediately if symptoms occur.
Withdrawal: Anticonvulsants should not be discontinued abruptly because of the possibility of increasing seizure frequency; therapy should be withdrawn gradually to minimize the potential of increased seizure frequency, unless safety concerns require a more rapid withdrawal.
Renal function impairment: Use caution with renal impairment; dosage adjustment may be necessary. In patients with end-stage renal disease requiring hemodialysis, it is recommended that immediate-release formulations be used instead of extended-release formulations.
Hematologic effects: Decreases in red blood cell counts, hemoglobin, hematocrit, white blood cell counts and neutrophils have been observed. Case of eosinophilia, agranulocytosis, and lymphocytosis have also been reported.

Pregnancy: Category C.
Adverse events have been observed in animal reproduction studies. Levetiracetam crosses the placenta and can be detected in the neonate at birth. Concentrations in the umbilical cord at delivery are similar to those in the maternal plasma. Serum concentrations of levetiracetam may be decreased as pregnancy progress; monitor carefully throughout pregnancy and postpartum.
Lactation: Levetiracetam is distributed into milk. Because of the potential for serious adverse reactions to levetiracetam in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the woman.

Common: Gastrointestinal: loss of appetite (3% to 8%), vomiting (15%).
Immunologic: infectious disease (13%).
Musculoskeletal: decreased bone mineral density (70%), neck pain (2% to 8%).
Neurologic: asthenia (15%), dizziness (5% to 9%), headache (14% to 19%).
Psychiatric: abnormal behavior (7% to 37.6%), irritability (6% to 12%).
Respiratory: cough (2% to 9%), nasopharyngitis (7% to 15%).
Other: fatigue (10% to 11%).
Serious: Dermatologic: Stevens-Johnson syndrome, toxic epidermal necrolysis.
Hematologic: decreased erythrocyte production, decreased white blood cell count (2.4% to 3.2%), eosinophil count raised (8.6%), neutropenia (2.4%), pancytopenia, thrombocytopenia.
Hepatic: liver failure.
Immunologic: anaphylaxis.
Neurologic: somnolence (8% to 45%).
Psychiatric: suicidal intent (0.5%), suicide.
Other: Angioedema.

Concomitant use of levetiracetam and other anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid) does not appear to affect the pharmacokinetics of levetiracetam.
Concomitant use of levetiracetam and digoxin does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., cardiac rhythm effects) of digoxin; digoxin also does not affect the pharmacokinetics of levetiracetam.
Concomitant use of levetiracetam and oral contraceptives does not appear to affect the pharmacokinetics of oral contraceptives.
Concomitant use of levetiracetam and probenecid does not effect on levetiracetam pharmacokinetics was observed, but steady-state plasma concentrations of the principal inactive metabolite were approximately doubled due to a 60% reduction in renal clearance.
Concomitant use of levetiracetam and warfarin does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., prothrombin time) of warfarin; warfarin also does not affect the pharmacokinetics of levetiracetam.

Store below 30°C.

Anticonvulsants

N03AX14 - levetiracetam ; Belongs to the class of other antiepileptics.

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