Leviticam

Levitsitam is an anticonvulsant.

[1]

Indications of the leviticam

It is used to eliminate such disorders (as monotherapy): attacks having a partial character and a secondary form of generalization (or without it) in adolescents aged 16 and adults who were first diagnosed with epilepsy.

They are also used in the combined treatment of the following disorders:

• partial seizures that have a secondary form of generalization (or not) in children older than 6 years and adults with epilepsy;
• seizures of myoclonic nature in adolescents over 12 years of age and adults suffering from Yants syndrome;
• generalized attacks of seizures (tonic-clonic type) of a primary nature in adolescents from 12 years of age and adults suffering from IGE.

Release form

The release is carried out in tablets with a volume of 0.25 and 0.5 g. Inside the blister pack - 10 tablets. In the box - 3 or 6 of these packages.

Pharmacodynamics

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

In vitro tests revealed that Levitsitam affects the internal neural parameters of Ca2 + by partially suppressing the current through Ca2 + (N-type) channels, as well as reducing the volume of Ca2 + release from intra-neuronal depots. At the same time, it partially neutralizes the suppression of GABA-, as well as the glycine-regulated current, provoked by the effect of β-carbolines and zinc. In addition, in in vitro tests, the preparation was synthesized with specific areas inside the brain tissue of rodents. The synthesis site is a protein with a synaptic character of vesicle 2A, which participates in the combination of vesicles and the processes of release of neurotransmitters.

The affinity of the preparation and its analogs relative to the protein of the vesicles 2A (synaptic character) correlates with the strength of their anticonvulsant influence within the models of epilepsy of audiogenic character in mice. These data suggest that the interaction between the drug and the synaptic vesicular (2A) protein may explain the anticonvulsant drug exposure to some extent.

Element levetiracetam creates in animals conditions for protection from seizures within a wide range of models of seizures that have a partial, as well as primarily generalized character, without provoking the development of an anticonvulsive effect. The main product of metabolism has no drug activity.

The effect of the medication has been confirmed with regard to generalized and focal seizures of epilepsy (epileptiform signs or photoparoxysmal phenomena).

[2], [3], [4], [5], [6],

Pharmacokinetics

Absorption.

After ingestion, the substance is rapidly absorbed from the digestive tract. In this case, the size of the portion of the drug and the time of eating do not affect the degree of absorption. The bioavailability level is approximately 100%. Peak plasma parameters are noted after 1.3 hours after ingestion of the 1st dose of the drug. With a one-time admission, this is 31 μg / ml, and twice a day, 43 μg / ml. Equilibrium values of the drug reaches after 2 days with a two-time application of Leviticam.

Distribution processes.

There is no information on the distribution of the drug within the tissues of the human body. Synthesis of the active substance and its main product of metabolism 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 inside the body.

Metabolic processes.

Levetiracetam is subjected to only a minor metabolism within the human body. Its main route (24% of the intake) is the enzymatic hydrolysis of elements from the acetamide group. Formation of the main product of a metabolism that does not have a drug activity (ucb L057) is performed without the involvement of hepatic hemoprotein P450. The process of hydrolysis of elements of the acetamide group occurs inside a large number of cells, among which are blood cells.

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

Other undefined items constitute only 0.6% of the portion.

Excretion.

The half-life of the substance from the blood plasma in an adult is approximately 7 ± 1 hour (this value does not depend on the size of the dose and the method of application). The average total clearance is approximately 0.96 ml / minute / kg.

95% of the drugs are excreted through the kidneys (about 93% of the portion is excreted in the 48-hour period). Feces excreted only 0.3% of the portion. Cumulative excretion of the substance and its main 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 equal to 0.6 and 4.2 ml / minute / kg, respectively. This shows that the substance is excreted by glomerular filtration with subsequent reabsorption of the tubules, and the main decay product, in addition to glomerular filtration, is excreted by the active secretion of the tubules. Excretion of levetiracetam correlates with QC values.

Elderly patients.

