Description
Release form
Tablets, covered with a blue film sheath, oval, biconvex, marked on one side with an engraving L, on the other – 250 at the kink – the core is white or white with a yellowish tint.
Packing
10 pcs. – blisters (3) – packs of cardboard.
30 pcs – polymer cans (1) – packs of cardboard.
Pharmacological action
Anticonvulsant. Levetiracetam, the active substance of the drug Levetinol ®, is a pyrrolidone derivative (S-enantiomer -Ethyl-2-oxo-1-pyrrolidinacetamide) and differs in chemical structure from other anticonvulsants.
The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of other anticonvulsants. In vitro and in vivo experiments have shown that levetiracetam does not affect the basic properties of the cell and normal neural transmission.
In vitro studies have shown that, by partially decreasing N-type calcium currents and decreasing the release of calcium ions from intracellular depots of neurons, levetiracetam changes the concentration of calcium ions inside neurons. In addition to this, it partially eliminates the decrease in the currents of the GABA and glycine channels caused by zinc and β-carbolines. Moreover, in vitro studies have shown that levetiracetam binds to special areas of the rat brain. This site is synaptic vesicle 2A protein, which is thought to be involved in the process of vesicle fusion and exocytosis of neurotransmitters. Levetiracetam and its analogues binding to synaptic vesicle 2A protein, exhibit anticonvulsant activity in an audiogenic model of mouse epilepsy, and the stronger the bond, the higher the activity. These data imply that the binding of levetiracetam to synaptic vesicle 2A protein implements its anticonvulsant effect.
Levetiracetam exerts an anticonvulsant effect on many models of partial and primary generalized seizures in animals without a concomitant seizure effect. The main metabolite of levetiracetam is inactive.
Levetiracetam exhibits anticonvulsant activity in partial and generalized epilepsy in humans (epileptiform burst / photoparoxysmal response), which confirms its wide spectrum of pharmacological action.
Pharmacokinetics
Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and interindividual variation. After prolonged use, changes in clearance do not occur. Evidence of gender, racial or diurnal differences is missing. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable.
Due to complete and linear absorption, plasma concentration can be predicted by the dose of levetiracetam in mg / kg body weight. Therefore, it is not necessary to control the plasma concentration of levetiracetam.
In adults and children, a high correlation between the concentration of levetiracetam in plasma and saliva is shown (the ratio of saliva / plasma ranges from 1-1.7 for tablets for oral administration and for oral solution 4 hours after taking the latter).
Adults and teenagers
Absorption
After oral administration, levetiracetam is rapidly absorbed. Absolute bioavailability after oral administration is close to 100%. Cmax is reached after 1.3 hours. An equilibrium state is reached after 2 days when taking the drug 2 times / day.
Cmax is usually 31 and 43 mcg / ml after, respectively, a single dose of 1000 mg and 1000 mg of the drug 2 times / day.
Absorption is independent of dose and food intake.
Distribution
Distribution data for humans are not available.
Levetiracetam and its main metabolite are weakly bound to plasma proteins (
Vd of levetiracetam is about 0.5-0.7 L / kg, which approximately corresponds to the volume of water in the body.
Metabolism
Levetiracetam is poorly metabolized in the human body. The main metabolic pathway (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Liver cytochrome P450 isoenzymes do not participate in the formation of the main metabolite (ucb L057). The hydrolysis of the acetamide group occurs in many tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.
2 minor metabolites have also been detected. The first is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose), the second – by opening the pyrrolidone ring (0.9% of the dose).
Other unidentified metabolites make up only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite in vivo was not detected.
Levetiracetam and its main metabolite do not inhibit the main isoenzymes of human liver cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6) and in vitro epoxy hydroxylase. Levetiracetam also does not affect the glucuronidation of valproic acid in vitro.
In human hepatocyte culture, levetiracetam had little or no effect on the activity of CYP1A2, SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induced the activity of CYP2B6 and CYP3A4 isoenzymes. Data on drug interactions with oral contraceptives, digoxin and warfarin in vivo show that significant induction of enzymes in vivo is not expected. Therefore, the interaction of levetiracetam with other substances is unlikely.
