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Levetam 500mg

Levetam 500mg

Category: Tablets 
Classification: CNS Drug
Product English Name: Levetam
Product Arabic Name: ليفيتام
Scientific Name English: Levetiracetam
Scientific Name Arabic: ليفيتيراسيتام
Product Unit: 30 Tablet
Product Strength: 500mg

Description

Clinical Pharmacology

Mechanism of Action:

The precise mechanism(s) by which Levetiracetam exerts its antiepileptic effect is unknown. However, experimental data indicate that Levetiracetam binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle fusion and neurotransmitter exocytosis. 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.

Pharmacodynamics:

In vitro studies show that Levetiracetam prevents seizure activity via affecting intraneuronal Ca2+levels by partial inhibition of N-type Ca2+currents and by reducing the release of Ca2+from intraneuronal stores in which the intraneuronal Ca2+ions are the main cause of convulsions. Both partial and generalized epilepsy models (epileptiform discharge/ photoparoxysmal response) confirmed the broad spectrum preclinical pharmacological profile.

Additional information

Pharmacokinetics

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear and time independent with low intrasubject and intersubject 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.

The pharmacokinetics of Levetiracetam are similar when used as monotherapy or as adjunctive therapy for the treatment of partial-onset seizures.
Absorption and Distribution

Absorption of Levetiracetam is rapid, with peak plasma concentrations occurring in about an hour following oral administration in fasted subjects. The oral bioavailability of Levetiracetam tablets is 100% and the tablets and oral solution are bioequivalent in rate and extent of absorption. Food does not affect the extent of absorption of Levetiracetam but it decreases Cmax by 20% and delays T max by 1.5 hours. The pharmacokinetics of Levetiracetam are linear over the dose range of 500 to 5000 mg. Steady state is achieved after 2 days of multiple twice-daily dosing. 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.

Metabolism:

Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of dose) and is not dependent on any liver cytochrome P450 isoenzymes. Therefore the interaction of Levetiracetam with other substances, or vice versa, is unlikely.

Elimination:

Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated administration. The major route of excretion is via urine, accounting for a mean 95% of the dose, with approximately 93% of the dose excreted within 48 hours. The total body clearance is 0.96 ml/min/kg and the renal clearance is 0.6 ml/min/kg. The mechanism of excretion is glomerular filtration with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular filtration and active tubular secretion with a renal clearance of 4 ml/min/kg.
Indications and Usage for Levetam

Partial-Onset Seizures:

Levetiracetam is indicated for the treatment of partial-onset seizures in patients 1 month of age and older.

Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy:

Levetiracetam tablets are indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.

Primary Generalized Tonic-Clonic Seizures:

Levetiracetam tablets 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.
Dosage and Administration

Important Administration Instructions:

Levetiracetam tablet is given orally with or without food. The Levetiracetam dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function.

Dosing for Partial-Onset Seizures:

The recommended dosing for monotherapy and adjunctive therapy is the same as following:

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.

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.

– 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).

For Levetiracetam tablets 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 tablets 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).

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 more than 3000 mg/day has not been studied.

Dosing for Primary Generalized Tonic-Clonic Seizures:

– 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). Increase dosage by 1000 mg/day every 2 weeks to the recommended daily dose of 3000 mg. The effectiveness of doses more 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).

Contraindications:

Levetiracetam tablets are contraindicated in patients with a hypersensitivity to Levetiracetam. Reactions have included anaphylaxis and angioedema.
Warnings and Precautions

Behavioral Abnormalities and Psychotic Symptoms

Levetiracetam tablets may cause behavioral abnormalities and psychotic symptoms, so treated patients with Levetiracetam should be monitored for psychiatric signs and symptoms.

Suicidal Behavior and Ideation:

Antiepileptic drugs (AEDs), including Levetiracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Somnolence and Fatigue:

Levetiracetam may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on Levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

Asthenia:

In controlled clinical studies in adult patients with epilepsy, 15% of patients taking levetiracetam developed asthenia, compared with 9% of patients taking placebo.

Anaphylaxis and Angioedema:

Levetiracetam can cause anaphylaxis or angioedema after the first dose or at any time during treatment.

Serious Dermatological Reactions:

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in some pediatric and adult patients treated with Levetiracetam.

Coordination Difficulties:

Levetiracetam may cause coordination difficulties.

Withdrawal Seizures:

As with most antiepileptic drugs, Levetiracetam tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus.

Hematologic Abnormalities:

Levetiracetam can cause hematologic abnormalities.

Increase in Blood Pressure:

In a randomized, placebo-controlled study in patients 1 month to <4 years of age, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam tablets-treated patients (17%).

Side Effects:

Like all medicines, this medicine can cause side effects, although not everybody gets them.

Asthenia, somnolence, headache, infection, dizziness, pain, pharyngitis, depression, nervousness, rhinitis, anorexia, ataxia, vertigo, amnesia, anxiety, cough, diplopia, emotional lability, hostility, paresthesia, sinusitis

Drug Interactions:

Pre-marketing data from clinical studies conducted in adults indicate that levetiracetam 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 levetiracetam. As in adults, there is no evidence of clinically significant medicinal product interactions in paediatric patients receiving up to 60 mg/kg/day levetiracetam.

Methotrexate:

Concomitant administration of levetiracetam and methotrexate has been reported to decrease methotrexate clearance, resulting in increased/prolonged blood methotrexate concentration to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with the two drugs.

Oral contraceptives:

Levetiracetam 1000 mg daily did not influence the pharmacokinetics of oral contraceptives.
Use in Specific Population

Pregnancy:

Levetiracetam can be used during pregnancy, if after careful assessment it is considered clinically needed.

Lactation:

Levetiracetam is excreted in human breast milk. Because of the potential for serious adverse reactions in breastfeeding infants from Levetam, a decision should be made whether to discontinue breastfeeding or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use:

The safety and effectiveness of Levetiracetam tablets for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established. The dosing recommendation in these pediatric patients varies according to age group and is weight-based.

Geriatric Use:

Overall differences in safety were observed between these subjects and younger subjects.

Renal Impairment:

Clearance of Levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Dose adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis.

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