Levetinol, 500 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 caused by zinc and β-carbolines.

In addition, in in vitro studies, levetiracetam has been shown to bind to specific sites in 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 from 16 years of age with a first-time diagnosis of epilepsy.

Levetiracetam is indicated as adjunctive therapy:

Active ingredient

Composition

Associates:

crospovidone – 16.5 mg,

povidone – 14 mg,

colloidal anhydrous silica – 7 mg,

magnesium stearate – 2.5 mg,

film coating Opadray® II Yellow 85F32371 (polyvinyl alcohol partially hydrolyzed – 40%, titanium dioxide (E171) – 23.92%, macrogol 4000 – 20.2%, talc – 14.8%, indigo carmine dye (E132) – 0.11%, iron oxide yellow dye (E172) – 0.97%) – 16.2 mg.

How to take, the dosage

Monotherapy in adults and adolescents from 16 years of age

The recommended starting dose is 250 mg 2 times/day, which should be increased after 2 weeks to an initial therapeutic dose of 500 mg 2 times/day. The dose may be increased in increments of 250 mg twice daily every 2 weeks depending on clinical response. The maximum dose is 1500 mg 2 times daily.

Auxiliary therapy in adults (≥18 years) and adolescents (12-17 years) with a body weight of 50 kg or more

The initial therapeutic dose is 500 mg 2 times/day. This dose is allowed from the first day of treatment.

Depending on clinical response and tolerability, the daily dose may be increased to 1500 mg 2 times daily. The dose may be increased or decreased by 500 mg twice daily every 2 to 4 weeks.

Patients in the elderly (65 years and older)

In elderly patients with impaired renal function, adjustment of the dose is recommended.

Renal impairment

The daily dose is adjusted individually depending on the degree of renal impairment. To use the dose adjustment table, the patient’s CK in ml/min must be calculated. The CK in ml/min can be determined using the serum creatinine concentration (mg/dL) according to the following formula (for adults and adolescents with a body weight of 50 kg or more):

CK (ml/min) = [140 – age (years)] × body weight (kg)/72× plasma creatinine concentration (mg/dL)×(0.85 for women)

Then a correction for body surface area (BSA) is entered as follows:

CK (ml/min/1.73 m2) = CK (ml/min)/PPT patient (m2)×1.73

Dose adjustment in adults and adolescents with impaired renal function whose body weight >50 kg

(1) On the first day, a loading dose of 750 mg is recommended.

(2)After completion of hemodialysis, an additional dose of 250 or 500 mg is recommended.

Because clearance of levetiracetam depends on renal function, in children with renal insufficiency the dose is adjusted according to CK. These recommendations are based on studies in adult patients. CK in ml/min/1.73 m2 in children and adolescents can be estimated from plasma creatinine concentration (in mg/dL) using the following formula (Schwartz formula):

CK (ml/min/1.73 m2) = height (cm)×ks/plasma creatinine concentration (mg/dL)

where ks = 0.45 for children under 1 year of age; 0.55 for children aged 1-13 years and female adolescents; 0.7 for male adolescents.

Dose adjustment in children and adolescents with impaired renal function whose body weight

(1) The oral solution is used for doses (2) On the first day, a loading dose of 15 mg/kg (0.15 ml/kg).
(3)After completion of hemodialysis, an additional dose of 5-10 mg/kg (0.05-0.1 ml/kg) is recommended.

Hepatic impairment

In patients with mild to moderate hepatic impairment, no dose adjustment is required. In patients with severe hepatic impairment the CK value may be misleading about the degree of renal impairment. Therefore, if CK < 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 required dose.

The tablets are not intended for use in children under 6 years of age. In such patients, the drug is recommended to be prescribed in the dosage form of oral solution. In addition, the available tablet dosages are not suitable for initial dosing in children with a body weight less than 25 kg, patients who are unable to swallow tablets, or if a dose of < 250 mg is required. In all the above cases it is recommended to use an oral solution.

Monotherapy

The efficacy and safety of levetiracetam in children and adolescents under 16 years of age as monotherapy has not been established. No data are available.

Advanced therapy in children 6-17 years of age and with a body weight less than 50 kg

The initial dose is 10 mg/kg 2 times/day. Depending on clinical response and tolerability, 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 with body weight 50 kg or more is the same as in adults.

Recommended doses in children from 6 years of age

(1)In children weighing 25 kg or less, it is recommended to prescribe the drug in the dosage form of oral solution, 100 mg/ml
(2)The dosage regimen in children weighing 50 kg or more is the same as in adults.

The drug is taken orally with plenty of water, regardless of meals. The daily dose is divided into 2 equal doses.

Interaction

Anticonvulsants

According to pre-registration clinical studies, levetiracetam has no effect on 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.

As in adults, levetiracetam does not interact with other drugs in children at doses up to 60 mg/kg/day. A retrospective evaluation of pharmacokinetic interactions in children and adolescents with epilepsy (4-17 years) confirms that levetiracetam as adjuvant therapy has no effect on the Css of concurrent carbamazepine and valproic acid. However, there is evidence that the clearance of levetiracetam in children taking anticonvulsants – inducers of microsomal liver enzymes is increased by 20%. No dose adjustment is required.

Probenecid

Probenecid (500 mg 4 times/day) is a blocker of renal tubular secretion and has been shown to inhibit renal clearance of the main metabolite but not of levetiracetam. However, the concentration of the main metabolite remains low. It is expected that other drugs that are excreted by active tubular secretion may decrease the renal clearance of the main metabolite. The effect of levetiracetam on probenecid has not been studied; the effect of levetiracetam on other drugs that are excreted by active tubular secretion, including NSAIDs, sulfonamide and methotrexate, is not known.

