Evalep tab. 250mg N50

Form

tableti saghech i

Dosage mg

250

Pack

50

International Nonproprietary Name: Levetiracetam Composition: One film-coated tablet contains: Active substance: Levetiracetam 250mg, 500mg or 1000mg Excipients: 250mg tablets: Microcrystalline cellulose (Comprecel M102), Hydroxypropylcellulose (LH21), Colloidal silicon dioxide, Magnesium stearate, Opadry II 85F30673 Blue (Talc, FD&C Blue #2 Aluminium Lake, Iron oxide black, Polyethylene glycol, Titanium dioxide, Polyvinyl alcohol); 500mg tablets: Microcrystalline cellulose (Comprecel M102), Hydroxypropylcellulose (LH21), Colloidal silicon dioxide, Magnesium stearate, Opadry II 85F38036 Yellow (Talc, Iron oxide black, Iron oxide yellow, Polyethylene glycol, Titanium dioxide, Polyvinyl alcohol); 1000mg tablets: Microcrystalline cellulose (Comprecel M102), Hydroxypropylcellulose (LH21), Colloidal silicon dioxide, Magnesium stearate, Opadry II 85F18422 White (Partially hydrolyzed polyvinyl alcohol, Titanium dioxide, Macrogol 3350, Talc) Description 250mg tablets: Film-coated, oval-shaped, blue tablets, with "250mg" engraved on one side and a dividing line on the other. 500mg tablets: Film-coated, oval-shaped, yellow tablets, with "500mg" engraved on one side and a dividing line on the other. 1000mg tablets: Film-coated, oval-shaped, white tablets, with "1000mg" engraved on one side and a dividing line on the other. Pharmacotherapeutic group: Antiepileptic agent Pharmacological properties: Levetiracetam is an antiepileptic drug, a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide). It differs in chemical structure from other known antiepileptic drugs. The mechanism of action of levetiracetam is not fully understood, but it is clear that it differs from known antiepileptic drugs in its mechanism of action. In vitro and in vivo studies have shown that levetiracetam does not affect the basic properties of cells and normal nerve conduction. In vitro studies have shown that levetiracetam affects intracellular Ca2+ concentration by partially blocking N-type Ca2+ channels and reducing Ca2+ release from intracellular stores. In addition, levetiracetam partially restores the flow through GABA- and glycine-dependent channels, which is reduced by the action of zinc and β-carbolines. Pharmacodynamics: The efficacy of levetiracetam has been demonstrated for both partial and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal response). Pharmacokinetics: Absorption: Levetiracetam is well absorbed from the gastrointestinal tract after oral administration. Its bioavailability is approximately 100%. The maximum plasma concentration (Cmax) is reached 1.3 hours after administration. Steady state is achieved 2 days after twice-daily dosing. After a single dose of 1000mg and repeated twice-daily dosing of 1000mg, the maximum plasma concentration (Cmax) of the drug is 31 mcg/mL and 43 mcg/mL, respectively. The degree of absorption is dose- and food-independent. Distribution: The plasma protein binding of levetiracetam and its main metabolite is less than 10%. The volume of distribution of levetiracetam is approximately 0.5-0.7 L/kg. Biotransformation: In the human body, levetiracetam does not undergo intensive metabolism. The main metabolic pathway is enzymatic hydrolysis of the acetamide group (24% of the dose). The formation of the primary pharmacologically inactive metabolite (ucbL057) occurs in the liver without the involvement of cytochrome P450 isoenzymes. Excretion: In adults, the plasma elimination half-life is 7±1 hours, and it is not affected by the dose, route of administration, or repeated administration. The mean clearance is 0.96 mL/min/kg. 95% of the administered dose is excreted by the kidneys (approximately 93% of the administered dose is excreted within 48 hours). 0.3% of the dose is excreted in the feces. The renal clearance of levetiracetam and its primary metabolite in the first 48 hours is 66% and 24% of the administered dose, respectively. Pharmacokinetics in Special Populations: Renal/Hepatic Insufficiency: The clearance of levetiracetam and its primary metabolite is related to creatinine clearance, so dose adjustment is recommended for patients with moderate and severe renal insufficiency based on creatinine clearance. In end-stage renal disease, in anuric adult patients, the half-life between dialysis sessions is 25 hours and 3.1 hours during dialysis. During a 4-hour dialysis session, the clearance of levetiracetam is 51%. Patients with mild to moderate hepatic impairment do not show significant changes in levetiracetam clearance. In severe hepatic insufficiency with concomitant renal insufficiency, levetiracetam clearance is reduced by more than 50%. Pediatric Patients (4-12 years): In children with epilepsy (6-12 years), the elimination half-life of levetiracetam is 6 hours after a single