Levetinol, 250 mg 30 pcs.

The active ingredient of the drug Levetinol^® is levetiracetam. It is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidinacetamide) and differs from other similar anticonvulsants by its chemical structure.

The mechanism of action of levetiracetam is not fully understood, but it differs from that of other similar anticonvulsants. In vitro and in vivo experiments have shown that this active ingredient does not affect basic cell properties and normal nerve transmission.

The results of in vitro studies have shown that by partially reducing N-type calcium currents and reducing the release of calcium ions from intracellular depots of neurons, levetiracetam changes the concentration of calcium ions inside neurons. In addition, it partially eliminates the reduction of GABA- and glycine channel currents induced by zinc and β-carbolines. In addition, levetiracetam has been shown in in vitro studies to bind to specific areas of the rat brain.

This site is the synaptic vesicle protein 2A, which is thought to be involved in vesicle fusion and exocytosis of neurotransmitters. Levetiracetam and its analogues, which bind to synaptic vesicle protein 2A, show anticonvulsant activity in an audiogenic model of epilepsy in mice, and the stronger the binding, the higher the activity. These data imply that the binding of levetiracetam to synaptic vesicle protein 2A implements its anticonvulsant activity.

Levetiracetam has anticonvulsant effects in many models of partial and primary generalized seizures in animals without concomitant proconvulsant effects. The main metabolite of levetiracetam is inactive.

Levetiracetam exhibits anticonvulsant activity in human partial and generalized epilepsy (epileptiform burst/photoparoxysmal response), confirming its broad spectrum of pharmacological action.

Pharmacokinetics

Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra- and inter-individual variation. There is no change in clearance after long-term use. There is no evidence of sexual, racial or diurnal differences. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable.

Due to complete and linear absorption, plasma concentrations are predictive of levetiracetam dose values expressed in mg/kg body weight. Therefore, it is not necessary to monitor the plasma concentration of levetiracetam.

In adults and children, a high correlation has been shown between plasma and saliva concentrations of levetiracetam (the saliva/plasma ratio ranges from 1-1.7 for oral tablets and for oral solution 4 hours after the latter administration).

Adults and adolescents

Intake

Levetiracetam is rapidly absorbed after oral administration. Absolute bioavailability after oral administration is close to 100%. C_max is reached in 1.3 h. The equilibrium state is reached in 2 days if the drug is taken 2 times/day.

The C_max is usually 31 and 43 mcg/mL after a single dose of 1000 mg and taking 1000 mg of the drug 2 times/day, respectively.

The magnitude of absorption is independent of dose and food intake.

Distribution

There are no data on distribution in humans.

Levetiracetam and its main metabolite bind weakly to plasma proteins (

The V_d of levetiracetam is about 0.5-0.7 L/kg, which is approximately 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 enzymatic hydrolysis of the acetamide group. Liver cytochrome P450 isoenzymes are not involved in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites have also been found. The first is formed by hydroxylation of the pyrrolidone ring (1.6% of the dose) and the second by opening the pyrrolidone ring (0.9% of the dose).

Other unidentified metabolites account for only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite in vivo has not been detected.

Levetiracetam and its major metabolite do not inhibit major human liver cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6) and epoxide hydroxylase in vitro. Levetiracetam also has no effect on valproic acid glucuronidation in vitro.

In human hepatocyte culture, levetiracetam had little or no effect on the activity of the CYP1A2, SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induced the activity of CYP2B6 and CYP3A4 isoenzymes. The data on drug interactions with oral contraceptives, digoxin and warfarin in vivo show that no significant induction of enzymes in vivo is expected. Therefore, interactions of levetiracetam with other substances are unlikely.

T_1/2 in adults is 7±1 and is independent of dose, route of administration, or duration of administration. Mean total clearance is 0.96 ml/min/kg.

The main route of elimination is excretion with the urine (about 95% of the dose, of which 93% is excreted within 48 hours). Excretion with the 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 h, respectively. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg, respectively, indicating excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and of the main metabolite by active tubular secretion along with glomerular filtration.

The elimination of levetiracetam correlates with CK.

