Levicitam

Levicitam is an anticonvulsant.

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Indications Levicitam

It is used to eliminate the following disorders (as monotherapy): seizures of a partial nature and a secondary form of generalization (or without it) in adolescents from 16 years of age and adults who have been diagnosed with epilepsy for the first time.

It is also used in combination treatment of the following disorders:

• partial seizures, with or without secondary generalization, in children over 6 years of age and adults suffering from epilepsy;
• myoclonic seizures in adolescents over 12 years of age and adults suffering from Janz syndrome;
• generalized seizures (tonic-clonic type) of primary nature in adolescents from 12 years of age and adults suffering from IGE.

Release form

The product is produced in tablets of 0.25 and 0.5 g. There are 10 tablets in a blister pack. There are 3 or 6 such packs in a box.

Pharmacodynamics

Levetiracetam is a pyrrolidone derivative (S-enantiomer of the element α-ethyl-2-oxo-1-pyrrolidine-acetamide), and differs in its chemical composition from other known anticonvulsants. The scheme of action of levetiracetam has not yet been sufficiently studied, but it has already been revealed that it differs from the type of therapeutic action of other known anticonvulsants. The conducted in vitro and in vivo tests allow us to assume that the drug does not change the main parameters of nerve cells and stable neurotransmission.

In vitro tests have shown that Levicitam affects internal neuronal Ca2+ parameters by partially suppressing the current through Ca2+ channels (N-type), as well as reducing the volume of Ca2+ element release from intraneuronal depots. At the same time, it partially neutralizes the suppression of GABA-, as well as glycine-regulated current, provoked by the influence of β-carbolines and zinc. In addition, in vitro tests showed that the drug was synthesized with specific areas inside the brain tissue of rodents. The site of synthesis is the protein of synaptic vesicles 2A, which is involved in the connection of vesicles and the processes of neurotransmitter release.

The affinity of the drug and its analogues for the synaptic vesicle protein 2A is consistent with the strength of their anticonvulsant effects in mouse models of audiogenic epilepsy. These data suggest that the interaction between the drug and the synaptic vesicular (2A) protein may to some extent explain the pattern of anticonvulsant effects of the drug.

The element levetiracetam creates conditions for protection against seizures in animals within a wide range of seizure models, having a partial, as well as primarily generalized character, without provoking the development of an anticonvulsant effect. The main metabolic product has no medicinal activity.

The effect of the drug has been confirmed in relation to generalized and focal epileptic seizures (epileptiform signs or photoparoxysmal phenomena).

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Pharmacokinetics

Absorption.

After oral administration, the substance is rapidly absorbed from the gastrointestinal tract. The portion size of the drug and the time of food intake do not affect the degree of absorption. The bioavailability level is approximately 100%. Peak plasma levels are observed 1.3 hours after oral administration of 1 g of the drug. With a single dose, this indicator is 31 mcg/ml, and with twice-daily use - 43 mcg/ml. The drug reaches equilibrium values after 2 days with twice-daily use of Levitcitam.

Distribution processes.

There is no information regarding the distribution of the drug within the tissues of the human body. The synthesis of the active substance and its main metabolic product with plasma protein is 10%. The distribution volume of the substance is about 0.5-0.7 l/kg, and this figure is approximately equal to the total volume of fluid within the body.

Metabolic processes.

Levetiracetam undergoes only minor metabolism in the human body. Its main route (24% of the dose taken) is enzymatic hydrolysis of elements from the acetamide group. The formation of the main metabolic product, which does not have medicinal activity (ucb L057), is carried out without the participation of hepatic hemoprotein P450. The process of hydrolysis of elements of the acetamide group occurs inside a large number of cells, including blood cells.

In addition, two minor degradation products were noted. One is formed by hydroxylation of the pyrrolidone ring (approximately 1.6% of the portion), and the second is formed by opening of this ring (approximately 0.9% of the portion).

Other unspecified elements make up only 0.6% of the serving.

Excretion.

The half-life of the substance from blood plasma in adults is approximately 7±1 hours (this indicator does not depend on the dose size and method of administration). The average values of total clearance are approximately 0.96 ml/minute/kg.

