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Pharmacological properties

levetiracetam - a pyrrolidone derivative (s-enantiomer of alpha-ethyl-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from known antiepileptic drugs. the mechanism of action of levetiracetam is not well understood, but it has been established that it differs from the mechanism of action of known antiepileptic drugs. based on in vitro and in vivo studies, it is suggested that levetiracetam does not alter the basic characteristics of a nerve cell and normal neurotransmission.

In vitro studies have shown that levetiracetam affects intranuronal Ca levels2+ by partially suppressing current through Ca2+ N-type channels and Ca release2+ from intraneuronal depot. It also partially eliminates the inhibition of GABA and glycine-regulated current due to the action of zinc and β-carbolines. In addition, during in vitro studies, levetiracetam bound to specific sites in rodent brain tissue. The binding site is the synaptic vesicle 2A protein, which is involved in the fusion of the vesicles and the release of neurotransmitters. The affinity of levetiracetam and the corresponding analogs to the synaptic vesicle 2A protein correlated with the potency of their anticonvulsant effect in models of audiogenic epilepsy in mice. These results suggest that the interaction between levetiracetam and synaptic vesicle 2A protein may partially explain the mechanism of antiepileptic action of the drug.

Levetiracetam provides protection against seizures in a wide range of models of partial and primary-generalized seizures in animals, without exerting an anticonvulsant effect.

The activity of the drug is confirmed both with respect to focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).

Pharmacokinetics Levetiracetam is characterized by high solubility and permeability. Pharmacokinetics is linear, time-independent and characterized by low inter- and intrasubject variability. After repeated use of the drug, the clearance does not change. No evidence of gender, race, or circadian rhythm effects on pharmacokinetics. The pharmacokinetics profile was similar in healthy volunteers and epilepsy patients.

Due to complete and linear absorption, plasma levels of the drug can be predicted based on the oral dose of levetiracetam, expressed in mg / kg body weight. Therefore, there is no need to monitor plasma levels of levetiracetam.

In adults and children, there was a significant correlation between the concentration of the drug in saliva and blood plasma (the ratio of concentrations in saliva / blood plasma ranged from 1 to 1.7 for tablets and 4 hours after taking the oral solution).

Suction. Levetiracetam is rapidly absorbed after oral administration.

Absolute oral bioavailability is close to 100%. WITHmax in blood plasma is achieved 1.3 hours after taking the drug. The equilibrium state is reached after 2 days of using the drug 2 times a day. WITHmax usually 31 and 43 μg / ml after a single dose of 1000 mg and a repeated dose of 1000 mg 2 times a day, respectively. The degree of absorption does not depend on the dose and does not change under the influence of food.

Distribution. There is no data on the distribution of the drug in human tissues. Neither levetiracetam nor its main metabolite significantly bind to plasma proteins (10%).

The distribution volume of levetiracetam is approximately 0.5 to 0.7 l / kg body weight, which is approximately equal to the total volume of water in the body.

Metabolism. The metabolism of levetiracetam in humans is negligible. The main route of metabolism (24% of the dose) is the enzymatic hydrolysis of the acetamide group. Isoforms of cytochrome P450 do not participate in the formation of the main metabolite, ucb L057. Hydrolysis of the acetamide group was observed in a large number of cells, including blood cells.

The metabolite ucb L057 is pharmacologically inactive.

Two minor metabolites have also been identified.One is the result of hydroxylation of the pyrrolidone ring (1.6% of the dose), the other is the result of rupture of the pyrrolidine ring (0.9% of the dose).

Other uncertain components accounted for only 0.6% of the dose.

Mutual conversion of the enantiomers of levetiracetam or its main metabolite was not observed in vivo.

During in vitro studies, levetiracetam and its main metabolite did not inhibit the activity of the main isoforms of cytochrome P450 (CYP 3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase. Also, levetiracetam does not inhibit glucuronidation of valproic acid in vitro.

In human hepatocyte culture, levetiracetam had little or no effect on the conjugation of ethinyl estradiol or on CYP 1A1 / 2. In high concentrations (680 μg / ml), levetiracetam exhibited weak induction of CYP 2B6 and CYP 3A4, however, in concentrations similar to Cmax after repeated use of 1500 mg 2 times a day, this effect was not biologically significant. Therefore, the interaction of levetiracetam with other substances or vice versa is unlikely.

T½ from plasma in adults was 7 ± 1 h and was not dependent on the dose, route of administration or repeated use. The average total clearance is 0.96 ml / min / kg.

The main amount of the drug, on average 95% of the dose, was excreted by the kidneys (about 93% of the dose within 48 hours). With feces, only 0.3% of the dose is excreted.

Cumulative urinary excretion of levetiracetam and its main metabolite was 66 and 24% of the dose in the first 48 hours, respectively. The renal clearance of levetiracetam and ucb L057 was 0.6 and 4.2 ml / min / kg, respectively, which indicates the removal of levetiracetam by glomerular filtration followed by reabsorption in the tubules and that the main metabolite is also excreted by active tubular secretion in addition to glomerular filtration. Excretion of levetiracetam correlates with creatinine clearance.