Elderly patients

The T_1/2 in the elderly is increased by 40% (up to 10-11 h) due to decreased renal function in this population.

Renal failure

The apparent clearance of levetiracetam and its major metabolite is CK dependent. Therefore, in patients with moderate to severe renal impairment, it is recommended that the maintenance dose of the drug be adjusted according to CKD.

In adult patients with terminal renal failure, the T_1/2 is 25 h between hemodialysis sessions and 3.1 h during the procedure itself.

In a typical four-hour hemodialysis session, approximately 51% of levetiracetam is removed.

Hepatic impairment

In patients with mild to moderate hepatic impairment, the clearance of levetiracetam changes only slightly. In most patients with severe hepatic impairment, levetiracetam clearance decreases by more than 50% due to concomitant renal impairment.

Children aged 4-12 years

After a single dose of 20 mg/kg, the T_1/2 in children 6-12 years is 6 hours. The weight-adjusted apparent clearance is 30% higher than that of adults with epilepsy. After long-term administration of the drug at a dose of 20-60 mg/kg/day, absorption of levetiracetam in children 4-12 years old is rapid. C_max is reached within 0.5-1 h. C_max and AUC are linear and proportional to dose. The terminal T_1/2 is 5 h. The apparent clearance is 1.1 ml/min/kg.

Indications

As monotherapy for the treatment of partial seizures with or without secondary generalization in patients over 16 years of age with a newly diagnosed epilepsy.

As an adjuvant therapy, levetiracetam is indicated for the treatment of:

partial seizures with or without secondary generalization in patients with epilepsy from 6 years of age;
myoclonic seizures in patients with juvenile myoclonic epilepsy from 12 years of age;
primary generalized tonic-clonic seizures in patients with idiopathic generalized epilepsy from 12 years of age.

Pharmacological effect

The active ingredient of the drug Levetinol® is levetiracetam. It is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidineacetamide) and differs in chemical structure from other similar anticonvulsants.

The mechanism of action of levetiracetam is not fully understood, but it differs from the mechanism of action of other similar anticonvulsants. In vitro and in vivo experiments have shown that this active substance does not affect the basic properties of the cell and normal nerve transmission.

The results of an in vitro study showed that, by partially reducing N-type calcium currents and reducing the release of calcium ions from the intracellular stores of neurons, levetiracetam changes the concentration of calcium ions inside neurons. In addition, it partially eliminates the decrease in GABA and glycine channel currents caused by zinc and β-carbolines. In addition, in vitro studies have shown that levetiracetam binds to specific areas of the rat brain.

This site is synaptic vesicle protein 2A, which is thought to be involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and its analogues, which bind to synaptic vesicle protein 2A, exhibit anticonvulsant activity in an audiogenic mouse model of epilepsy, with the stronger the binding, the higher the activity. These data imply that binding of levetiracetam to synaptic vesicle protein 2A mediates its anticonvulsant effect.

Levetiracetam has anticonvulsant effects in many animal models of partial and primary generalized seizures without concomitant proconvulsant effects. 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 long-term use, there is no change in clearance. There is no evidence of sex, race, or diurnal differences. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable.

Due to complete and linear absorption, plasma concentrations can be predicted from the dose of levetiracetam, expressed in mg/kg body weight. Therefore, it is not necessary to monitor plasma concentrations of levetiracetam.

In adults and children, a high correlation is shown between the concentration of levetiracetam in plasma and saliva (the saliva/plasma ratio ranges from 1-1.7 for oral tablets and for oral solution 4 hours after taking the latter).

Adults and teenagers

Suction

After oral administration, levetiracetam is rapidly absorbed. Absolute bioavailability after oral administration is close to 100%. Cmax is reached after 1.3 hours. The equilibrium state is achieved after 2 days when taking the drug 2 times a day.

Cmax is usually 31 and 43 mcg/ml after a single dose of 1000 mg and 1000 mg of the drug 2 times a day, respectively.

The amount of absorption does not depend on the dose or food intake.

Distribution

There are no data on distribution in humans.

