Keppra - instructions for use, doses, side effects, contraindications

Excipients: sodium citrate 1.05 mg, citric acid monohydrate 0.06 mg, methyl parahydroxybenzoate 2.70 mg, propyl parahydroxybenzoate 0.30 mg, ammonium glycyrrhizate 1.50 mg, glycerol 85% 235.50 mg, maltitol 300.00 mg, acesulfame potassium 4.50 mg, grape flavor 501040A 0.30 mg, water purified 504.00 mg.

Description:

Solution: transparent, almost colorless solution with a characteristic odor.

Pharmacotherapeutic group:antiepileptic agent

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:

Pharmacodynamics

Levetiracetam, the active substance of the Keppra® preparation, is a derivative of pyrrolidoy (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide) differs in chemical structure from known antiepileptic drugs.

Mechanism of action

The mechanism of action of levetiracetam is not fully understood, but it is clear that it differs from the mechanism of action of known antiepileptic drugs. Experiments in vitro and in vivo showed that levetiracetam does not affect the basic characteristics of cells and normal transmission.

Research in vitro showed that levetiracetam affects the intra-neuronal concentration of Ca²⁺, partially inhibiting the current of Ca²⁺ through the channels Ntype and reducing the release of calcium from intra-neural depots. Besides, levetiracetam partially restores currents through GABA- and glycine-dependent channels, reduced by zinc and β-carbolines.

One of the proposed mechanisms is based on proven binding to the glycoprotein of synaptic vesicles SV2A, contained in the gray matter of the brain and spinal cord. It is believed that the anticonvulsant effect is realized in this way, which is expressed in counteracting the hypersynchronization of neuronal activity.

Also levetiracetam affects the receptors of GABA and glycine receptors, modulating these receptors through various endogenous agents. Does not change the normal neurotransmission, but suppresses epileptiform neural flares induced by GABA agonist bicuculine, and the excitation of glutamate receptors.

Pharmacodynamic effects

The activity of the drug has been confirmed with respect to both focal and generalized epileptic seizures (epileptiform manifestations / photoperiodic reaction). Levetiracetam induces protection against seizures in a variety of animal models.

Additional therapy for partial seizures with or without secondary generalization the of adults, adolescents and children from 1 month with epilepsy:

In adults, the efficacy of levetiracetam has been shown in 3 double-blind, placebo-controlled studies. It was shown that the proportion of patients who showed a 50% or more reduction in the frequency of partial seizures per week relative to the baseline with a constant intake of levetiracetam at doses of 1000 mg, 2000 mg or 3000 mg in two divided doses for 12-14 weeks was 27.7% , 31.6% and 41.3%, respectively, and 12.6% in patients taking placebo.

Pediatric population

The efficacy of levetiracetam in patients aged 4 to 16 years was established in a double-blind, placebo-controlled study of 14 weeks, involving 198 patients. The dose of levetiracetam was 60 mg / kg / day in two divided doses.

44.6% of patients taking levetiracetam and 19.6% of patients taking placebo showed a 50% or more reduction in the frequency of partial seizures per week relative to baseline.

During the treatment period, 11.4% of patients had no seizures during 6 months, at least, and 7.2% - for one year, at least.

The efficacy of levetiracetam in patients between the ages of one month and 4 years was established in a double-blind, placebo-controlled study of 116 patients with a treatment duration of 5 days. The dose of levetiracetam in the form of oral solution for infants from one to 6 months was 20 mg / kg / day in two doses followed by titration up to 40 mg / kg / day, for infants and children from 6 months to 4 years - 25 mg / kg / day in two doses followed by titration up to 50 mg / kg / day.

At the initial efficacy evaluation, the response rate (the percentage of patients with a decrease in the frequency of partial seizures per day relative to the baseline level by 50% or more) was determined using an anonymous reader when conducting a 48-hour video electroencephalography. The efficacy score is based on an analysis of 109 patients who received electroencephalography within 24 hours, at least. Respondents were 43.6% of patients who took levetiracetam and 19.6% of patients taking placebo. During long-term treatment 8,6% of patients had no seizures during 6 months, at least, and 7.8% for 1 year, at least.

