Composition
| of 1 tab. | |
| levetiracetam | 500 mg |
Auxiliary substances:
crospovidon – 16.5 mg,
povidone – 14 mg,
silicon dioxide colloidal anhydrous – 7 mg,
magnesium stearate – 2.5 mg,
film coating Opadry® II Yellow 85F32371 (polyvinyl alcohol partially hydrolyzed to 40%, titanium dioxide (E171) – 23.92%, macrogol 4000 – 20.2%, talc – 14.8%, the dye Indigo Carmine (E132) – 0.11%, dye iron oxide yellow (E172) – 0.97%) – 16.2 mg.
Pharmacological action
The Active ingredient of Levetinol® is levetiracetam. It is a derivative of pyrrolidone (the S-enantiomer of α-ethyl-2-oxo-1-pyrrolidinacetamide) 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 ingredient does not affect the basic properties of the cell and normal neural 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 depot of neurons, levetiracetam alters the concentration of calcium ions inside neurons. In addition, it partially eliminates the decrease in GABA and glycine channel currents caused by zinc and beta-carbolines.
In addition, in vitro studies have shown that levetiracetam binds to specific areas of the rat brain. This site is protein 2A of synaptic vesicles, which is supposed to be involved in the process of vesicle fusion and exocytosis of neurotransmitters. Levetiracetam and its analogues that bind to synaptic vesicle protein 2A exhibit anticonvulsant activity in an audiogenic model of epilepsy in mice, and the stronger the connection, the higher the activity. These data suggest that the binding of levetiracetam to synaptic vesicle protein 2A implements its anticonvulsant effect.
Levetiracetam has an anticonvulsant effect on many models of partial and primary generalized convulsions in animals without concomitant pro-convulsive effect. The main metabolite of levetiracetam is inactive.
Levetiracetam shows anticonvulsant activity in partial and generalized epilepsy in humans (epileptiform burst/photoparoxysmal response), which confirms its wide range of pharmacological action.
Pharmacokinetics
Levetiracetam is a highly soluble and permeable compound. The pharmacokinetic profile is linear with low intra-and inter-individual variation. After prolonged use, there is no change in clearance. There is no evidence of gender, race, or diurnal differences. The pharmacokinetic properties of levetiracetam in patients with epilepsy and healthy volunteers are comparable.
Due to the complete and linear absorption, the plasma concentration can be predicted by the dose of levetiracetam, expressed in mg/kg of body weight. Therefore, it is not necessary to monitor the plasma concentration of levetiracetam.
In adults and children, a high correlation between the concentration of levetiracetam in plasma and saliva is shown (the saliva/plasma ratio varies between 1-1.7 for oral tablets and for oral solution 4 hours after taking the latter).
Adults and teenagers
Suction
Levetiracetam is rapidly absorbed after oral use. Absolute bioavailability after oral use is close to 100%. Cmax is reached after 1.3 h. The equilibrium state is reached after 2 days when taking the drug 2 times/day.
Cmax is usually 31 and 43 mcg / ml after a single dose of 1000 mg and 1000 mg of the drug 2 times/day, respectively.
The amount of absorption does not depend on the dose and on food intake.
Distribution
There are no data on human distribution.
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 P 450 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 ucb L057 metabolite is pharmacologically inactive.
Two minor metabolites were also 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 account for only 0.6% of the dose. Optical isomerization of levetiracetam and its main metabolite was not detected in vivo.
Levetiracetam and its main metabolite do not inhibit the main human liver cytochrome P 450 isoenzymes (CYP3A4,2A6,2C9,2C19,2D6,2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6), and epoxidohydroxylase 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 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 indicate that no significant in vivo enzyme induction is expected. Therefore, the interaction of levetiracetam with other substances is unlikely.
Elimination
of T1/2 in adults is 7±1 and does not depend on the dose, route of use 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). Fecal excretion is only 0.3% of the dose.
The total amount of 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, which indicates the excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and the main metabolite by active tubular secretion along with glomerular filtration.
Elimination of levetiracetam correlates with creatinine clearance.
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 creatinine clearance. In this regard, in patients with moderate to severe renal insufficiency, it is recommended to adjust the maintenance dose of the drug depending on the creatinine clearance.
In adult patients with end-stage renal insufficiency, 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.