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 enzymatic hydrolysis of the acetamide group. Liver cytochrome P450 isoenzymes are not involved in the formation of the main metabolite (ucb L057). Hydrolysis of the acetamide group occurs in many tissues, including blood cells. Metabolite ucb L057 is pharmacologically inactive.

2 minor metabolites were also detected. The first is formed due to hydroxylation of the pyrrolidone ring (1.6% of the dose), the second – by opening of the pyrrolidone ring (0.9% of the dose).

Other unidentified metabolites account for only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite in vivo has not been detected.

Levetiracetam and its main metabolite do not inhibit the major human liver cytochrome P450 isoenzymes (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxide hydroxylase in vitro. Levetiracetam also does not affect the glucuronidation of valproic acid in vitro.

In cultured human hepatocytes, levetiracetam had little or no effect on the activity of the CYP1A2, SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induced the activity of the CYP2B6 and CYP3A4 isoenzymes. In vivo drug interaction data with oral contraceptives, digoxin, and warfarin indicate that significant enzyme induction is not expected in vivo. Therefore, interaction of levetiracetam with other substances is unlikely.

Removal

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 excretion in the urine (about 95% of the dose, of which 93% is excreted within 48 hours). Excretion in feces is only 0.3% of the dose.

The total excretion of levetiracetam and its main metabolite is 66% and 24% of the administered dose, respectively, during the first 48 hours. The renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml/min/kg, respectively, indicating excretion of levetiracetam through glomerular filtration followed by tubular reabsorption, and the main metabolite through, along with glomerular filtration – 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 renal function in this population group.

Kidney failure

The apparent clearance of levetiracetam and its main metabolite depends 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.

During a typical four-hour hemodialysis session, about 51% of levetiracetam is removed.

Liver dysfunction

In patients with mild to moderate hepatic impairment, the clearance of levetiracetam changes slightly. In most patients with severe hepatic impairment, levetiracetam clearance is reduced by more than 50% due to concomitant renal impairment.

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 old is 6 hours. The apparent clearance, adjusted for body weight, is 30% higher than that in adults with epilepsy. After long-term administration of the drug at a dose of 20-60 mg/kg/day, absorption of levetiracetam in children 4-12 years old is rapid. Cmax is achieved within 0.5-1 hour. Cmax and AUC are linear and proportional to the dose. Terminal T1/2 is 5 hours. Apparent clearance is 1.1 ml/min/kg.

Special instructions

Cancellation of therapy

It is recommended to discontinue the drug gradually. For example, in adults and adolescents weighing more than 50 kg, the dose should be reduced in increments of 500 mg 2 times a day no more often than every 2-4 weeks; in children over 6 years of age weighing less than 50 kg, the dose should be reduced in increments of no more than 10 mg/kg 2 times a day no more often than every 2 weeks.

Kidney failure

The use of levetiracetam in patients with renal failure may require dose adjustment. In patients with severe hepatic impairment, it is recommended to evaluate renal function before dose adjustment.

Suicide

Suicide, suicide attempts, and suicidal thoughts and behavior have been reported in patients taking anticonvulsants (including levetiracetam). A meta-analysis of randomized placebo-controlled trials of anticonvulsants showed a small increase in the risk of suicidal ideation and behavior. The mechanism for its implementation is unknown.

In view of the above, it is necessary to monitor patients with symptoms of depression or suicidal thoughts and behavior and prescribe appropriate therapy. Patients (and their caregivers) should be advised to seek medical attention if they experience symptoms of depression and/or suicidal thoughts and behavior.

Use in pediatrics

The tablets are not intended for use in children under 6 years of age.

According to available data, levetiracetam does not affect growth and puberty. However, long-term effects on learning, intelligence, growth, endocrine function, puberty, and fertility in children are not known.

Impact on the ability to drive vehicles and operate machinery

Studies on the effect on the ability to drive vehicles and operate machinery have not been conducted.

Due to individual differences in susceptibility, drowsiness and other CNS disturbances may occur in some patients, especially at the beginning of therapy and after dose increases. Therefore, it is recommended to be careful when driving vehicles and engaging in other activities that require increased concentration and speed of psychomotor reactions. If these symptoms occur, patients should avoid such activities until they are sure that these symptoms do not significantly affect them.