dose (20 mg/kg). In these children, total clearance is 30% higher than in adults and is body weight-dependent. In children (4-12 years), after repeated administration of levetiracetam at doses of 20-60 mg/kg, it is rapidly absorbed from the gastrointestinal tract. The maximum plasma concentration is reached 0.5-1 hour later. The elimination half-life is approximately 5 hours, and the apparent clearance is 1 mL/min/kg. Geriatric Patients: In elderly patients, the elimination half-life increases by 40% (10-11 hours) due to decreased renal function. Indications for Use: Used as monotherapy: For the treatment of partial seizures in adults, children, and adolescents, with or without secondary generalization, in newly diagnosed epilepsy. Used in combination therapy for the following conditions: - Myoclonic seizures - in adults and adolescents over 12 years of age with juvenile myoclonic epilepsy. - Primary generalized tonic-clonic seizures - in adults and adolescents over 12 years of age with idiopathic generalized epilepsy. Contraindications: Hypersensitivity to levetiracetam, other pyrrolidine derivatives, or any of the excipients. Special Precautions: Discontinuation of the drug: If treatment with Evalep™ needs to be discontinued, gradual dose reduction is recommended (e.g., in adults, reduce the dose by 500mg twice daily over 2-4 weeks; in children and adolescents weighing less than 50kg, the dose reduction should not exceed 10 mg/kg twice daily over 2 weeks). Hepatic/Renal Insufficiency: Patients with renal insufficiency may require dose adjustment. For patients with severe hepatic impairment, renal function should be assessed when selecting the dosage regimen. Suicide: Suicidal behavior, suicidal ideation, and suicide attempts have been reported in patients treated with antiepileptic drugs (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of antiepileptic drugs showed a small increase in the risk of suicidal thoughts and behaviors. In case of possible emergence of depression and/or suicidal intentions, the patient should be monitored and appropriate treatment provided. Patients and their relatives should be warned to seek immediate medical attention if any signs of depression and/or suicidal intentions appear. Pediatric Patients: Evalep™ is not intended for use in patients under 4 years of age. Existing data suggest that the use of the drug in children does not have any negative impact on their development and sexual maturation, but the impact of individual treatment outcomes on children's learning ability, cognitive development, growth, endocrine glands, sexual development, and fertility is unknown. Interactions with Other Medicinal Products: Antiepileptic drugs: Pre-marketing clinical trial data in adult patients showed no interactions between levetiracetam and antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone). Probenecid: Probenecid (500mg four times daily), a blocker of tubular secretion, inhibits the renal clearance of the primary metabolite of levetiracetam. The concentration of this metabolite is low. Other drugs with active tubular secretion may also reduce the renal clearance of the metabolite. The effect of levetiracetam on probenecid and other actively secreted drugs (e.g., NSAIDs, sulfonamides, and methotrexate) is unknown. Interaction with oral contraceptives and other drugs: Levetiracetam at a daily dose of 1000mg does not alter the pharmacokinetics and endocrine parameters (luteinizing hormone and progesterone levels) of oral contraceptives (ethinylestradiol and levonorgestrel). Levetiracetam at a daily dose of 2000mg does not alter the pharmacokinetics of digoxin and warfarin; the prothrombin time remains unchanged. Digoxin, oral contraceptives, and warfarin, in turn, do not affect the pharmacokinetics of levetiracetam. Antacids: No data on the effect of antacids are available. Laxatives: In rare cases, when taken with the osmotic laxative macrogol, the effect of levetiracetam is reduced. Therefore, macrogol should not be taken 1 hour before or after levetiracetam. Food and Alcohol: Food intake does not affect the complete absorption of levetiracetam, but it slightly reduces the rate of absorption. There are no reports of interaction between levetiracetam and alcohol. Use during Pregnancy and Lactation: The use of Evalep™ during pregnancy is recommended only when absolutely necessary. Levetiracetam is excreted in breast milk, so breastfeeding is not recommended during treatment with levetiracetam. If levetiracetam is used during lactation, the risk/benefit ratio of treatment compared to the importance of breastfeeding should be assessed. Effect on Ability to Drive and Use Machines: Studies on the effect of Evalep™ on the ability to drive and operate machinery have not been conducted. Due to individual sensitivity to the drug, some patients may