Excretion of
T1 / 2 in adults is 7 ± 1 and does not depend on the dose, route of administration or duration of use. The average total clearance is 0.96 ml / min / kg.
The main route of elimination is urinary excretion (about 95% of the dose, of which 93% is excreted within 48 hours). Excretion with feces is only 0.3% of the dose.
The total excretion of levetiracetam and its main metabolite is 66% and 24% of the dose taken during the first 48 hours, respectively. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, indicating levetiracetam excretion by glomerular filtration followed by tubular reabsorption, and the main metabolite, along with glomerular filtration, by active tubular secretion.
Elimination of levetiracetam correlates with CC.
Elderly patients
T1 / 2 in the elderly increases by 40% (up to 10-11 hours), which is due to a decrease in kidney function in this population.
Renal failure
The apparent clearance of levetiracetam and its main metabolite is dependent on QC. In this regard, in patients with moderate and severe renal failure, it is recommended to adjust the maintenance dose of the drug depending on the CC.
In adult patients with end-stage renal failure, T1 / 2 is 25 hours between hemodialysis sessions and 3.1 hours during the procedure itself.
About 51% of levetiracetam is removed during a typical four-hour hemodialysis session.
Impaired liver function
In patients with mild to moderate hepatic insufficiency, the clearance of levetiracetam changes slightly. In most patients with severe hepatic insufficiency, the clearance of levetiracetam is reduced by more than 50%, due to concomitant renal failure.
Children aged 4 12 years
After a single dose of the drug at a dose of 20 mg / kg, T1 / 2 in children 6 12 years of age is 6 hours. Apparent clearance adjusted by body weight is 30% higher than that in adults with epilepsy. After prolonged use of the drug at a dose of 20-60 mg / kg / day, the absorption of levetiracetam in children 4-12 years old is fast. Cmax is reached within 0.5-1 hours. Cmax and AUC are linear and proportional to the dose. The terminal T1 / 2 is 5 hours. The apparent clearance is 1.1 ml / min / kg.
Contraindications
children under 6 years of age
hypersensitivity to the components of the drug
hypersensitivity to pyrrolidone derivatives.
Use in cases of impaired liver function
Dose adjustment is not required in patients with mild to moderate hepatic insufficiency.
Application for impaired renal function
Depending on the degree of impaired renal function, the daily dose is selected individually.
Use in children
The drug is prescribed in the most convenient dosage form and dosage, depending on age, body weight and the required dose.
Tablets are not intended for use in children under the age of 6 years. For such patients, the drug is recommended to be prescribed in a dosage form for oral administration. In addition, the available dosages of tablets are not intended for the initial selection of a dose in children with a body weight of less than 25 kg, for patients unable to swallow tablets, and also if necessary, take a dose of <250 mg. In all these cases, it is recommended to use a solution for oral administration. Use in elderly patients In elderly patients with impaired renal function, it is recommended to adjust the dose as in case of renal failure. Special instructions Discontinuation of therapy It is recommended that drug withdrawal be gradual. For example, in adults and adolescents with a body weight of more than 50 kg, the dose should be reduced in increments of 500 mg 2 times / day no more than every 2-4 weeks in children from 6 years old with body weight less than 50 kg the dose should be reduced in increments no more than 10 mg / kg 2 times a day no more often than every 2 weeks. Renal failure The use of levetiracetam in patients with renal failure may require dose adjustment. In patients with severe hepatic insufficiency, it is recommended to evaluate renal function before starting dose selection. Suicide Patients taking anticonvulsants (including levetiracetam) have experienced suicide, attempted suicide, suicidal thoughts and behavior. A meta-analysis of randomized, placebo-controlled trials of anticonvulsant drugs showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism for its implementation is not known. In connection with the foregoing, it is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy for them. Patients (and those caring for them) should be informed about the need to seek medical help if they experience symptoms of depression and (or) suicidal thoughts and behavior. Pediatric Use Tablets are not intended