Active ingredient

Levetiracetam

Composition

1 tab.
levetiracetam
250 mg

Excipients:

crospovidone – 8.25 mg,

povidone – 7 mg,

silicon dioxide colloidal anhydrous – 3.5 mg,

magnesium stearate – 1.25 mg,

film coating Opadry® II Blue 85F20440 (partially hydrolyzed polyvinyl alcohol – 40%, titanium dioxide (E171) – 22.29%, macrogol 4000 – 20.2%, talc – 14.8%, indigo carmine dye (E132) – 2.71%) – 8.1 mg.

Pregnancy

Data on the use of levetiracetam during pregnancy are insufficient. Animal studies have shown reproductive toxicity. The potential risk to humans is unknown.

Use of the drug during pregnancy, as well as in women of childbearing age who do not use reliable methods of contraception, only in cases where the expected benefit of therapy for the mother outweighs the potential risk to the fetus.

As with other anticonvulsants, physiological changes during pregnancy may affect levetiracetam concentrations. During pregnancy, a decrease in the plasma concentration of levetiracetam is observed. This decrease is most pronounced during the third trimester (up to 60% of the baseline concentration observed before pregnancy). Pregnant women taking levetiracetam should be closely monitored. Withdrawal of anticonvulsant therapy can lead to exacerbation of the disease, which can negatively affect the condition of the mother and fetus.

Levetiracetam is excreted in breast milk. Breastfeeding while taking the drug is not recommended. However, if levetiracetam therapy is to be continued during breastfeeding, the expected benefits and possible risks of treatment should be weighed against the importance of breastfeeding.

In animal studies, no effect on fertility was found. There are no clinical data and the potential risk to humans is unknown.

Use in children

The drug is prescribed in the most convenient dosage form and dosage depending on age, body weight and the required dose.

The tablets are not intended for use in children under 6 years of age. For such patients, it is recommended to prescribe the drug in dosage form as an oral solution. In addition, the available dosages of tablets are not intended for initial dose selection in children weighing less than 25 kg, in patients who are unable to swallow tablets, or when a dose of <250 mg is required. In all of these cases, it is recommended to use the solution for oral administration.

Contraindications

children under 6 years of age;
hypersensitivity to the components of the drug;
hypersensitivity to pyrrolidone derivatives.

Use for liver dysfunction

In patients with mild to moderate hepatic impairment, no dose adjustment is required.

Use for renal impairment

Depending on the degree of renal dysfunction, the daily dose is selected individually.

Use in elderly patients

In elderly patients with impaired renal function, it is recommended to adjust the dose as in renal failure.

Side Effects

The adverse reaction profile presented below is based on the results of an analysis of placebo-controlled clinical trials of levetiracetam for all indications (total number of patients – 3416).

These data are supplemented by information on the use of levetiracetam in open-label extension clinical studies, as well as post-marketing 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 (adults and children), and does not depend on approved indications for use (various types of epilepsy).

Adverse reactions identified in clinical studies and as part of post-registration monitoring (in adults, adolescents and children over 1 month) are presented in the table by system-organ class and frequency. Frequency gradation: very often (≥1/10), often (≥1/100 and

Very often
Often
Uncommon
Rarely
Infections and infestations
nasopharyngitis
infections
From the hematopoietic system
thrombocytopenia, leukopenia1
pancytopenia1,2, neutropenia1
Metabolism
anorexia
loss1 or increase in body weight
From the mental side
depression, hostility or aggression1, sleep disturbance, nervousness, irritability
suicide attempts1, suicidal ideation1, psychotic disorders1, conduct disorder1, hallucinations, anger, confusion, emotional lability, mood changes, agitation
completed suicide1, personality disorder, thought disorder
From the nervous system
drowsiness, headache
convulsions, imbalance, dizziness, lethargy, tremors
amnesia, memory impairment, incoordination or ataxia, paresthesia1, attention disorder
choreoathetosis1, dyskinesia1, hyperkinesia
From the side of the organ of vision
diplopia, visual impairment
From the organ of hearing and balance
vertigo
From the respiratory system
cough
From the digestive system
abdominal pain, diarrhea, dyspepsia, vomiting, nausea
pancreatitis1
From the liver and biliary tract
impairment of liver function tests1
liver failure1, hepatitis1
From the skin and subcutaneous tissues
rash
alopecia1, eczema, itching
toxic epidermal necrolysis1, Stevens-Johnson syndrome, erythema multiforme1
From the musculoskeletal system
muscle weakness, myalgia
General disorders
asthenia or fatigue
injury
1Adverse reactions identified in the post-registration period
2In some cases, inhibition of bone marrow hematopoiesis has been established