Monotherapy of partial seizures with or without secondary generalization in patients with 16 years of age with newly diagnosed epilepsy

The efficacy of levetiracetam as monotherapy was comparable to that of carbamazepine with controlled release in a parallel group in a double-blind study in 576 patients at age 16 with a newly diagnosed epilepsy with unprovoked partial seizures or generalized tonic-clonic seizures. Patients were randomly selected for treatment with a controlled release of carbamazepine 400-200 mg / day or levetiracetam at a dose of 1000-3000 mg / day. The duration of treatment was up to 121 weeks depending on the answer.

No seizures during 6 months was noted in 73% of patients receiving levetiracetam and 72.8% of patients receiving carbamazepine with controlled release.The agreed absolute difference between treatment rates was 0.2% (95% confidence interval-7.8 8.2). More than half of the patients had no seizures within 12 months (56.6% of patients on levetiracetam and 58.5% of the carbamazepine with controlled release, respectively).

In a clinical trial, concomitant antiepileptic drugs could be withdrawn for a limited number of patients who responded to additional therapy with levetiracetam (36 adult patients out of 69).

Additional therapy of myoclonic seizures in adults and adolescents with age 12 with juvenile myoclonic epilepsy

The efficacy of levetiracetam has been established in a double-blind, placebo-controlled study of 16 weeks for patients with 12 years with idiopathic generalized epilepsy with various myoclonic seizure syndromes. Most patients had juvenile myoclomical epilepsy. The dose of levetiracetam was 3000 mg / day in two divided doses. 58.3% of patients receiving levetiracetam, and 23.3% of patients taking placebo had at least a 50% reduction in myoclonic seizures per week.During continuous long-term treatment, 28.6% of patients did not have myoclonic seizures during 6 months, at least 21% of patients for one year, at least.

Supplementary therapy for primary generalized convulsive (tonic-clonic) seizures in adults and adolescents with age 12 with idiopathic generalized epilepsy

The efficacy of levetiratsitam was established during a 24-year, double-blind, placebo-controlled study that included adults, adolescents, and a limited number of children with idiopathic generalized epilepsy with primary generalized tonic clonic seizures, with various syndromes (juvenile myoclonic epilepsy, juvenile absence epilepsy, child absences-epilepsy or epilepsy with generalized tonic-clonic seizures upon awakening).

In this study, the daily dose of levetiracetam was 3000 mg / day for adults and adolescents or 60 mg / kg / day for children in two divided doses. 72.2% of patients receiving levetiracetam, and 45.2% of patients taking placebo showed a 50% or more reduction in seizure frequency during the week in patients with primary generalized tonic-clonic seizures.

During continuous long-term treatment, 47.4% of patients did not have tonic-clonic seizures during 6 months, at least, and 31.5% of patients did not have tonic-clonic seizures for one year, at least.

Pharmacokinetics:

Levetiracetam has a high solubility and permeability. The pharmacokinetic profile is linear with low variability and is comparable in healthy volunteers and patients with epilepsy. After repeated introduction, the change in clearance was not observed.

There was no dependence of pharmacokinetics on sex, race and time of day. Absorption occurs completely and is linear in nature, as a result of which the plasma concentration can be predicted based on the dose of levetiracetam, expressed in mg / kg of body weight.

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

Suction

After oral administration levetiracetam well absorbed from the gastrointestinal tract. The degree of absorption does not depend on the dose and time of food intake.Bioavailability is approximately 100%. The maximum concentration in plasma (C_mOh) is achieved after 1.3 hours after oral administration of levetiracetam in a dose 1000 mg and at a single admission is 31 μg / ml, after repeated administration (2 times a day) - 43 μg / ml.

Distribution

The binding of levetiracetam and its main metabolite plasma protein is less than 10%. Volume of distribution (V_d) is about 0.5-0.7 l / kg.

Metabolism

Levetiracetam inactive metabolizes in the human body. The main pathway of metabolism (24% of the dose) occurs by enzymatic hydrolysis of the acetamide group. Formation of a primary pharmacologically inactive metabolite (ucb L057) occurs without the involvement of cytochrome P₄₅₀ liver. Hydrolysis of the acetamide group was minimal for a large number of tissues, including blood cells.

Two secondary metabolites were also identified. The first was obtained by hydroxylation of the pyrrolidone cycle (1.6% of the dose) and the second by the opening of the pyrrolidone cycle (0.9% of the dose). Other components found are 0.6% of the dose.