for use in children under the age of 6 years. According to reports, levetiracetam does not affect growth and puberty. However, the long-term impact on learning, intelligence, growth, endocrine function, puberty, and fertility in children are not known. Influence on the ability to drive vehicles and control mechanisms Studies on the effects on the ability to drive vehicles and work with mechanisms have not been conducted. Due to individual differences in susceptibility, some patients may experience drowsiness and other disorders of the central nervous system, especially at the beginning of therapy and after increasing the dose. Therefore, caution is advised when driving vehicles and engaging in other activities that require an increased concentration of attention and speed of psychomotor reactions. If these symptoms occur, patients should abandon such activities until they are convinced that these symptoms do not have a significant effect on them. Composition 1 tab. levetiracetam 250 mg Excipients: crospovidone – 8.25 mg, povidone – 7 mg, silica anhydrous colloid – 3.5 mg, magnesium stearate – 1.25 mg, partially coated Blue oprolidrovidrovidrovidrovidrovpidrovid® 85 40%, titanium dioxide (E171) – 22.29%, macrogol 4000 – 20.2%, talc – 14.8%, indigo carmine dye (E132) – 2.71%) – 8.1 mg. Dosage and administration of Monotherapy in adults and adolescents from 16 years of age The recommended initial dose is 250 mg 2 times / day, which must be increased after 2 weeks to the initial therapeutic 500 mg 2 times / day. The dose may be increased in increments of 250 mg 2 times / day every 2 weeks, depending on the clinical response. The maximum dose is 1500 mg 2 times / day. Ancillary therapy in adults (? 18 years old) and adolescents (12-17 years old) with a body weight of 50 kg or more The initial therapeutic dose is 500 mg 2 times / day. This dose is allowed to be used from the first day of treatment. Depending on the clinical response and tolerance, the daily dose may be increased to 1500 mg 2 times / day. The dose may be increased or decreased by 500 mg 2 times / day every 2-4 weeks. Elderly patients (65 years of age and older) In elderly patients with impaired renal function, it is recommended to adjust the dose of the drug. Renal failure Depending on the degree of impaired renal function, the daily dose is selected individually. To use the dose adjustment table, it is necessary to calculate the patient’s QC in ml / min. KK in ml / min can be determined using the value of serum creatinine concentration (mg / dl) according to the following formula (for adults and adolescents with a body weight of 50 kg or more): KK (ml / min) = [140 – age (years) ]? body weight (kg) / 72? plasma creatinine concentration (mg / dl)? (0.85 for women) Then the correction for body surface area (PPT) is introduced as follows: KK (ml / min / 1.73 m2) = KK ( ml / min) / patient’s PPT (m2)? 1. 73 Dose adjustment in adults and adolescents with impaired renal function, body weight> 50 kg
KK group
(ml / min / 1.73 m2) Dose and frequency of administration
Norm> 80 500-1500 mg 2 times / day
Light 50 -79 500-1000 mg 2 times / day
Moderate 30-49 250-750 mg 2 times / day
Severe 250-500 mg 2 times / day
Terminal stage renal failure – patients on hemodialysis (1) – 500 -1000 mg 1 time / day (2)
(1) On the first day, a loading dose of 750 mg is recommended.
(2) Upon completion of hemodialysis, an additional dose of 250 or 500 mg is recommended.
Due to the fact that the clearance of levetiracetam depends on the function of the kidneys, for children with renal failure, its dose is selected depending on the CC. These recommendations are based on studies in adult patients. KK in ml / min / 1.73 m2 in children and adolescents can be estimated by the plasma creatinine concentration (in mg / dl) according to the following formula (Schwartz formula):
KK (ml / min / 1.73 m2) = height (cm)? Ks / plasma creatinine concentration (mg / dl)
where ks = 0.45 for children under the age of 1 year 0.55 – for children aged 1-13 years and female adolescents 0.7 – male adolescents.
Dose adjustment in children and adolescents with impaired renal function, body weight of which
QC group (ml / min / 1.73 m2) Dose and frequency of administration of
from 6 years old
Normal> 80 10-30 mg / kg 2 times / day
Light 50-79 10-20 mg / kg 2 times / day
Moderate 30-49 5-15 mg / kg 2 times / day
Severe 5-10 mg / kg 2 times / day
Terminal stage renal failure – patients those on hemodialysis (1) 10-20 mg / kg 1 time / day (2) (3)
(1) An oral solution is used for doses (2) On the first day, a loading dose of 15 mg / kg (0.15 ml) is recommended / kg).