Impaired liver function
In patients with mild to moderate hepatic insufficiency, the clearance of levetiracetam varies slightly. In most patients with severe hepatic insufficiency, the clearance of levetiracetam decreases by more than 50%, due to concomitant renal insufficiency.
Children aged 4-12 years
After a single dose of 20 mg/kg, T1/2 in children aged 6-12 years is 6 hours. Body weight-adjusted apparent clearance is 30% higher than that of adults with epilepsy. After long-term use of the drug at a dose of 20-60 mg/kg/day, the absorption of levetiracetam in children aged 4-12 years is rapid. Cmax isreached within 0.5-1 h. Cmax and AUC are linear and proportional to the dose. Terminal T1/2 is 5 h. 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 adjunctive 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.
Use during pregnancy and lactation
Data on the use of levetiracetam during pregnancy are insufficient. Animal studies have shown the presence of reproductive toxicity. The potential risk to humans is not known.
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 exceeds the potential risk to the fetus.
As with other anticonvulsants, physiological changes during pregnancy can affect the concentration of levetiracetam. During pregnancy, there is a decrease in the plasma concentration of levetiracetam. 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 properly monitored.Discontinuation of anticonvulsant therapy can lead to an 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 should be continued during breastfeeding, the expected benefit and possible risk of treatment and the importance of breastfeeding should be weighed.
In animal studies, no effect on fertility was found. There are no clinical data available, and the potential risk to humans is not known.
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, the drug is recommended to be prescribed in the dosage form of an oral solution. In addition, the available tablet dosages are not intended for initial dose selection in children with a body weight of less than 25 kg, patients who are unable to swallow tablets, or if a dose is necessary. In all these cases, it is recommended to use a solution for oral use.
Contraindications
- children under 6 years of age;
- hypersensitivity to the components of the drug;
- hypersensitivity to pyrrolidone derivatives.
Use in patients with liver function disorders
No dose adjustment is required in patients with mild to moderate hepatic insufficiency.
Use in patients with impaired renal function
Depending on the degree of impaired renal function, 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 case of 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 data on the use of levetiracetam in open-label extended clinical trials, as well as post-marketing data. The most frequently 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 variants of epilepsy).
Adverse reactions identified in clinical studies and post-marketing monitoring (in adults, adolescents, and children older than 1 month) are presented in the table by systemic organ classes and frequency. Frequency gradation: very common (≥1/10), common (≥1/100 and higher).
| Very Often | Often | Infrequently | Rarely |
| Infections and infestations | |||
| nasopharyngitis | infections | ||
| From the hematopoietic system | |||
| thrombocytopenia, leukopenia 1 | pancytopenia 1,2, neutropenia 1 | ||
| From the side of metabolism | |||
| anorexia | 1 decrease or increase in body weight | ||
| Mental disorders | |||
| depression, hostility or aggression 1, sleep disorders, nervousness, irritability | suicidal attempts 1, suicidal thoughts 1, psychotic disorders 1, behavioral disorders 1, hallucinations, anger, confusion, emotional lability, mood changes, agitation | completed suicide 1, personality disorder, thinking disorder | |
| Nervous system | |||
| disorders drowsiness, headache | convulsions, balance disorders, dizziness, lethargy, tremor | amnesia, memory impairment, coordination disorders or ataxia, paresthesia 1, attention disorder | choreoathetosis 1, dyskinesia 1, hyperkinesia |
| From the side of the organ of vision | |||
| diplopia, visual impairment | |||
| Hearing and balance | |||
| disorders vertigo | |||
| From the respiratory system | |||
| cough | |||
| From the digestive system | |||
| abdominal pain, diarrhea, dyspepsia, vomiting, nausea | pancreatitis 1 | ||
| From the side of the liver and biliary tract | |||
| violation of liver function tests 1 | liver failure 1, hepatitis 1 | ||
| Skin and subcutaneous tissue | |||
| disorders rash | alopecia 1, eczema, pruritus | toxic epidermal necrolysis 1, Stevens-Johnson syndrome, erythema multiforme 1 | |
| Musculoskeletal system disorders | |||
| : muscle weakness, myalgia | |||
| General disorders | |||
| of asthenia or fatigue | trauma | ||
| 1 Adverse reactions detected in the post-marketing period 2 In some cases, inhibition of bone marrow hematopoiesis has been established | |||
Description of individual adverse reactions
With the simultaneous use of topiramate and levetiracetam, the risk of developing anorexia increases.