Peroral contraceptives, digoxin and warfarin

Levetiracetam at a dose of 1000 mg/day had no effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); hormonal status (LH and progesterone levels) was not changed.

Levetiracetam at a dose of 2000 mg/day had no effect on the pharmacokinetics of digoxin and warfarin; prothrombin time was not altered. Concomitant use of digoxin, oral contraceptives and warfarin had no effect on 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 degree of absorption of levetiracetam, but slightly reduces its rate.

There are no data on the interaction of levetiracetam with ethanol.

Special Instructions

Cancellation of therapy

Cancellation of the drug is recommended to be done gradually. For example, in adults and adolescents with a body weight greater than 50 kg the dose should be reduced in increments of 500 mg 2 times daily no more frequently than every 2-4 weeks; in children from 6 years of age with a body weight less than 50 kg the dose should be reduced in increments of no more than 10 mg/kg 2 times daily no more frequently than every 2 weeks.

Renal failure

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

Suicide

Patients who have taken anticonvulsants (including levetiracetam) have reported suicide, suicide attempts, suicidal thoughts and behavior. A meta-analysis of randomized placebo-controlled trials of anticonvulsant medications showed a small increase in the risk of suicidal thoughts and behavior. Its mechanism is not known.

In view of the above, patients with symptoms of depression or suicidal thoughts and behavior should be monitored and appropriate therapy should be administered. Patients (and their caregivers) should be informed to seek care if they have symptoms of depression and/or suicidal ideation or behavior.

Pediatric use

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

Levetiracetam is not reported to affect growth and puberty. However, long-term effects on learning, intelligence, growth, endocrine function, puberty, and fertility in children are not known.

Impact on driving and operating machinery

There have been no studies on the effects on driving and operating machinery.

Due to individual differences in susceptibility, some patients may experience somnolence and other CNS disturbances, especially at the beginning of therapy and after increasing the dose. Therefore, caution is recommended when driving vehicles and engaging in other activities requiring increased concentration and rapid psychomotor reactions. If these symptoms occur, patients should discontinue such activities until they are sure that these symptoms do not affect them significantly.

Contraindications

Hepatic impairment use

Dose adjustment is not required in patients with mild to moderate hepatic impairment.

The use in renal impairment

The daily dose is adjusted individually depending on the degree of renal impairment.

The use in elderly patients

In elderly patients with impaired renal function, it is recommended that the dose be adjusted as in renal impairment.

Side effects

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

The data are supplemented by information on the use of levetiracetam in open-label extended clinical trials as well as post-registration data. The most commonly reported adverse reactions were nasopharyngitis, somnolence, headache, weakness, and dizziness.

The safety profile of levetiracetam generally does not differ by age (in adults and children), nor does it depend on the approved indication for use (various epilepsy variants).

The adverse reactions identified in clinical trials and post-registration monitoring (in adults, adolescents, and children older than 1 month) are presented in a table by system-organ class and frequency. Frequency gradation: Very frequent (≥1/10), Frequent (≥1/100 and

Description of individual adverse reactions

The risk of anorexia increases when topiramate and levetiracetam are used simultaneously.

In some cases, alopecia has been reversed after withdrawal of levetiracetam.

Children

The placebo-controlled and open-label extended-release studies treated 645 patients aged 4-16 years, 233 of whom received levetiracetam in placebo-controlled trials. Post-registration experience with levetiracetam was additionally available for both age ranges.

The safety profile of levetiracetam generally does not differ by age (in adults and children), nor does it depend on the approved indications for use (various epilepsy variants). 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 of adults in placebo-controlled trials. 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%), conduct disorder (common, 5.6%) and lethargy (common, 3.9%) were more common than in other age ranges.

The cognitive and neuropsychological effects of levetiracetam in children 4-16 years of age with partial seizures were evaluated in double-blind, placebo-controlled safety profile studies using a non-minor safety design.

Levetiracetam was shown to be no different (no less safe) than placebo in changes from baseline on the Leiter-R Attention and Memory, Memory Screen Composite scale in patients subjected to “per protocol” analysis. Behavioral and emotional findings confirming that levetiracetam causes aggressive behavior were obtained using a standardized method with a validated instrument, the Achenbach Child Behavior Checklist.

However, patients who took levetiracetam long-term in open studies did not show abnormal behavioral and emotional functioning, and in particular aggressive behavior did not differ from baseline.

Overdose

Symptoms: drowsiness, agitation, aggression, depression of consciousness, respiratory depression and coma.

Treatment: after an acute overdose it is necessary to flush the stomach or induce vomiting. No antidote for levetiracetam has been found. Treatment is symptomatic and may include the use of hemodialysis.

The dialysis activity for levetiracetam is 60% and 74% for the main metabolite.

Pregnancy use

There are insufficient data on the use of levetiracetam in pregnancy. Reproductive toxicity has been shown in animal studies. The potential risk to humans is not known.

The use of the drug in pregnancy, as well as in women of childbearing age who do not use reliable methods of contraception, only when the expected benefits of therapy for the mother exceed the potential risk to the fetus.

As with other anticonvulsants, physiological changes in pregnancy may affect levetiracetam concentrations. A decrease in plasma concentrations of levetiracetam has been noted in pregnancy. 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 appropriately monitored. Discontinuation of anticonvulsant therapy may lead to an exacerbation of the disease, which may adversely affect the mother and fetus.

Levetiracetam is excreted with breast milk. Breastfeeding while taking the drug is not recommended. However, if therapy with levetiracetam should be continued while 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 not known.

The 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. In such patients, the drug is recommended to be prescribed in the dosage form of oral solution. In addition, the available tablet dosages are not suitable for initial dosing in children with a body weight less than 25 kg, patients who are unable to swallow tablets, or if a dose of < 250 mg is required. In all of the above cases, oral solution is recommended.

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