In elderly people the half-life of medicines is prolonged by 40%, amounting to approximately 10-11 hours - this is associated with a decrease in renal function in this group of patients.

In disorders of renal activity.

The apparent level of the overall clearance of the active element of the drug and its basic metabolic product correlates with the QC values. Because of this, people with disorders in the work of the kidneys in a severe or moderate degree need to adjust the size of the maintenance dose of drugs, taking into account the level of QC.

In persons with anuria on the background of the terminal phase of kidney disease, the half-life of drugs is approximately 25 and 3.1 hours, respectively, between the dialysis procedures and during its implementation. During the 4-hour dialysis procedure, up to 51% of the medication is withdrawn.

With problems in the liver.

In people with disorders of hepatic function in mild or moderate form there are no significant changes in the drug clearance rates. In patients with pathology in severe degree, the level of clearance of the drug decreases by more than 50% (mainly due to a decrease in the parameters of renal clearance).

Children from the age group 4-12 years.

When a child receives epilepsy with a single dose of LS (20 mg / kg), the half-life of the active substance will be 6 hours. The level of apparent clearance is 1.43 ml / minute / kg.

With repeated ingestion (20-60 mg / kg / day), absorption of levetiracetam occurs rapidly. Pharmacokinetic values of drugs in children are linear. In the interval of portions of 20-60 mg / kg / day, the drug reaches its peak after 30-60 minutes. The half-life is approximately 5 hours. The apparent total clearance is approximately 1.1 ml / minute / kg.

Dosing and administration

The medicine is taken orally, washed down with water, without binding to the reception of food. The daily portion should be divided into 2 equal receptions.

Monotherapy begins with a dose of 0.5 g / day (twice daily for 0.25 g). After 2 weeks, the portion is allowed to be raised to 1 g / day (twice daily for 0.5 g). Further, the dosage of the drug is allowed to be increased by 0.25 g twice a day with interruptions of 2 weeks, taking into account the clinical picture. For a day, you can take no more than 3 grams of medicine (twice a day for 1.5 grams).

Ancillary treatment.

As an auxiliary treatment for children from 6 years and people weighing less than 50 kg, it is necessary to prescribe the drug, starting with a dose of 10 mg / kg twice a day. Taking into account the medicinal effect and tolerability, the dose is allowed to be increased to 30 mg / kg with a two-time intake per day. It is forbidden to increase or decrease the dosage by more than 10 mg / kg twice a day for less than 14 days.

It is recommended to use the drug in minimally effective dosages. The doctor must choose the most appropriate form of drugs, the method of taking it and the number of uses, taking into account the weight of the patient and the size of the portion.

For adolescents over 12 years old (weighing more than 50 kg) and adults, therapy is started with 1 g of drugs per day (0.5 g twice a day). Taking into account the effectiveness and tolerability of the medicament, the daily dose may be increased to a maximum of 3 g / day (1.5 g twice a day). Correct the portion size by 0.5 g twice a day is allowed at intervals of 0.5-1 month.

In connection with the fact that Levitsitam excreted from the body with the help of kidneys, when it is prescribed to people with kidney failure and elderly patients, it is necessary to change the dosage size taking into account the QC parameters.

Considering the serum creatinine values, the optimal level of QC for men is calculated according to the following scheme: KK values (ml / minute) = [from 140 to take the figure of the person's age (in years)], multiplied by its weight (kg), and then divided by the number, the result obtained here: [72 multiplied by serum CC (mg / dL)].

The level of QC in women is calculated by multiplying the result by a factor of 0.85.

Further, the correction of the QC value is carried out in accordance with the body surface area (PPT value). This needs to be done according to the following scheme: CC level (ml / minute / 1.73 m ² ) = KK index (ml / minute) / patient's PPT (m ² ) (x 1.73).