experience side effects affecting the central nervous system (such as drowsiness), especially at the beginning of treatment or when the dose is increased. Therefore, caution should be exercised when driving and operating potentially hazardous machinery. Dosage and Administration: Evalep™ film-coated tablets are taken orally, independently of food intake, with a large amount of water. The daily dose is taken in two divided doses. Monotherapy: Adults and adolescents over 16 years of age: The recommended starting dose is 250mg twice daily; after 2 weeks, the dose is increased to the initial therapeutic dose of 500mg twice daily. Based on clinical efficacy, the dose can be increased by 250mg twice daily every 2 weeks; the maximum daily dose is 1500mg twice daily. Combination Therapy: Adults (18 years and older) and adolescents (12-17 years) weighing 50kg or more: The initial therapeutic dose is 500mg twice daily; this dose should be taken from the first day of treatment. Depending on the clinical efficacy and tolerability of the drug, the dose can be increased up to 1500mg twice daily. Dose adjustments (increase or decrease) by 500mg twice daily can be made every 2-4 weeks. Children aged 4-11 years and adolescents (12-17 years) weighing less than 50kg: Children aged 4 years and older are prescribed levetiracetam in the form of an oral solution. The initial therapeutic dose is 10 mg/kg twice daily. Based on clinical efficacy and tolerability, the dose can be increased up to 30 mg/kg twice daily. Dose adjustments (increase or decrease) should not exceed 10 mg/kg twice daily every 2 weeks. The minimum effective dose should be used. For children weighing 50kg or more, the doses are the same as for adults. The doctor should prescribe the drug in the appropriate form and dose according to the patient's body weight. Recommended doses for children and adolescents: Weight (kg) | Starting dose 10 mg/kg twice daily | Maximum dose 30 mg/kg twice daily ------- | -------- | -------- 15kg (1) | 150mg twice daily | 450mg twice daily 20kg (1) | 200mg twice daily | 600mg twice daily 25kg | 250mg twice daily | 750mg twice daily 50kg and above (2) | 500mg twice daily | 1500mg twice daily (1) For children weighing 25kg or less, it is recommended to start treatment with levetiracetam oral solution. (2) Doses for children weighing 50kg and above are the same as for adults. Additional data for special populations: Renal/Hepatic Insufficiency: Daily dose adjustment should be made according to the patient's renal function parameters. In adult patients, dose adjustment is made according to the table below. Before using this table, the patient's creatinine clearance (CC mL/min) must be determined. Creatinine clearance (CC mL/min) for adults and adolescents weighing 50kg or more is calculated from serum creatinine concentration (mg/dL) using the following formula: CC (mL/min) = [140-Age (years)] × Body Weight (kg) / 72 × Serum Creatinine (mg/dL) (for women: result × 0.85). Finally, CC is adjusted for body surface area using the following formula: CC (mL/min/1.73m2) = CC (mL/min) / Body Surface Area (m2) × 1.73. Dose adjustment for adults and adolescents weighing more than 50kg with renal insufficiency: Renal function | Creatinine clearance (mL/min/1.73m2) | Dose and frequency of administration ------- | -------- | -------- Normal | >80 | 500-1500mg twice daily Mild renal insufficiency | 50-79 | 500-1000mg twice daily Moderate renal insufficiency | 30-49 | 250-750mg twice daily Severe renal insufficiency | <30 | 250-500mg twice daily End-stage renal disease, patients on dialysis (1) | - | 500-1000mg once daily (2) (1) On the first day of treatment, it is recommended to take levetiracetam at a dose of 750mg. (2) An additional dose of 250-500mg is recommended after dialysis. For children with renal insufficiency, levetiracetam dose adjustment is made considering the degree of renal insufficiency, using the recommendations for adults. Creatinine clearance (CC mL/min/1.73 m2) in children and adolescents can be calculated from serum creatinine concentration (mg/dL) using the following formula (Schwartz formula): CC (mL/min/1.73 m2) = Height (cm) × K/Serum Creatinine (mg/dL). K=0.55 in children under 13 years and adolescent girls, K=0.7 in adolescent boys. Dose adjustment for children and adolescents weighing less than 50kg with renal insufficiency: Renal function | Creatinine clearance (mL/min/1.73m2) | Dose and frequency of administration in children over 4 years and adolescents weighing less than 50kg ------- | -------- | -------- Normal | >80 | 10-30 mg/kg (0.10-0.30 mL/kg) twice daily Mild renal insufficiency | 50-79 | 10-20 mg/kg (0.10-0.20 mL/kg) twice daily Moderate renal insufficiency | 30-49 | 5-15 mg/kg (0.05-0.15 mL/kg) twice daily Severe renal insufficiency | <30 | 5-10 mg/kg (0.05-0.10 mL/kg) twice daily