Leveget 1000mg 30 tablets

Levegeți Levetiracetam Tablets USP Film-coated Tablets 500 mg, 750 mg, and 1000 mg Description Levegeți (levetiracetam) is a piracetam analog. The chemical name of levetiracetam, the single enantiomer, is (−)-(S)-α-ethyl-2-oxo-1-pyrrolidineacetamide. Its molecular formula is C 8 H 14 N 2 O 2 and its structural formula is: Qualitative and quantitative composition Levegeți (levetiracetam) is intended for oral administration as: 1) Levegeți Tablets 500 mg Each film-coated tablet contains: Levetiracetam USP...500 mg 2) Levegeți Tablets 750 mg Each film-coated tablet contains: Levetiracetam USP...750 mg 3) Levegeți Tablets 1000 mg Each film-coated tablet contains: Levetiracetam USP...1000 mg Clinical pharmacology Mechanism of action The mechanism of action of levetiracetam is not yet fully understood. In vitro and in vivo experiments indicate that levetiracetam does not alter the basic characteristics of cells and normal neurotransmission. In vitro studies have shown that levetiracetam affects the intracellular Ca 2+ level by partially inhibiting N-type Ca 2+ currents and reducing the release of Ca 2+ from intracellular stores. In addition, it partially reverses the reduction of GABA- and glycine-dependent currents induced by zinc and β-carbolines. Furthermore, in vitro studies have shown that levetiracetam binds to a specific site in rodent brain tissue. This binding site is synaptic vesicle protein 2A, which is likely involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and its related analogs show a rank order of affinity for binding to synaptic vesicle protein 2A, which correlates with their anticonvulsant efficacy in the audiogenic model of epilepsy in mice. This finding suggests that the interaction between levetiracetam and synaptic vesicle protein 2A appears to contribute to the antiepileptic mechanism of action of the medicinal product. Pharmacokinetics Adults and adolescents Absorption Levetiracetam is rapidly absorbed after oral administration. The absolute bioavailability of oral administration is close to 100%. The maximum plasma concentration (Cmax) is reached 1.3 hours after administration. Steady state is reached two days after a twice-daily dosing regimen. Peak concentrations (Cmax) are typically 31 and 43 µg/mL after a single 1,000 mg dose and a repeated 1,000 mg twice-daily dose, respectively. The extent of absorption is dose-dependent and is not affected by food intake. Distribution Data on distribution in human tissues are not available. Neither levetiracetam nor its main metabolite are significantly bound to plasma proteins (<10%). The volume of distribution of levetiracetam is approximately 0.5 to 0.7 L/kg, which is close to the total body water volume. Biotransformation Levetiracetam is not extensively metabolized in humans. The main metabolic pathway (24% of the dose) is enzymatic hydrolysis of the acetamide group. The production of the main metabolite, ucb L057, is not supported by hepatic cytochrome P450 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 is obtained by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the other by opening of the pyrrolidone ring (0.9% of the dose). Other unidentified components accounted for only 0.6% of the dose. No enantiomeric interconversion was observed in vivo for either levetiracetam or its main metabolite. In vitro, levetiracetam and its main metabolite were shown not to inhibit the activity of major human liver cytochrome P450 isoforms (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, and 1A2), glucuronosyltransferase (UGT1A1 and UGT1A6), and epoxide hydroxylase. In addition, levetiracetam does not affect the glucuronidation of valproic acid in vitro. In a culture of human hepatocytes, levetiracetam had little or no effect on CYP1A2, SULT1E1, or UGT1A1. Levetiracetam caused mild induction of CYP2B6 and CYP3A4. In vitro data and in vivo interaction data with oral contraceptives, digoxin, and warfarin suggest that significant enzyme induction in vivo is not expected. Therefore, interactions of levetiracetam with other substances, or vice versa, are unlikely. Elimination The plasma half-life in adults was 7±1 hours and did not change with dose, route of administration, or repeated administration. The total body clearance was 0.96 mL/min/kg. The main route of excretion is via urine, accounting for an average of 95% of the dose (approximately 93% of the dose is excreted within 48 hours). Excretion in feces accounted for only 0.3% of the dose. Cumulative urinary excretion of levetiracetam and its primary metabolite was 66% and 24% of the dose, respectively, within the first 48 hours. 