Dosing scheme for people with kidney failure and for children weighing more than 50 kg:

• normal renal activity: at a level of CC> 80 (ml / minute / 1.73 m ² ) - take 0.5-1.5 g of medicine twice a day;
• an easy stage of the disorder: at a QC value within the range of 50-79 ml / min / 1.73 m ² - use 0.5-1 g of the drug twice a day;
• Moderate stage of the disorder: at CC values within the range of 30-49 ml / min / 1.73 m ² - intake of 0.25-0.75 g of medicinal products twice per day;
• severe stage of impairment: with a QC value of <30 ml / minute / 1.73 m ² - twice daily for 0.25-0.5 g of the drug;
• persons who are on dialysis (terminal phase) - on the first day should take a saturating dose of 0.75 grams, and then use drugs once a day at a dosage of 0.5-1 g (with the dialysis procedure you should use an additional dose, which is 0.25-0.5 g).

In calculating the dosage consider child CC value is calculated by Schwartz formula: QC index (ml / min / 1.73 m ² ) = height (in inches), multiplied by ks / QC serum (mg / dl).

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

Dosage correction regimens for children weighing less than 50 kg and with disorders of renal activity:

• normal kidney function: at a level of CC> 80 ml / minute / 1.73 m ² - taking drugs in a dose of 10-30 mg / kg twice a day;
• a slight form of the disorder: with a KK value within the range of 50-79 ml / min / 1.73 m ² - twice daily apply 10-20 mg / kg of the drug;
• moderate stage of impairment: at a QC level within 30-49 ml / minute / 1.73 m ² - twice a day to use 5-15 mg / kg of the drug;
• severe form of the disorder: at CC values <30 ml / minute / 1.73 m ² - twice daily for 5-10 mg / kg of medication;
• persons who are on dialysis (terminal phase) - use once a day for 10-20 mg / kg of LS. Thus, on the first day of therapy, a saturable dose of 15 mg / kg should be taken, and an additional 5-10 mg / kg of substance should be used after dialysis.

In people with severe forms of disorders of hepatic activity, the level of QC may not adequately reflect the degree of kidney failure. Because of this, people with a QC value of <60 ml / minute / 1.7Zm ² need to reduce the daily maintenance dose by 50%.

Elderly people with kidney deficiency should adjust the dosage size, taking into account the QC values.

[11]

Use of the leviticam during pregnancy

Data from animal tests show that levetiracetam has reproductive toxicity. An analysis of information on approximately 1,000 pregnant women who used the drug in the form of monotherapy in the first trimester did not confirm a significant increase in the risk of severe developmental anomalies, but it is still impossible to completely exclude it.

The use of several anticonvulsants simultaneously increases the risk of the appearance of malformations in the development of the fetus (in comparison with the monotherapy).

It is forbidden to prescribe Leviticam to pregnant women, except for cases when it is necessary to use it under strict indications, because it is necessary to take into account that the intervals in anticonvulsant treatment can worsen the patient's condition, which will harm both her and the fetus.

It is forbidden to prescribe levetiracetam for women who are in reproductive age and who do not use contraception. As in the case of taking other anticonvulsants, the physiological changes occurring during pregnancy can change the indices of the medicine. The most noticeable decrease in medication values can be observed in the 3rd trimester (up to about 60% of the level observed before pregnancy).

The drug is excreted with the mother's milk, because of what it is forbidden to prescribe to nursing women. If its use is necessary, you need to evaluate the risk and benefit of such therapy, and in addition the importance of breastfeeding for the baby.

Contraindications

Contraindicated use in the presence of intolerance with levetiracetam or other derivatives of pyrrolidone, and in addition other medicinal elements.

[7], [8], [9]

Side effects of the leviticam

Taking a medication can trigger the appearance of such side effects:

• disorders of the central nervous system: often develop headaches and a feeling of drowsiness. Cramps, dizziness, tremors, lethargy and balance disorders are often noted. Sometimes there is a disturbance of attention, a weakening of memory, a sense of confusion, amnesia, paresthesia and problems with coordination / ataxia. Occasionally there is dyskinesia or hyperkinesia, as well as choreoathetosis;
• mental disorders: often there is a feeling of aggressiveness, irritability, hostility or anxiety, and besides insomnia and depression. Sometimes there are psychotic disorders, feelings of anger or excitement, hallucinations, panic attacks, mood changes, abnormal behavior, emotional lability, and thoughts about suicide and attempts to commit it. Occasionally, personality disorder develops, abnormal thoughts appear, and suicide also occurs;
• problems with digestive activity: often there is diarrhea, pain in the abdomen, vomiting, dyspeptic symptoms and nausea. Single pancreatitis appears;
• lesions of the liver and ZHVP: occasionally develop hepatitis or liver failure. Also, the medicine affects the indications of liver tests;
• disturbances of metabolic processes: anorexia is often noted (the likelihood of development increases with combination of drugs with topiramate). Sometimes the weight rises or decreases. Occasionally, hyponatremia develops;
• disorders of auditory function and vestibular apparatus: vertex often occurs;
• problems with visual organs: sometimes loss of visual clarity occurs or diplopia appears;
• disruption of the function of connective tissue and skeletal muscle: sometimes there is weakness in the muscles or myalgia;
• infection, wound lesions and complications: sometimes there are accidental injuries;
• infectious or invasive lesions: often develops nasopharyngitis. Occasionally there are diseases caused by infections;
• disorders of respiratory function: cough is often noted;
• Immune disorders: symptoms of allergy to levetiracetam or additional elements from the composition of the medication may occur. Occasionally, the reaction to a drug with eosinophilia, as well as a syndrome of hypersensitivity to the drug (DRESS-syndrome) develops;
• problems with the skin and subcutaneous layers: often there are rashes. Sometimes it develops alopecia (in some cases, this problem was after the withdrawal of the medicine), eczema or itching. Occasionally, erythema multiforme, TEN or Stevens-Johnson syndrome are noted;
• reactions from the hematopoietic system: sometimes leukemia or thrombocytopenia develops. Occasionally there is agranulocytosis, neutropenic or pancytopenia (sometimes with suppression of the bone marrow);
• systemic disorders: often there is a feeling of severe fatigue or asthenia.

[10]

Overdose

Among the signs of intoxication: a feeling of excitement, confusion, aggression or drowsiness, and in addition a coma and suppression of respiratory function.

To eliminate acute poisoning, induce vomiting or make a gastric lavage. The drug has no antidote. If required, symptomatic interventions at the inpatient clinic, incl. With the use of hemodialysis (excreted up to 60% of the active element of drugs and 74% of its primary degradation product).

Interactions with other drugs

The drug has no interaction with other anticonvulsants (such as carbamazepine, phenytoin, phenobarbital with valproic acid, and in addition primidone and gabapentin with lamotrigine).

It is assumed that the level of clearance of the drug in children using anticonvulsants containing enzymes is higher by 22%, but dosage adjustment is not necessary.

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

The daily portion of levetiracetam, amounting to 2 g, does not affect the pharmacokinetic parameters of warfarin with digoxin. At the same level, the PTV indicators remain. 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 dose of 0.5 g), blocking the tubular secretion inside the kidneys, depresses the clearance occurring in them of the main product of the decay of Leviticam (and here the clearance of its active element does not change). But the indices of this metabolic product remain low. There is an opinion that other drugs excreted by active secretion of tubules can also lower 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 active-secretion drugs (such as sulfonamides and NSAIDs with methotrexate) is not known.

There is no information on the effect of antacids on the absorption of Leviticam. The degree of its absorption does not change under the influence of the food consumed, although the speed of this process decreases.

There is no information about the interaction of drugs with alcohol.

[12], [13]

Storage conditions

Leviticam should be kept out of the reach of children. Temperatures are a maximum of 25 ° C.

[14]

Shelf life

Levitsitam can be used for 3 years since the release of the drug.

Application for children

Tablets are prohibited for children under 6 years of age. This category of patients, as well as those whose weight does not reach 25 kg, it is necessary to take Levitsi in the form of a solution for ingestion (dose 100 mg / ml).

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

Analogues

Analogues of the drug are such drugs: Levetiracetam-Teva and Levetiracetam Lupine, and also Normeg, Keppra and Thiramax.