95% of the drug is excreted through the kidneys (about 93% of the dose is excreted within 48 hours). Only 0.3% of the dose is excreted with feces. The cumulative excretion of the substance and its main breakdown product with urine is 66% and 24%, respectively (during the first 48 hours).

The clearance of the drug (active element and metabolic product) inside the kidneys is 0.6 and 4.2 ml/min/kg, respectively. This shows that the substance is excreted by glomerular filtration followed by tubular reabsorption, and the main decay product is excreted by active tubular secretion in addition to glomerular filtration. Levetiracetam excretion is related to CC values.

Elderly patients.

In elderly people, the half-life of the drug is extended by 40%, amounting to approximately 10-11 hours – this is due to a decrease in renal function in this group of patients.

For renal dysfunction.

The apparent level of total clearance of the active substance of the drug and its main metabolic product is related to the CC values. Because of this, people with severe or moderate renal impairment need to adjust the size of the maintenance dose of the drug taking into account the CC level.

In individuals with anuria in the background of the terminal phase of renal disease, the half-life of the drug is approximately 25 and 3.1 hours, respectively, at the stage between dialysis procedures and during its implementation. During a 4-hour dialysis procedure, up to 51% of the drug is eliminated.

For problems with liver function.

In people with mild or moderate liver dysfunction, there are no significant changes in drug clearance rates. In people with severe pathology, the drug clearance rate decreases by more than 50% (mainly due to a decrease in renal clearance rates).

Children from the age category 4-12 years.

When a child with epilepsy takes a single dose of the drug (20 mg/kg), the half-life of the active substance is 6 hours. The apparent clearance rate is 1.43 ml/minute/kg.

With repeated oral administration (20-60 mg/kg/day), levetiracetam is rapidly absorbed. The pharmacokinetic values of the drug in children are linear. In the range of doses of 20-60 mg/kg/day, the drug reaches its peak values after 30-60 minutes. The half-life is approximately 5 hours. The apparent total clearance rate is approximately 1.1 ml/minute/kg.

Dosing and administration

The medicine is taken orally with water, without reference to food intake. The daily dose should be divided into 2 equal doses.

Monotherapy begins with a dose of 0.5 g/day (0.25 g twice a day). After 2 weeks, the dose may be increased to 1 g/day (0.5 g twice a day). Then the dosage may be increased by 0.25 g twice a day with 2-week intervals, taking into account the clinical picture. No more than 3 g of the drug may be taken per day (1.5 g twice a day).

Adjuvant treatment.

As an adjuvant treatment for children aged 6 years and over and people weighing less than 50 kg, the drug should be prescribed starting with a dose of 10 mg/kg twice a day. Taking into account the drug effect and tolerability, the dose may be increased to 30 mg/kg with two doses per day. It is prohibited to increase or decrease the dosage by more than 10 mg/kg twice a day for a period of less than 14 days.

It is recommended to use the drug in the minimum effective dosages. The doctor should select the optimal form of the drug, the method of its administration and the number of uses, taking into account the patient's weight and portion size.

For adolescents over 12 years of age (weighting over 50 kg) and adults, therapy begins with 1 g of the drug per day (0.5 g twice a day). Taking into account the effectiveness and tolerability of the drug, the daily dose can be increased to a maximum of 3 g/day (1.5 g twice a day). Adjusting the portion size by 0.5 g twice a day is allowed at intervals of 0.5-1 month.

Since Levicitam is excreted from the body via the kidneys, when prescribing it to people with renal insufficiency and elderly patients, it is necessary to change the dosage size taking into account the CC indicators.

Given serum creatinine levels, the optimal CK level for men is calculated as follows: CK levels (ml/minute) = [140 minus the person's age (in years)], multiplied by their weight (kg), and then divided by the number obtained here: [72 multiplied by the serum CK level (mg/dL)].

The level of CC in women is calculated by multiplying the obtained figure by a coefficient of 0.85.

Next, the CC indicator is adjusted in accordance with the body surface area (BSA value). This should be done according to the following scheme: CC level (ml/minute/1.73 m2 ⁾ = CC indicator (ml/minute)/patient's BSA (m2 ⁾ (x1.73).