In some cases, alopecia was reversed after discontinuation of levetiracetam.
Children
The placebo-controlled and open-label extended-duration trials included 645 patients aged 4-16 years,233 of whom received levetiracetam in placebo-controlled trials. 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 (in adults and children), and also does not depend on approved indications for use (various variants of epilepsy). With the exception of behavioral and psychiatric adverse reactions, which occurred more frequently in children than in adults, in placebo-controlled studies, the safety profile of levetiracetam in children was comparable to that in adults. 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 disorders (common,5.6%), and lethargy (common,3.9%) were observed more often than in other age ranges.
The cognitive and neuropsychological effects of levetiracetam in children aged 4-16 years with partial seizures were evaluated in double-blind, placebo-controlled safety profile studies using a no less safe design.
Levetiracetam has been shown to be no different (no less safe) from placebo by changes from baseline values on the Leiter-R Attention and Memory scale, the Memory Screen Composite scale in patients subjected to protocol analysis. The results of a study of behavioral and emotional functions that confirm that aggressive behavior occurs against the background of levetiracetam use were obtained using a standardized method using a validated tool-the Achenbach Child Behavior Checklist.
However, patients who took levetiracetam long-term in open-label studies did not experience behavioral and emotional disorders, in particular, the level of aggressive behavior did not differ from the 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.
Similarly to adults, levetiracetam does not interact with other drugs in children at doses up to 60 mg/kg/day. A retrospective assessment of the pharmacokinetic interaction in children and adolescents with epilepsy (4-17 years) confirms that levetiracetam as adjunctive 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 – inducers of microsomal liver enzymes, increases by 20%. No dose adjustment is required.
Probenecid
Probenecid (500 mg 4 times a day) is a renal tubular secretion blocker, and 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 through 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 did not affect 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 did not affect the pharmacokinetics of digoxin and warfarin, and the prothrombin time did not change. Concomitant 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 degree of absorption of levetiracetam, but slightly reduces its rate.
There are no data on the interaction of levetiracetam with ethanol.
How to take, course of use and 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 the initial therapeutic 500 mg 2 times/day. The dose can 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.
Adjunctive therapy in adults (≥18 years) and teenagers (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 can be used from the first day of treatment.
Depending on the clinical response and tolerability, the daily dose can be increased to 1500 mg 2 times / day. The dose can be increased or decreased by 500 mg 2 times / day every 2-4 weeks.
Elderly patients (65 years and older)
In elderly patients with impaired renal function, it is recommended to adjust the dose of the drug.
Kidney failure
Depending on the degree of impaired renal function, the daily dose is selected individually. To use the dose adjustment table, you need to calculate the patient’s creatinine clearance in ml/min. CC 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):
CC (ml / min) = [140 — age (years)] × body weight (kg)/72×plasma creatinine concentration (mg/dl)×(0.85 for women)
Then a correction for the body surface area (BTA) is introduced as follows:
CC (ml / min/1.73 m2) = KK (ml / min)/Patient’s BTA (m2)×1.73
Dose adjustment in adults and adolescents with impaired renal function, body weight >50 kg >
| Creatinine clearance group (ml / min/1.73 m2) | Dose and frequency of use | |
| Norm | >80> | 500-1500 mg 2 times / day |
| Light | 50-79 | 500-1000 mg 2 times / day |
| Moderate grade | 30-49 | 250-750 mg 2 times / day |
| Heavy | 250-500 mg 2 times / day | |
| End-stage renal failure-patients on hemodialysis(1) | – | 500-1000 mg 1 time / day(2) |
(1)Â A loading dose of 750 mg is recommended on the first day
. (2) An additional dose of 250 or 500 mg is recommended at the end of hemodialysis.