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 followed by tubular reabsorption, and that the main metabolite is also excreted by active tubular secretion in addition to glomerular secretion. Elimination of levetiracetam correlates with creatinine clearance. Special populations Elderly In the elderly, the half-life increases by approximately 40% (from 10 to 11 hours). This is related to impaired renal function in this population. Renal insufficiency The apparent clearance of both levetiracetam and its main metabolite from the body correlates with creatinine clearance. Therefore, adjustment of the maintenance daily dose of levetiracetam is recommended, taking into account creatinine clearance in patients with moderate and severe renal insufficiency. In adult subjects with end-stage renal disease, the half-life was approximately 25 and 3.1 hours during the interdialytic and intradialytic periods, respectively. The fractional removal of levetiracetam was 51% during a typical 4-hour dialysis session. Hepatic insufficiency No significant modification of levetiracetam clearance was observed in subjects with mild and moderate hepatic insufficiency. In most subjects with severe hepatic insufficiency, levetiracetam clearance was reduced by more than 50% due to concomitant renal insufficiency. Pediatric population Children (4 to 12 years) In children with epilepsy (6 to 12 years), after a single oral dose (20 mg/kg), the half-life of levetiracetam was 6.0 hours. The apparent clearance adjusted for body weight was approximately 30% higher than in adults with epilepsy. In children with epilepsy (4 to 12 years), after repeated oral doses (20 to 60 mg/kg/day), levetiracetam was rapidly absorbed. The maximum plasma concentration was observed 0.5-1.0 hours after administration. A linear and dose-proportional increase was observed for plasma peak concentration and area under the curve. The half-life was approximately 5 hours. The apparent body clearance was 1.1 mL/min/kg. Infants and children (1 month to 4 years) In children with epilepsy (1 month to 4 years), after a single dose (20 mg/kg) of a 100 mg/mL oral solution, levetiracetam was rapidly absorbed, and the maximum plasma concentration was observed approximately 1 hour after administration. Pharmacokinetic results showed that the half-life was shorter (5.3 h) than in adults (7.2 h) and the apparent clearance was faster (1.5 mL/min/kg) than in adults (0.96 mL/min/kg). In a population pharmacokinetic analysis conducted in patients aged 1 month to 16 years, body weight was significantly correlated with apparent clearance (clearance increased with increasing body weight) and apparent volume of distribution. Age also affected both parameters. This effect was pronounced in younger infants and decreased with age, becoming insignificant around 4 years of age. An approximately 20% increase in apparent clearance of levetiracetam was observed in both population pharmacokinetic analyses when co-administered with enzyme-inducing antiepileptic drugs. Therapeutic indications Levetiracetam is indicated as monotherapy for the treatment of partial onset seizures, with or without secondary generalization, in adults and adolescents aged 16 years and older with newly diagnosed epilepsy. Levetiracetam is indicated as adjunctive therapy • for the treatment of partial onset seizures, with or without secondary generalization, in adults, adolescents, children, and infants with epilepsy from 1 month of age. • for the treatment of myoclonic seizures in adults and adolescents aged 12 years and older with juvenile myoclonic epilepsy. • for the treatment of primary generalized tonic-clonic seizures in adults and adolescents aged 12 years and older with idiopathic generalized epilepsy. Levegeți Dosage and administration Partial onset seizures In monotherapy (from 16 years of age) and adjunctive therapy, the recommended dose is the same as described below. All indications 