Description of selected adverse reactions

With simultaneous use of topiramate and levetiracetam, the risk of developing anorexia increases.

In some cases, alopecia has reversed after discontinuation of levetiracetam.

Children

A total of 645 patients aged 4–16 years were treated in placebo-controlled and open-label extension studies, 233 of whom received levetiracetam in placebo-controlled studies. For both age ranges, additional data are available on post-marketing experience with levetiracetam.

The safety profile of levetiracetam generally does not differ depending on age (adults and children), and does not depend on approved indications for use (various types of epilepsy). With the exception of behavioral and psychiatric adverse reactions, which occurred more frequently in children than in adults, the safety profile of levetiracetam in children was comparable to that in adults in placebo-controlled studies.

In children aged 4-16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood changes (common, 2.1%), emotional lability (common, 1.7%), aggression (common, 8.2%), behavioral disturbances (common, 5.6%) and lethargy (common, 3.9%) were reported more often than in other age ranges.

The cognitive and neuropsychological effects of levetiracetam in children 4–16 years of age with partial-onset seizures were assessed in double-blind, placebo-controlled safety profile studies using a noninferiority design. Levetiracetam has been shown to be no different (no less safe) from placebo in changes from baseline in the Leiter-R Attention and Memory scale and the Memory Screen Composite in patients subjected to per-protocol analysis.

The results of the study of behavioral and emotional functions confirming that aggressive behavior occurs during the use of levetiracetam were obtained using a standardized method using a validated instrument – the Achenbach Child Behavior Checklist.

However, in patients taking levetiracetam long-term in open-label studies, behavioral and emotional dysfunctions did not occur, in particular, the level of aggressive behavior did not differ from baseline.

Interaction

Anticonvulsants

According to pre-marketing clinical studies, levetiracetam does not affect the serum concentrations of other anticonvulsants: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone, and these anticonvulsants do not affect the pharmacokinetics of levetiracetam.

Similar to adults, in children in doses up to 60 mg/kg/day, levetiracetam does not interact with other drugs. A retrospective evaluation of the pharmacokinetic interaction in children and adolescents with epilepsy (4-17 years) confirms that levetiracetam as an adjuvant therapy does not affect the Css of concomitantly administered carbamazepine and valproic acid.

However, there is evidence that the clearance of levetiracetam in children taking anticonvulsants that are inducers of microsomal liver enzymes increases by 20%. No dose adjustment is required.

Probenecid

Probenecid (500 mg 4 times / day) is a blocker of tubular secretion in the kidneys; it has been shown to inhibit the renal clearance of the main metabolite, but not levetiracetam. However, the concentration of the main metabolite remains low. It is expected that other drugs excreted by active tubular secretion may reduce the 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 had no effect on the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel); hormonal status (LH and progesterone levels) did not change.

Levetiracetam at a dose of 2000 mg/day had no effect on the pharmacokinetics of digoxin and warfarin, and the prothrombin time did not change. The simultaneous use of digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam.

Antacids

There are no data on the effect of antacids on the absorption of levetiracetam.

Food and alcohol

Food does not affect the extent of absorption of levetiracetam, but slightly reduces its rate.

There are 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 rinse the stomach or induce vomiting. No antidote for levetiracetam has been found.

Treatment is symptomatic and may include hemodialysis. Dialysis activity against levetiracetam is 60%, against the main metabolite – 74%.

Storage conditions

In a dry place, protected from light, at a temperature not exceeding 25 °C

Shelf life

3 years in original packaging

Manufacturer

Geropharm LLC, Russia