Due to the fact that the clearance of levetiracetam depends on renal function, the dose of levetiracetam in children with renal insufficiency is selected depending on the creatinine clearance. These guidelines are based on studies in adult patients. Creatinine clearance in ml / min/1.73 m2 in children and adolescents can be estimated by plasma creatinine concentration (in mg / dl) using the following formula (Schwartz formula):
CC (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 whose body weight
| is in the creatinine clearance Group (ml / min/1.73 m2) | Dose and frequency of use | |
| from 6 years of age | ||
| Norm | >80> | 10-30 mg / kg 2 times / day |
| Light | 50-79 | 10-20 mg / kg 2 times / day |
| Moderate grade | 30-49 | 5-15 mg / kg 2 times / day |
| Severe | 5-10 mg / kg 2 times / day | |
| End-stage renal failure – patients on hemodialysis(1) | 10-20 mg / kg 1 time / day(2) (3) |
(1) The oral solution is used for doses of (2) On the first day, a loading dose of 15 mg/kg (0.15 ml/kg) is recommended. (3) At the end of hemodialysis, an additional dose of 5-10 mg/kg (0.05-0.1 ml/kg) is recommended.
Impaired liver function
No dose adjustment is required in patients with mild to moderate hepatic insufficiency. In patients with severe hepatic insufficiency, the CC value may be misleading about the degree of renal insufficiency. Therefore, with QC
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, the drug is recommended to be prescribed in the dosage form of an oral solution. In addition, the available tablet dosages are not intended for initial dose selection in children with a body weight of less than 25 kg, patients who are unable to swallow tablets, or if a dose is necessary. In all these cases, it is recommended to use a solution for oral use.
Monotherapy
The efficacy and safety of levetiracetam in children and adolescents under 16 years of age as monotherapy has not been established. No data available.
Auxiliary therapy in children aged 6-17 years and weighing less than 50 kg
The initial dose is 10 mg / kg 2 times / day. Depending on the clinical response and tolerability, the dose may be increased to 30 mg/kg 2 times / day. The dose can 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 for children with a body weight of 50 kg or more does not differ from adults.
Recommended doses for children from 6 years of age
| 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 | 1500 mg 2 times/day |
(1)Â Children with a body weight of 25 kg or less are recommended to be prescribed the drug in the dosage form of an oral solution,100 mg / ml (2)Â The dosage regimen for children with a body weight of 50 kg or more does not differ from adults.
The drug is taken orally, washed down with a sufficient amount of water, regardless of food intake. The daily dose is divided into 2 equal doses.
Overdose
Symptoms:Â drowsiness, agitation, aggression, depression of consciousness, respiratory depression and coma.
Treatment:Â after an acute overdose, it is necessary to flush the stomach or induce vomiting. No levetiracetam antidote was found. Treatment is symptomatic and may include the use of hemodialysis.
Dialysis activity for levetiracetam is 60%, for the main metabolite – 74%.
Special instructions
Discontinuation of therapy
Discontinuation of the drug is recommended gradually. For example, in adults and adolescents with a body weight of more than 50 kg, dose reduction should be carried out in increments of 500 mg 2 times / day no more often than every 2-4 weeks; in children from 6 years of age with a body weight of less than 50 kg, dose reduction should be carried out in increments of no more than 10 mg / kg 2 times
Kidney failure
The use of levetiracetam in patients with renal insufficiency 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 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. The mechanism of its implementation is not known.
In view of the above, patients with symptoms of depression or suicidal thoughts and behaviors should be monitored and given appropriate therapy. Patients (and their caregivers) should be informed about the need to seek medical attention if they experience symptoms of depression and / or suicidal thoughts and behaviors.
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, the long-term effects on children’s learning, intelligence, growth, endocrine function, puberty, and fertility are not known.
Influence on the ability to drive motor vehicles and manage mechanisms
Studies on the effect on the ability to drive vehicles and work with mechanisms have not been conducted.
Due to individual differences in susceptibility, somnolence and other CNS disorders may occur in some patients, especially at the beginning of therapy and after increasing the dose. Therefore, it is recommended to use caution when driving vehicles and engaging in other activities that require increased concentration of attention and speed of psychomotor reactions. If these symptoms occur, patients should refrain from such activities until they are satisfied that they are not significantly affected by these symptoms.
Form of production
Tablets
Storage conditions
Store in a dry place, protected from light, at a temperature not exceeding 25 °C
Shelf
life 3 years in the original packaging
Active ingredient
Levetiracetam
Conditions of release from pharmacies
By prescription
Dosage form
Tablets
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