(3) Upon completion of hemodialysis, an additional dose of 5 10 mg / kg (0.05 0.1 ml / kg) is recommended.
Impaired liver function
Dose adjustment is not required in patients with mild to moderate hepatic insufficiency. In patients with severe hepatic insufficiency, the QC value may be misleading about the degree of renal failure. Therefore, with CC <60 ml / min / 1.73 m2, the maintenance dose of the drug should be reduced by 50%. Children The drug is prescribed in the most convenient dosage form and dosage, depending on age, body weight and the required dose. Tablets are not intended for use in children under the age of 6 years. For such patients, the drug is recommended to be prescribed in a dosage form for oral administration. In addition, the available dosages of tablets are not intended for the initial selection of a dose in children with a body weight of less than 25 kg, for patients unable to swallow tablets, and also if necessary, take a dose of <250 mg. In all these cases, it is recommended to use a solution for oral administration. Monotherapy The efficacy and safety of levetiracetam in children and adolescents under 16 years of age as a monotherapy has not been established. No data available. Ancillary therapy in children 6-17 years old and weighing less than 50 kg The initial dose is 10 mg / kg 2 times / day. Depending on the clinical response and tolerance, the dose may be increased to 30 mg / kg 2 times / day. The dose may be increased or decreased in increments of 10 mg / kg 2 times / day every 2 weeks. The lowest effective dose should be used. The dosage regimen in children weighing 50 kg and more does not differ from adults. Recommended doses in children from 6 years old Body weight Initial dose: 10 mg / kg 2 times / day Maximum dose: 30 mg / kg 2 times / day 25 kg (1) 250 mg 2 times / day 750 mg 2 times / day from 50 kg (2) 500 mg 2 times / day 1,500 mg 2 times / day (1) Children with a body weight of 25 kg or less are recommended to prescribe the drug in the dosage form, oral solution, 100 mg / ml (2 ) The dosage regimen in children weighing 50 kg or more does not differ from adults. The drug is taken orally, drinking plenty of water, regardless of the meal. The daily dose is divided into 2 equal doses. Side effects The side reaction profile presented below is based on an analysis of placebo-controlled clinical studies of levetiracetam for all indications (total number of patients – 3416). These data are supplemented by information on the use of levetiracetam in open, extended clinical trials, as well as post-registration data. The most commonly reported adverse reactions were nasopharyngitis, drowsiness, headache, weakness, and dizziness. The safety profile of levetiracetam generally does not differ depending on age (in adults and children), and also does not depend on approved indications for use (various options for epilepsy). Adverse reactions identified in clinical trials and in the framework of post-registration monitoring (in adults, adolescents and children older than 1 month) are presented in the table by systemic organ classes and frequency. Frequency gradation: very often (? 1/10), often (? 1/100 and Very often Often Infrequently Rarely Infections and infestations nasopharyngitis infections From the hematopoietic system thrombocytopenia, leukopenia1 pancytopenia1,2, neutropenia s1 substances anorexia decrease1 or increase in body weight Psyche depression, hostility or aggression1, sleep disturbance, nervousness, irritability suicidal attempts1, suicidal thoughts1, psychotic disorders1, behavioral disorder1, hallucinations, anger, confusion, emotional lability, mood changes, agitation suicide1, personality disorder, thinking disorder nervous system drowsiness, headache balance, dizziness, lethargy, amnesia tremor, memory impairment, impaired coordination of movements or ataxia, paresthesia1, attention disorder choreoathetosis1, dis ineziya1, hyperkinesia part of the vision diplopia, blurred vision the part of the organ of hearing and balance vertigo Respiratory system cough part of the digestive system abdominal pain, diarrhea, dyspepsia, vomiting, nausea pancreatitis1 from the liver and biliary tract impaired liver function tests1 liver failure1, hepatitis1 from the skin and subcutaneous tissue rash alopecia1, eczema, itching toxic epidermal necrolysis1, Stevens-Johnson syndrome of the muscular system, many bone form1, many muscle weakness, myalgia General disorders asthenia or fatigue injury 1 Undesirable reactions detected in the post-registration period 2 In some cases, angle ix medullary hematopoiesis Description of individual side reactions With simultaneous application of topiramate, and levetiracetam increases the risk of anorexia. In some cases, alopecia underwent a reverse development