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 initiated on the first day of treatment. However, a lower initial dose of 250 mg twice daily may be given based on the physician's assessment of potential side effects versus seizure reduction. After two weeks, the dose may be increased to 500 mg twice daily. Depending on clinical response and tolerance, the daily dose may be increased to 1,500 mg twice daily. Dose adjustments can be made by increasing or decreasing the dose by 250 mg or 500 mg twice daily every two to four weeks. Adolescents (12 to 17 years) and children from 1 month of age weighing less than 50 kg The physician should prescribe the most appropriate pharmaceutical form, dosage form, and dosage according to weight, age, and dose. Discontinuation When levetiracetam administration is to be discontinued, it is recommended to withdraw it gradually (e.g., in adults and adolescents weighing more than 50 kg: decrease by 500 mg twice daily every two to four weeks; in infants, children, and adolescents weighing less than 50 kg aged 6 months or older: dose reduction should not exceed 10 mg/kg twice daily every two weeks; in infants (less than 6 months old): dose reduction should not exceed 7 mg/kg twice daily every two weeks). Special populations Elderly (65 years and older) Dose adjustment is recommended in elderly patients with impaired renal function. Renal insufficiency The daily dose should be individualized according to renal function. For adult patients, refer to the following table and adjust the dose accordingly. Group Creatinine clearance (mL/min/1.73 m 2 ) Dose and frequency Normal ≥ 80 500 to 1,500 mg twice daily Mild 50-79 500 to 1,000 mg twice daily Moderate 30-49 250 to 750 mg twice daily Severe < 30 250 to 500 mg twice daily Patients with end-stage renal disease undergoing dialysis (1) - 500 to 1,000 mg once daily (2) (1) A loading dose of 750 mg is recommended on the first day of levetiracetam treatment. (2) An additional dose of 250 to 500 mg is recommended after dialysis. For children with renal insufficiency, levetiracetam dose adjustment is necessary according to renal function, as levetiracetam clearance is related to renal function. Group Creatinine clearance (mL/min/1.73 m 2 ) Dose and frequency (1) Infants 1 to 6 months 6 to 23 months Infants, children, and adolescents weighing less than 50 kg Normal ≥ 80 7 to 21 mg/kg (0.07 to 0.21 mL/kg) twice daily 10 to 30 mg/kg (0.10 to 0.30 mL/kg) twice daily Mild 50-79 7 to 14 mg/kg (0.07 to 0.14 mL/kg) twice daily 10 to 20 mg/kg (0.10 to 0.20 mL/kg) twice daily Moderate 30-49 3.5 to 10.5 mg/kg (0.035 to 0.105 mL/kg) twice daily 5 to 15 mg/kg (0.05 to 0.15 mL/kg) twice daily Severe < 30 3.5 to 7 mg/kg (0.035 to 0.07 mL/kg) twice daily 5 to 10 mg/kg (0.05 to 0.10 mL/kg) twice daily Patients with end-stage renal disease undergoing dialysis -- 7 to 14 mg/kg (0.07 to 0.14 mL/kg) once daily (2) (4) 10 to 20 mg/kg (0.10 to 0.20 mL/kg) once daily (3) (5) 1) Levetiracetam oral solution should be used for doses less than 250 mg, for doses that are not multiples of 250 mg when the dosing recommendation cannot be achieved by splitting a tablet, and for patients who cannot swallow tablets. (2) A loading dose of 10.5 mg/kg (0.105 mL/kg) is recommended on the first day of levetiracetam treatment. (3) A loading dose of 15 mg/kg (0.15 mL/kg) is recommended on the first day of levetiracetam treatment. (4) An additional dose of 3.5 to 7 mg/kg (0.035 to 0.07 mL/kg) is recommended after dialysis. (5) An additional dose of 5 to 10 mg/kg (0.05 to 0.10 mL/kg) is recommended after dialysis. Hepatic insufficiency No dose adjustment is required in patients with mild and moderate hepatic insufficiency. In patients with severe hepatic insufficiency, creatinine clearance may not be sufficient to assess renal impairment. Therefore, a 50% reduction in the daily maintenance dose is recommended when creatinine clearance is < 60 mL/min/1.73 m 2 . Pediatric population The tablet form is not suitable for use in infants and children under 6 years of age. Furthermore, the available dosage strengths of the tablets are not suitable for children weighing less than 25 kg for initial treatment, for patients who cannot swallow tablets, or for doses less than 250 mg. The safety and efficacy of levetiracetam