Levetiracetam does not affect the enzymatic activity of hepatocytes. In conditions in vitro levetiracetam and its main metabolite did not inhibit the main isoenzymes of cytochrome P₄₅₀ (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), as well as the activity of glucuronyl transferase (UGT1A1 and UGT1A6) and epoxy hydroxylase. Levetiracetam It also did not affect the glucuronation of valproic acid in vitro.

In the culture of human hepatocytes levetiracetam has no effect or very little effect on the enzymatic activity of hepatocytes CYP1A2, SULT1E1 and UGT1A1. Levetiracetam causes a slight induction CYP2B6 and CYP3A4.

Excretion

Most of the drug (95%) is excreted by the kidneys (about 93% is excreted within 48 hours). The total excretion of levetiracetam and its main metabolite accounted for 66% and 24% of the dose, respectively. The renal clearance of levetiracetam and ucb L057 was 0.6 and 4.2 mL / min / kg, respectively. This indicates that levetiracetam is excreted by glomerular filtration followed by tubular reabsorption, and that the primary metabolite of the drug is excreted by active tubular secretion in addition to glomerular filtration. The removal of levetiracetam correlates with the clearance of creatinine.

Excretion with faeces is 0.3% of the dose.

The average overall clearance is 0.96 ml / min / kg.

The half-life (T_1/2) from the blood plasma of an adult is 7 ± 1 h and does not depend on the mode of administration and the dosing regimen or repeated administration.

Have elderly patients T_1/2increases by 40% and is 10-11 hours, which is associated with impaired renal function in this category of people.

Have patients with impaired renal function the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, patients with renal insufficiency are recommended to select a dose depending on the creatinine clearance and the degree of renal failure. In the terminal stage of renal failure in adult patients, T_1/2is 25 hours between dialysis sessions and 3.1 hours during dialysis. During a 4-hour dialysis session, up to 51% of levetiracetam is removed.

Have patients with impaired liver function light and moderate degrees of significant changes in the clearance of levetiracetam do not occur. In most patients with severe impairment of liver function with concomitant renal failure, the clearance of levetiracetam declines by more than 50%.

Children from 4 to 12 years old

T_1/2 in children aged 4-12 years after a single oral administration of the drug at a dose of 20 mg / kg body weight is 6 hours.The total clearance of levetiracetam in children 4-12 years old is approximately 30% higher than in adults and is directly related to body weight.

After repeated oral administration at a dose of 20-60 mg / kg of body weight to children of 4-12 years of age, the maximum plasma concentration is achieved after 0.5-1.0 hours and increases linearly and proportionally to the dose. The average overall clearance is 1.1 ml / min / kg.

Children from 1 month to 4 years

T_1/2 in children aged 1 month to 4 years after a single oral administration of 20 mg / kg body weight of the oral solution at a concentration of 100 mg / ml is 5.3 hours. The maximum plasma concentration is achieved approximately 1 hour after taking the drug. The average total clearance is 1.5 ml / min / kg.

The pharmacokinetic analysis of the population was conducted on patients aged 1 month to 16 years. The clearance and the observed volume of distribution had a significant dependence on the body weight (the clearance increased in direct proportion to the increase in body weight). Age also influenced both parameters. This effect was more pronounced for patients of early age and decreased with increasing age, becoming insignificant by 4 years.

Indications:

As a monotherapy in the treatment of:

partial seizures with secondary generalization or without it in adults and adolescents with 16 years of age with newly diagnosed epilepsy.

In the complementary therapy in the treatment:

partial seizures with secondary generalization or without it in adults and children from 1 month with epilepsy;
myoclonic seizures in adults and adolescents with 12 years of age with juvenile myoclonic epilepsy;
primary-generalized convulsive tonic-clonic seizures in adults and adolescents from the age of 12 with idiopathic generalized epilepsy.

Contraindications:

- Hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as to any components of the drug;

- impaired tolerance to fructose;

- Children under 1 month of age (safety and efficacy not established).

Carefully:

- Patients of advanced age (over 65 years);

- liver disease in the stage of decompensation;

- renal insufficiency.

Pregnancy and lactation:

Pregnancy

In post-marketing data obtained from several prospective pregnancy registries, more than 1,000 cases of monotherapy with levetiracetam in the first trimester of pregnancy have been recorded.

In general, these data do not indicate a significant increase in the risk of serious congenital malformations, although teratogenic risk can not be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, which is why monotherapy in pregnant women is more appropriate.