Dosage regimen for people with renal insufficiency and for children weighing over 50 kg:

• normal renal function: if the CC level is >80 (ml/minute/1.73 m2 ⁾ – take 0.5-1.5 g of the medicine twice a day;
• mild stage of the disorder: with a CC indicator within 50-79 ml/minute/1.73 m2 ^– take 0.5-1 g of the drug twice a day;
• moderate stage of the disorder: with CC values within the range of 30-49 ml/minute/1.73 m2 ^– taking 0.25-0.75 g of the drug twice a day;
• severe stage of the disorder: with a CC value of <30 ml/minute/1.73 m2 ^– take 0.25-0.5 g of the drug twice a day;
• persons undergoing dialysis (terminal phase) – on the first day, a saturating dose of 0.75 g should be taken, and then the drug should be taken once a day at a dosage of 0.5-1 g (after the dialysis procedure, an additional dose of 0.25-0.5 g should be taken).

When calculating the pediatric dosage, the CC values are taken into account, calculated using the Schwartz formula: CC indicator (ml/minute/1.73 m2 ⁾ = height (in centimeters) multiplied by ks/serum CC level (mg/dl).

For children under 13 years of age, as well as teenage girls, the level ks=0.55; and for teenage boys – ks=0.7.

Dosage adjustment schemes for children weighing less than 50 kg and with renal dysfunction:

• normal renal function: with a CC level of >80 ml/minute/1.73 m2 ^– taking the drug in a dose of 10-30 mg/kg twice a day;
• mild form of the disorder: with a CC indicator within 50-79 ml/minute/1.73 m2 ^– use 10-20 mg/kg of the drug twice a day;
• moderate stage of the disorder: with a CC level within 30-49 ml/minute/1.73 m2 ^– take 5-15 mg/kg of the drug twice a day;
• severe form of the disorder: with CC values <30 ml/minute/1.73 m2 ^– take 5-10 mg/kg of the medication twice a day;
• Persons undergoing dialysis (terminal phase) – take 10-20 mg/kg of the drug once a day. In this case, on the first day of therapy, a saturating dose of 15 mg/kg of the drug should be taken, and after the dialysis procedure, an additional 5-10 mg/kg of the substance should be taken.

In people with severe forms of liver dysfunction, the level of CC may not adequately reflect the degree of renal failure. Because of this, people with a CC value of <60 ml/min/1.73 ^m2 need to reduce the daily maintenance portion by 50%.

In elderly patients with renal insufficiency, the dosage should be adjusted taking into account the CC indicators.

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Use Levicitam during pregnancy

Animal data indicate that levetiracetam has reproductive toxicity. An analysis of data from approximately 1,000 pregnant women who used the drug as monotherapy in the first trimester did not confirm a significant increase in the risk of severe malformations, but it cannot be completely ruled out.

The use of several anticonvulsants simultaneously increases the risk of fetal malformations (compared to monotherapy).

It is prohibited to prescribe Levicitam to pregnant women, except in cases where it is necessary to use it for strict indications, because it must be taken into account that intervals in anticonvulsant treatment can worsen the patient's condition, which will harm both her and the fetus.

Levetiracetam should not be prescribed to women of reproductive age who are not using contraception. As with other anticonvulsants, physiological changes that occur during pregnancy may alter the drug's parameters. The most noticeable decrease in the drug's parameters may be observed in the 3rd trimester (approximately up to 60% of the pre-pregnancy level).

The drug is excreted in breast milk, which is why it is prohibited to prescribe it to nursing women. If its use is necessary, it is necessary to evaluate the risks and benefits of such therapy, as well as the importance of breastfeeding for the baby.

Contraindications

Contraindicated for use in the presence of intolerance to levetiracetam or other derivatives of pyrrolidone, as well as other medicinal elements.

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Side effects Levicitam

Taking the medication may cause the following side effects:

• CNS dysfunction: headaches and drowsiness often develop. Convulsions, dizziness, tremors, lethargy and balance disorders are quite common. Attention deficit, memory loss, confusion, amnesia, paresthesia and coordination problems/ataxia sometimes occur. Dyskinesia or hyperkinesia, as well as choreoathetosis, occasionally occur;
• Mental disorders: often there is a feeling of aggression, irritability, hostility or anxiety, as well as insomnia and depression. Sometimes there are psychotic disorders, feelings of anger or excitement, hallucinations, panic attacks, mood swings, abnormal behavior, emotional lability, as well as suicidal thoughts and attempts. Rarely, a personality disorder develops, abnormal thoughts appear, and suicide occurs;
• problems with digestive activity: diarrhea, abdominal pain, vomiting, dyspeptic symptoms and nausea often occur. Pancreatitis appears occasionally;
• Liver and biliary tract damage: hepatitis or liver failure occasionally develop. The drug also affects liver function tests;
• metabolic disorders: anorexia is often observed (the probability of development increases when combining drugs with topiramate). Sometimes weight increases or decreases. Hyponatremia occasionally develops;
• disorders of auditory function and vestibular apparatus: vertigo often occurs;
• problems with the visual organs: sometimes there is a loss of visual clarity or diplopia appears;
• dysfunction of connective tissues and skeletal muscles: sometimes muscle weakness or myalgia appears;
• Infections, wounds and complications: accidental injuries sometimes occur;
• infectious or invasive lesions: nasopharyngitis often develops. Occasionally, diseases caused by infections appear;
• respiratory disorders: cough is often observed;
• immune disorders: symptoms of allergy to levetiracetam or additional components of the drug may occur. Rarely, a reaction to the drug with eosinophilia and drug hypersensitivity syndrome (DRESS syndrome) develops;
• problems with the skin and subcutaneous layers: rashes often appear. Sometimes alopecia develops (in some cases, this problem went away after stopping the medication), eczema or itching. Rarely, erythema multiforme, TEN or Stevens-Johnson syndrome are noted;
• reactions from the hematopoietic system: sometimes leukopenia or thrombocytopenia develops. Rarely, agranulocytosis, neutro- or pancytopenia appear (sometimes with suppression of bone marrow function);
• systemic disorders: often there is a feeling of severe fatigue or asthenia.

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Overdose

Signs of intoxication include a feeling of agitation, confusion, aggression or drowsiness, as well as a comatose state and suppression of respiratory function.

To eliminate acute poisoning, vomiting should be induced or gastric lavage should be performed. The drug has no antidote. If necessary, symptomatic measures can be taken in a hospital, including hemodialysis (in this case, up to 60% of the active element of the drug and 74% of its primary decay product are excreted).

Interactions with other drugs

The drug does not interact with other anticonvulsants (such as carbamazepine, phenytoin, phenobarbital with valproic acid, as well as primidone and gabapentin with lamotrigine).

It is possible that the clearance rate of the drug in children taking anticonvulsants containing enzymes is 22% higher, but there is no need to adjust the dosage.

Levetiracetam in a daily dose of 1 g does not change the pharmacokinetic properties of oral contraception (ethinyl estradiol with levonorgestrel); endocrine values (progesterone levels with luteinizing hormone) do not change either.

A daily dose of 2 g of levetiracetam does not affect the pharmacokinetic parameters of warfarin with digoxin. The PT parameters also remain at the same level. Warfarin with digoxin and oral contraception also do not affect the pharmacokinetic profile of levetiracetam.

There is information that probenecid (four times a day in a 0.5 g portion), by blocking tubular secretion inside the kidneys, inhibits the clearance of the main breakdown product of Levitan occurring in them (but the clearance of its active element does not change). But the indicators of this metabolic product remain low. There is an opinion that other drugs excreted with the help of active tubular secretion can also reduce the clearance of the metabolic product inside the kidneys.

The effect of the drug on probenecid has not been studied, and the effect it has on other drugs with active secretion (such as sulfonamides and NSAIDs with methotrexate) is unknown.

There is no information on the effect of antacids on the absorption of Levitate. The degree of its absorption is not affected by food intake, although the rate of this process is reduced.

There is no information regarding the interaction of the drug with alcoholic beverages.

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Storage conditions

Levitsitam should be kept out of reach of children. Temperature indicators – maximum 25°C.

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Shelf life

Levicitam can be used for 3 years from the date of release of the drug.

Application for children

Tablets are prohibited to be prescribed to children under 6 years of age. This category of patients, as well as those whose weight does not reach 25 kg, must take Levitsitam in the form of a solution for oral administration (dose 100 mg / ml).

The efficacy and safety of prescribing drugs to people under 16 years of age have not been studied.

Analogues

The following drugs are analogs of the drug: Levetiracetam-Teva and Levetiracetam Lupin, as well as Normeg, Keppra and Tiramax.