as monotherapy treatment in children and adolescents up to 16 years of age have not been established. Method of administration Film-coated tablets should be taken orally, swallowed with a sufficient amount of fluid, and may be taken with or without food. A bitter taste of levetiracetam may be perceived after oral administration. The daily dose is taken in two equally divided doses. Levegeți Contraindications Hypersensitivity to the active substance or to any of the pyrrolidone derivatives or to any of the excipients. Side effects Very common: nasopharyngitis, somnolence, and headache. Common: anorexia, depression, hostility/aggression, anxiety, insomnia, nervousness/irritability, seizures, balance disorder, dizziness, lethargy, tremor, vertigo, cough, abdominal pain, diarrhea, dyspepsia, vomiting, nausea, rash, and asthenia/fatigue. Uncommon: thrombocytopenia, leukopenia, weight loss, weight gain, attempted suicide, suicidal thoughts, psychotic disorder, behavioral disorders, hallucinations, anger, confusion, panic attack, emotional lability/mood swings, agitation, amnesia, memory impairment, coordination disorder/ataxia, paresthesia, attention disturbance, diplopia, blurred vision, abnormal liver function tests, alopecia, eczema, pruritus, muscle weakness, myalgia, and injuries. Rare: infection, pancytopenia, neutropenia, agranulocytosis, drug reaction with eosinophilia and systemic symptoms (DRESS), hypersensitivity (including angioneurotic edema and anaphylaxis), hyponatremia, completed suicide, personality disorder, thought disorder, delirium, choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, worsening of seizures, neuroleptic malignant syndrome, liver failure, hepatitis, acute renal failure, toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme, rhabdomyolysis, and increased serum creatine phosphokinase. Precautions Renal insufficiency In patients with renal insufficiency, administration of levetiracetam may require dose adjustment. In patients with severe hepatic impairment, renal function assessment is recommended before dose selection. Acute renal failure The use of levetiracetam is very rarely associated with acute renal failure, with onset times ranging from a few days to several months. Blood cell counts Rare cases of reduction in blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia, and pancytopenia) have been reported in association with levetiracetam intake, usually at the beginning of treatment. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders. Suicide Suicide, attempted suicide, suicidal thoughts, and behavior have been reported in patients treated with antiepileptic drugs (including levetiracetam). Therefore, patients should be monitored for signs of depression and/or suicidal thoughts and behavior, and appropriate treatment should be considered. Patients (and caregivers of patients) will be advised to seek medical attention if signs of depression and/or suicidal thoughts or behavior are observed. Abnormal and aggressive behaviors Levetiracetam can cause psychotic symptoms and behavioral disorders, including irritability and aggressiveness. Patients treated with levetiracetam should be monitored for the development of psychiatric signs indicating significant changes in mood and/or personality. If such behaviors are observed, dose adjustment or gradual discontinuation of treatment should be considered. Worsening of seizures As with other types of antiepileptic drugs, levetiracetam can rarely exacerbate the frequency or severity of seizures. This paradoxical effect has been primarily observed within the first month of starting levetiracetam or increasing the dose and was reversible upon discontinuation or dose reduction of the drug. QT interval prolongation on electrocardiogram Rare cases of QT interval prolongation have been observed during treatment with levetiracetam. Levetiracetam should be used with caution in patients with QTc interval prolongation, in patients being treated concomitantly with drugs that affect the QTc interval, or in patients with relevant pre-existing cardiac disease or electrolyte imbalances. Pediatric population The tablet form is not suitable for use in infants and children under 6 years of age. Data in children do not indicate an impact on growth and pubertal