Adequate and strictly controlled clinical trials on the safety of levetiracetam in pregnant women have not been conducted, so the drug should not be prescribed during pregnancy and in women with a preserved genital function, except in cases of clinical necessity.

Physiological changes in the body of a woman during pregnancy can affect the plasma concentration of levetiracetam as well as other antiepileptic drugs. During pregnancy, there was a decrease in the concentration of levetiracetam in plasma. This decrease is more pronounced in the third trimester (up to 60% of the baseline concentration during the third trimester). Treatment with levetiracetam pregnant women should be carried out under special supervision.Interruptions in antiepileptic therapy may lead to a worsening of the course of the disease, which can harm the health of both the mother and the fetus.

To monitor the effects of levetiracetam in pregnant women, doctors are recommended to register these patients in the European and International Registry for antiepileptic drugs (BURAP).

Breastfeeding period

Levetiracetam is excreted in breast milk, so breastfeeding during treatment with the drug is not recommended. However, if treatment with levetiracetam is necessary during the feeding period, the risk / benefit ratio of treatment should be carefully weighted relative to the importance of feeding.

Fertility

In studies on animals no effect on fertility was found. Clinical data on the effect on fertility are not available, the potential risk to humans is unknown.

Dosing and Administration:

Inside, regardless of food intake.

The daily dose of the drug is divided into two doses in the same dose.

Monotherapy

Adults and teenagers from 16 years of age treatment should begin with a daily dose of 500 mg divided into 2 divided doses (250 mg twice a day).After 2 weeks, the dose may be increased to the initial therapeutic dose of 1000 mg (500 mg twice a day). The maximum daily dose is 3000 mg (1500 mg twice a day).

In the complementary therapy

Adults from 18 years and adolescents (12 to 17 years) with a body weight of more than 50 kg treatment should begin with a daily dose of 1000 mg divided into 2 divided doses (500 mg twice a day). Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg (1500 mg twice a day). A dose change of 500 mg 2 times a day can be carried out every 2-4 weeks.

Children aged 6 months to 23 months, children aged 2 to 11 years and adolescents from 12 to 17 years of age with a body weight of less than 50 kg

Treatment should begin with a dose of 20 mg / kg body weight divided into 2 divided doses (10 mg / kg body weight 2 times a day). Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to 30 mg / kg 2 times a day. A dose change of 20 mg / kg (10 mg / kg body weight 2 times a day) of body weight can be done every 2 weeks. The minimum effective dose should be used.

Recommended dosages for children (from 6 months) and adolescents:

Body mass	Initial dose 10 mg / kg, 2 times a day	The maximum dose 30 mg / kg, 2 times a day
6 kg⁽¹⁾	60 mg (0.6 ml) twice daily	180 mg (1.8 ml) twice daily
10 kg⁽¹⁾	100 mg (1 ml) twice daily	300 mg (3 ml) 2 times daily
15 kg⁽¹⁾	150 mg (1.5 ml) twice daily	450 mg (4.5 ml) twice daily
20 kg⁽¹⁾	200 mg (2 ml) twice daily	600 mg (6 ml) twice daily
25 kg	250 mg twice daily	750 mg twice a day
From 50 kg⁽²⁾	500 mg twice a day	1500 mg twice a day

⁽¹⁾ Children with a body weight of 25 kg or less preferably begin treatment with a Keppra solution of 100 mg / ml orally.

⁽²⁾ Dosage for children and adolescents with a body weight of more than 50 kg is the same as in adults.

Children aged 1 month to 5 months

The initial treatment dose is 7 mg / kg twice a day.

Depending on the clinical efficacy and tolerability, the dose can be increased to 21 mg / kg twice a day. The dose change should not exceed plus or minus 7 mg / kg twice a day every two weeks. The minimum effective dose should be given.

Dosage recommendations for children aged up to 6 months:

Body mass	Initial dose: 7 mg / kg twice daily	Maximum dose: 21 mg / kg twice daily
4 kg	28 mg (0.3 ml) twice daily	84 mg (0.85 ml) twice daily
5 kg	35 mg (0.35 ml) twice daily	105 mg (1.05 ml) twice daily
7 kg	49 mg (0.5 ml) twice daily	147 mg (1.5 ml) twice daily

Dosage of the solution is carried out with the help of measuring syringes, included in the delivery of the drug.