Elderly patients

In elderly people, T½ increases by about 40% (10–11 hours). This is due to impaired renal function in this population.

Children aged 4–12 years

After taking a single dose (20 mg / kg) in children with epilepsy, T½ levetiracetam was 6 hours. Visible clearance was 1.43 ml / min / kg. After repeated oral administration (20-60 mg / kg / day) in children with epilepsy (aged 4-12 years), levetiracetam was rapidly absorbed. WITHmax in blood plasma is achieved after 0.5-1 hours after taking the dose. WITHmax and AUC increased linearly and were dose dependent. T½ is about 5 hours; visible total clearance - 1.1 ml / min / kg.

Children (ages 1 month to 4 years)

After a single dose (20 mg / kg) of an oral solution of 100 mg / ml in children with epilepsy (from 1 month to 4 years old), levetiracetam was rapidly absorbed, Cmax in the blood plasma was observed 1 hour after taking the drug.

Pharmacokinetic parameters indicated that T½ was shorter (5.3 h) than in adults (7.2 h), and the apparent clearance is faster (1.5 ml / min / kg) than in adults (0.96 ml / min / kg).

The results of a population analysis of pharmacokinetics conducted in patients aged 1 month to 16 years showed a significant correlation of body weight with visible clearance (clearance increased with increasing body weight) and the apparent volume of distribution. Age also influenced both parameters. This effect was more pronounced in young children, decreased with age and was minimal in children aged about 4 years.

The data of both population pharmacokinetic analyzes indicated an increase in the apparent clearance of levetiracetam by ≈20% with the simultaneous use of enzyme-inducing antiepileptic drugs.

Impaired renal function

The apparent overall clearance of levetiracetam and its main metabolite correlates with creatinine clearance. Therefore, patients with moderate and severe renal impairment are recommended to adjust the maintenance dose of levetiracetam according to creatinine clearance (see APPLICATION).

In patients with end-stage anuria of kidney disease T½ was approximately 25 and 3.1 hours, respectively, between the dialysis sessions and during its conduct. During a typical 4-hour dialysis session, 51% of levetiracetam is excreted.

Impaired liver function

The pharmacokinetics of levetiracetam did not change in patients with mild to moderate hepatic impairment (class A and B on the Child-Pugh scale). In patients with severely impaired liver function (Child-Pugh class C), the overall clearance was 50% lower than in patients with normal liver function, but this was mainly due to a decrease in renal clearance.

Patients with mild to moderate impaired liver function do not require dose adjustment. In people with severe hepatic impairment, creatinine clearance may not fully reflect the severity of renal failure. Therefore, when creatinine clearance is 60 ml / min / 1.73 m2 a maintenance daily dose is recommended to be reduced by 50%.

Indications

Monotherapy (the drug of first choice) in the treatment of:

  • partial attacks with or without secondary generalization in adults and adolescents over the age of 16 years, who were first diagnosed with epilepsy.

As part of complex therapy in the treatment of:

  • partial attacks with or without secondary generalization in adults and children over the age of 4 years with epilepsy (Keppra tablets);
  • partial seizures with or without secondary generalization in adults and children over 1 month old with epilepsy (Keppra oral solution);
  • myoclonic seizures in adults and adolescents over 12 years of age with juvenile myoclonic epilepsy;
  • primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over the age of 12 years, patients with idiopathic generalized epilepsy.

Application

The tablets are taken orally with a sufficient amount of liquid, regardless of the meal. the daily dose is divided into 2 identical doses.

Monotherapy in adults and adolescents over the age of 16 should be started with a dose of 250 mg 2 times a day. After 2 weeks, the dose can be increased to the initial therapeutic dose - 500 mg 2 times a day. In the future, the dose can be increased by 250 mg 2 times a day every 2 weeks, depending on the clinical response. The maximum daily dose is 1500 mg 2 times a day, that is, should not exceed 3 g.

As part of complex therapy in children over the age of 4 years, treatment should begin with a dose of 10 mg / kg body weight 2 times a day. An increase in the daily dose by 20 mg / kg body weight can be carried out every 2 weeks until the recommended daily dose is reached - 30 mg / kg body weight 2 times a day. If necessary, the daily dose can be reduced. It is recommended to use the minimum effective dose. Recommended doses, depending on the body weight of the child, are:

15–20 kg *: initial dose - 150 mg 2 times a day; maximum - 450 mg 2 times a day;

20-25 kg *: initial dose - 200 mg 2 times a day; maximum - 600 mg 2 times a day;

25-50 kg: initial dose - 250 mg 2 times a day; maximum - 750 mg 2 times a day.

* Children with a body weight of 25 kg are prescribed Keppra in the form of an oral solution, 100 mg / ml complete with a dosing device.