development. However, long-term effects on learning, intelligence, growth, endocrine function, pubertal development, and fertility potential in children are unknown. Drug interactions Antiepileptic drugs Pre-marketing data from clinical trials in adults indicate that levetiracetam does not affect the serum concentrations of existing antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone), and that these antiepileptic drugs did not affect the pharmacokinetics of levetiracetam. Similar to adults, there is no evidence of clinically significant drug interactions in pediatric patients taking levetiracetam at 60 mg/kg/day. Probenecid Probenecid (500 mg four times daily), a blocker of renal tubular secretion, has been shown to suppress the renal clearance of the main metabolite, but not of levetiracetam. Nevertheless, the concentration of this metabolite remains. Methotrexate Co-administration of levetiracetam and methotrexate is known to reduce methotrexate clearance, leading to increased/prolonged methotrexate concentrations in the blood to potentially toxic levels. Blood methotrexate and levetiracetam levels should be carefully monitored in patients treated concomitantly with these two drugs. Oral contraceptives and other pharmacokinetic interactions Levetiracetam 1,000 mg daily does not affect the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); endocrine parameters (luteinizing hormone and progesterone) were unchanged. Levetiracetam 2,000 mg daily does not affect the pharmacokinetics of digoxin and warfarin; prothrombin time was unchanged. Co-administration with digoxin, oral contraceptives, and warfarin did not affect the pharmacokinetics of levetiracetam. Laxatives There have been isolated reports of reduced efficacy of levetiracetam when the osmotic laxative macrogol was administered concomitantly with oral levetiracetam. Therefore, macrogol should not be taken orally one hour before and one hour after taking levetiracetam. Food and alcohol The extent of absorption of levetiracetam was not affected by food intake, but the rate of absorption was slightly reduced. There is no data on the interaction of levetiracetam with alcohol. Pregnancy Levetiracetam may be used during pregnancy if, after careful assessment, it is considered clinically necessary. In such cases, the lowest effective dose is recommended. Physiological changes during pregnancy may affect levetiracetam concentrations. A decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced in the third trimester (up to 60% of the baseline concentration before pregnancy). Adequate clinical management of pregnant women treated with levetiracetam should be ensured. Breastfeeding mothers Levetiracetam is excreted in breast milk. Therefore, breastfeeding is not recommended. However, if levetiracetam treatment is necessary during breastfeeding, the benefit/risk of treatment should be assessed considering the importance of breastfeeding. Effect on ability to drive and use machinery Levetiracetam has a minor effect on the ability to drive and use machinery. When driving or operating machinery, it should be borne in mind that dizziness or fatigue may occasionally occur. Overdose Symptoms Somnolence, agitation, aggression, decreased consciousness, respiratory depression, and coma have been observed in cases of levetiracetam overdose. Management of overdose Gastric emptying may be achieved by gastric lavage or induced vomiting after acute overdose. There is no specific antidote for levetiracetam. Treatment of overdose will be symptomatic and may include hemodialysis. The efficiency of extraction in the dialyzer is 60% for levetiracetam and 74% for the main metabolite. Storage Do not store above 30°C. Protect from light and moisture. The expiry date refers to the product correctly stored under the required conditions. How supplied Levegeți (levetiracetam) Tablets 500 mg are available in blister packs of 30. Levegeți (levetiracetam) Tablets 750 mg are available in blister packs of 30. Levegeți (levetiracetam) Tablets 1000 mg are available in blister packs of 30. Keep out of reach of children. Please read the contents carefully before use. This package insert is subject to continuous updates from time to time. Dispensing category: Pharmaceutical product group II, dispensed by prescription №3