End-stage renal disease, patients on dialysis (1) | - | 10-20 mg/kg (0.10-0.20 mL/kg) once daily (2) (3) (1) Oral solution is used for patients who have difficulty swallowing tablets and also for doses less than 250mg. (2) On the first day of treatment, it is recommended to take levetiracetam at a dose of 15 mg/kg (0.15 mL/kg). (3) An additional dose of 5-10 mg/kg (0.05-0.10 mL/kg) is recommended after dialysis. Dose adjustment is not required in mild and moderate hepatic insufficiency. For patients with CC less than 60 mL/min/1.73m2, it is recommended to reduce the daily dose by 50%. Pediatric Group: Evalep™ film-coated tablets are not used in children under 4 years of age; levetiracetam oral solution is intended for them. For children weighing less than 25kg, patients with swallowing difficulties, and for doses less than 250mg, the available tablet forms are not used. In such cases, levetiracetam is used in the form of an oral solution. Monotherapy with levetiracetam is not used in children under 16 years of age. Geriatric Group: Due to possible impairment of renal function, dose adjustment is recommended for elderly patients (65 years and older). Adverse Reactions: The most common adverse reactions are: nasopharyngitis, somnolence, headache, fatigue, dizziness. The safety profile is similar in different age groups (adults and pediatric patients). Frequency of adverse reactions: Very common (≥1/10); Common (≥1/100 to <1/10); Uncommon (≥1/1000 to <1/100); Rare (≥1/10000 to <1/1000); Very rare (<1/10000); Unknown frequency (cannot be estimated based on available data). Infections and infestations: Very common: nasopharyngitis. Rare: infections of the blood and lymphatic system. Uncommon: thrombocytopenia, leukopenia. Rare: neutropenia, pancytopenia, agranulocytosis. Immune system disorders: Rare: drug reaction with eosinophilia and systemic symptoms (DRESS). Metabolism and nutrition disorders: Common: anorexia. Uncommon: weight loss/gain; Rare: hyponatremia. Psychiatric disorders: Common: depression, hostility/aggression, anxiety, insomnia, nervousness/irritability; Uncommon: suicide attempt, suicidal thoughts, psychotic disorder, behavioral disorders, hallucinations, disturbance of consciousness, panic attacks, emotional lability/mood swings, anxiety. Rare: suicide, depersonalization, thought disorder. Nervous system disorders: Very common: insomnia, headache; Common: seizures, dizziness, tremor, lethargy; Uncommon: amnesia, memory impairment, balance disorder/ataxia, paresthesia, decreased concentration; Rare: choreoathetosis, dyskinesia, hyperkinesia. Eye disorders: Uncommon: diplopia, blurred vision. Ear and labyrinth disorders: Common: dizziness. Respiratory, thoracic and mediastinal disorders: Common: cough. Gastrointestinal disorders: Common: epigastric pain, diarrhea, dyspepsia, vomiting, nausea. Rare: pancreatitis. Hepatobiliary disorders: Uncommon: altered liver enzymes. Rare: liver failure, hepatitis. Skin and subcutaneous tissue disorders: Common: rash; Uncommon: alopecia, eczema, pruritus. Rare: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme. Musculoskeletal and connective tissue disorders: Uncommon: muscle weakness, myalgia. General disorders and administration site conditions: Common: asthenia/weakness. Injury, poisoning and procedural complications: Common: body injury. Description of some adverse events: Concomitant administration of levetiracetam with topiramate increases the risk of anorexia. In isolated cases, alopecia stops after discontinuation of levetiracetam. In some cases of pancytopenia, bone marrow suppression was diagnosed. Reporting of suspected adverse events: Reporting of suspected adverse reactions after the medicinal product is authorized is important. It allows for continuous monitoring of the benefit/risk balance of the medicinal product. In case of adverse events, consult your doctor. Overdose: Symptoms: Somnolence, agitation, impaired cognition, respiratory distress, coma were observed in cases of overdose. Treatment: In case of overdose, levetiracetam can be eliminated from the body by inducing artificial vomiting and gastric lavage. There is no specific antidote. Symptomatic treatment and hemodialysis are performed. The effect of hemodialysis on levetiracetam is 60%, and on its primary metabolite - 74%. Dosage Form: Evalep™ 250mg, 500mg or 1000mg film-coated tablets, in blister packs. 5 blisters (50 film-coated tablets) in a cardboard box with an instruction for use. Storage Conditions: Store at room temperature not exceeding 25°C, in the original packaging, out of reach of children. Shelf Life: 2 years. Do not use after the expiry date. Dispensing Conditions: Pharmaceutical product group II, dispensed by prescription N3. Manufacturer: Ali Raif İlaç San. A.Ş. İçiteli OSB Mahallesi 10. Cadde No:3/1A Başakşehir / Istanbul / Turkey