after discontinuation of levetiracetam. Children Placebo-controlled and open-label, extended-term studies included 645 patients aged 4 16 years, 233 of whom received levetiracetam as part of a placebo-controlled study. For both age ranges, additional data are available on the post-registration experience with levetiracetam. The safety profile of levetiracetam generally does not differ depending on age (in adults and children), and also does not depend on approved indications for use (various options for epilepsy). With the exception of behavioral and psychiatric adverse reactions that occurred more frequently in children than in adults, in the placebo-controlled studies, the safety profile of levetiracetam in children was comparable to that in adults. In children aged 4-16 years, vomiting (very often, 11.2%), agitation (often, 3.4%), mood changes (often, 2.1%), emotional lability (often, 1.7%), aggression (often, 8.2%), impaired behavior (often, 5.6%) and lethargy (often, 3.9%) were noted more often than in other age ranges. The cognitive and neuropsychological effects of levetiracetam in children 4 16 years old with partial seizures were evaluated in double-blind, placebo-controlled studies of the safety profile using a design of no less safety. It was shown that levetiracetam does not differ (no less safe) from placebo in changes from the initial values on the scale Attention and Memory Leiter-R (Leiter-R Attention and Memory), the scale of Comprehensive Monitoring of Memory (Memory Screen Composite) in patients subjected protocol analysis. The results of a study of behavioral and emotional functions that confirm that aggressive behavior occurs when levetiracetam is used is obtained using a standardized method using a validated tool, the Achenbach Child Behavior Checklist. However, in patients taking levetiracetam for a long time as part of an open study, behavioral and emotional dysfunctions did not occur, in particular, the level of aggressive behavior did not differ from the initial one. Drug Interactions Anticonvulsants According to pre-registration clinical trials, levetiracetam does not affect the serum concentrations of other anticonvulsants: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primaquamidecine pharmacophenetamine and primamidonecamidecone and primamidocamidec. Similar to adults, in children at doses up to 60 mg / kg / day, levetiracetam does not interact with other drugs. A retrospective assessment of the pharmacokinetic interaction in children and adolescents with epilepsy (4-17 years old) confirms that levetiracetam as an adjunct therapy does not affect the Css of the simultaneously used carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam in children taking anticonvulsants – inducers of microsomal liver enzymes increases by 20%. Dose adjustment is not required. Probenecid Probenecid (500 mg 4 times / day) is a blocker of tubular secretion in the kidneys, it is shown that it inhibits renal clearance of the main metabolite, but not levetiracetam. However, the concentration of the main metabolite remains low. Other drugs excreted through active tubular secretion are expected to reduce renal clearance of the main metabolite. The effect of levetiracetam on probenecid has not been studied. The effect of levetiracetam on other drugs excreted by active tubular secretion, including NSAIDs, sulfonamide and methotrexate, is not known. oral contraceptives, digoxin and warfarin Levetiracetam at a dose of 1000 mg / day did not affect the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel) hormonal status (LH and progesterone content) did not change. Levetiracetam at a dose of 2000 mg / day did not affect the pharmacokinetics of digoxin and warfarin, the prothrombin time did not change. The simultaneous use of digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam. Antacids No data are available on the effect of antacids on levetiracetam absorption. Food and alcohol Food does not affect the degree of absorption of levetiracetam, but slightly reduces its speed. No data on the interaction of levetiracetam with ethanol. Overdose Symptoms: drowsiness, agitation, aggression, depression of consciousness, respiratory depression and coma. Treatment: after an acute overdose, it is necessary to wash the stomach or cause vomiting. Levetiracetam antidote not found. Treatment is symptomatic and may include hemodialysis. Dialysis activity with levetiracetam is 60%, with 74% on the major metabolite. above 25 ° C. Shelf life 3 years. Terms and conditions Prescription dosage form tablets Possible product names LEVETINOL 0.25 N30 TABLE P / O Levetinol 250mg Tab. p / pl / rev X30 (R) LEVETINOL TAB. P.P.O. 250MG No. 30 LEVETINOL TAB. P / O CAPTURE. 250MG No. 30 Levetinol tablet p.p. 250 mg N30 Iceland-Russia