In children with a body weight of 50 kg, dosing is carried out according to the scheme given for adults.

Adults and adolescents over the age of 16 years with a body weight of 50 kg begin treatment with a dose of 500 mg 2 times a day. Depending on the clinical picture and tolerability of the drug, the daily dose can be increased to a maximum of 1,500 mg 2 times a day. A dose increase of 500 mg 2 times a day can be carried out every 2–4 weeks.

The oral solution is taken orally, regardless of the meal. The solution can be taken directly or after dilution in a glass of water. The daily dose is divided into 2 identical doses.

Monotherapy in adults and adolescents over the age of 16 years, the initial dose is 500 mg (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic - 1000 mg (500 mg 2 times a day). In the future, the dose can be increased by 250 mg 2 times a day every 2 weeks, depending on the clinical response.The maximum daily dose is 3000 mg (1500 mg 2 times a day).

As part of complex therapy.

Adults (18 years old) and adolescents (12-17 years old) with body weight ≥50 kg

The initial therapeutic dose is 1000 mg / day. With this dose, you can start on the 1st day of treatment.

Depending on the clinical response and tolerance, the dose can be increased to 3000 mg / day. The dose can be increased or decreased by 1000 mg / day every 2–4 weeks.

Children aged 6–23 months, children (aged 2–11 years) and adolescents (12–17 years) with a body weight of 50 kg

The initial therapeutic dose is 10 mg / kg body weight 2 times a day.

Depending on the clinical response and tolerance, the dose can be increased to 30 mg / kg body weight 2 times a day. The dose can be increased or decreased by more than 10 mg / kg body weight 2 times a day every 2 weeks. The lowest effective dose should be used.

In children weighing ≥50 kg, the same doses are used as in adults.

Recommended doses for children from 6 months of age, children and adolescents:

Body weight The initial dose is 10 mg / kg body weight 2 times a day The maximum dose is 30 mg / kg body weight 2 times a day
6 60 mg 2 times a day 180 mg 2 times a day
10 100 mg 2 times a day 300 mg 2 times a day
15 150 mg 2 times a day 450 mg 2 times a day
20 200 mg 2 times a day 600 mg 2 times a day
25 250 mg 2 times a day 750 mg 2 times a day
≥50 500 mg 2 times a day 1500 mg 2 times a day

Children aged 1 to 6 months

The initial therapeutic dose is 7 mg / kg body weight 2 times a day.

Depending on the clinical response and tolerance, the dose can be increased to 21 mg / kg body weight 2 times a day. The dose can be increased or decreased by more than 7 mg / kg body weight 2 times a day every 2 weeks. The lowest effective dose should be used.

Doses recommended for children under 6 months of age:

Body weight The initial dose is 7 mg / kg body weight 2 times a day The maximum dose is 21 mg / kg body weight 2 times a day
4 28 mg (0.3 ml) 2 times a day 84 mg (0.85 ml) 2 times a day
5 35 mg (0.35 ml) 2 times a day 105 mg (1.05 ml) 2 times a day
7 49 mg (0.5 ml) 2 times a day 147 mg (1.5 ml) 2 times a day

Method of administration of oral solution

Dosage is carried out using a measuring syringe, added to the package. Syringes of nominal capacity:

  • 10 ml (corresponding to 1000 mg of levetiracetam) with a division of 0.25 ml (corresponding to 25 mg) for children from 4 years of age, adolescents and adults;
  • 3 ml (corresponds to 300 mg) with a division of 0.1 ml (corresponds to 10 mg) for children aged 6 months to 4 years;
  • 1 ml (corresponds to 100 mg) with a division of 0.05 ml (corresponds to 5 mg) for children aged 1 to 6 months.

The measured dose is diluted in a glass of water (200 ml) in a bottle for feeding.

Patients with impaired renal function

The daily dose of levetiracetam must be selected individually, in accordance with the function of the kidneys, since creatinine clearance depends on it. Recommendations for dose adjustment for children with impaired renal function are based on the results of a study of adult patients with impaired renal function.

The dose should be corrected as shown in the tables below.

Since levetiracetam is excreted from the body by the kidneys, when prescribing the drug to patients with renal failure and the elderly, the dose should be corrected depending on the level of creatinine clearance.

In adults, creatinine clearance can be calculated based on the concentration of plasma creatinine, according to the formula:

Creatinine clearance for women can be calculated by multiplying the resulting value by a factor of 0.85.

For children, the Schwartz formula is used:

in full-term newborns under the age of 1 year, ks = 0.45; under the age of 13 years and adolescent girls ks = 0.55; in adolescent boys, ks = 0.7.

Dosage regimen for renal failure:

The severity of renal failure Creatinine clearance, ml / min Dosage regimen
Normal kidney function 80 500 to 1,500 mg 2 times a day
Mild 50–79 500 to 1000 mg 2 times a day
Medium grade 30–49 250 to 750