There are syringes with a nominal capacity;

- 10 ml (corresponding to 1000 mg levetiracetam) and with a fission rate of 0.25 ml (corresponding to 25 mg) for children aged 4 years and older, adolescents and adults;

- 3 ml (corresponding to 300 mg) with a fission rate of 0.1 ml (corresponding to 10 mg) for children aged 6 months to 4 years;

- 1 ml (corresponds to 100 mg) and the cost of dividing 0.05 ml (corresponding to 5 mg) for children aged 1 month to 6 months.

A metered dose of the drug is diluted in a glass of water or a baby bottle.

Instructions by dosing the solution with a measuring syringe:

- Open the vial: to do this, click on the cap and turn it counter-clockwise (Figure 1).

- Insert the syringe adapter into the neck of the vial, make sure it is well fixed, then take the syringe and place it in the adapter (Figure 2).

- Turn the bottle upside down (Figure 3).

- Fill the syringe with a small amount of solution by pulling the piston down (Figure 4), then push the piston upward to remove air bubbles (Figure 5).

- Fill the syringe with a solution, pulling the piston to the division corresponding to the number of milliliters of the solution prescribed by the doctor's dose (Figure 6).

- Turn (with such a neck up and pull the syringe out of the adapter.

- The contents of the syringe enter into a glass with water or a baby bottle, pushing the piston against the stop (Figure 7).

- Drink completely the entire contents of the glass (or baby bottle).

- Rinse the syringe with water (Figure 8).

- Close the bottle with a plastic lid.

Patients with renal insufficiency

Because the levetiracetam is excreted from the body by the kidneys, when the drug is administered patients with renal insufficiency and elderly patients (65 years and older) The dose should be adjusted depending on the amount of creatinine clearance.

The creatinine clearance (CK) for men can be calculated based on the serum creatinine concentration, according to the following formula:

CK (ml / min) = [140 - age (years)] * body weight (kg) / 72 x KK_serum (mg / dL)

The creatinine clearance for women can be calculated by multiplying the obtained value by a factor of 0.85.

Then the QC is adjusted taking into account the body surface area (PPT) according to the following formula:

KK (ml / min / 1.73 m²) = KK (ml / min) x 1.73 / PP'G of the object (m²)

Renal insufficiency	QC (ml / min / 1.73 m²)	Dosing regimen
Norm	>80	from 500 to 1500 mg twice a day
Lightweight	50-79	from 500 to 1000 mg twice a day
Moderate	30-49	from 250 to 750 mg twice a day
Heavy	<30	from 250 to 500 mg twice a day
Terminal stage (patients on dialysis *)		from 500 to 1000 mg once a day **

* The first day of treatment is recommended to take a saturating dose of 750 mg.

** After dialysis, an additional 250-500 mg dose is recommended.

Children with renal insufficiency correction of the dose of levetiracetam should be made taking into account the degree of renal failure.

Creatinine clearance (ml / min / 1.73 m²) can be assessed based on serum creatinine (mg / dL) for adolescents, children and newborns using the following formula (Schwartz formula):

KK (ml / min / 1.73 m²) = Height (cm) x ks / QC _serum (mg / dL)

ks= 0.45 for children under 1 year; ks= 0.55 for children under 13 years of age and adolescent females, ks= 0.7 for adolescent males.

Dosing for newborns, children and adolescents weighing less than 50 kg with impaired renal function

Renal insufficiency	QC (ml / min / 1.73 m²)	Dosing regimen
Renal insufficiency	QC (ml / min / 1.73 m²)	Age from 1 to 6 months	Age from 6 to 23 months
Norm	>80	7-21 mg / kg (0.07-0.21 ml / kg) twice daily	10-30 mg / kg (0.10-0.30 ml / kg) twice daily
Lightweight	50-79	7-14 mg / kg (0.07-0.14 ml / kg) twice daily	10-20 mg / kg (0.10-0.20 ml / kg) twice daily
Moderate	30-49	3,5-10,5 mg / kg (0,035-0,105 ml / kg) 2 times a day	5-15 mg / kg (0.05-0.15 ml / kg) twice daily
Heavy	<30	3.5-7 mg / kg (0.035-0.07 ml / kg) twice daily	5-10 mg / kg (0.05-0.10 ml / kg) twice daily
Terminal stage (patients on dialysis)		7-14 mg / kg (0.07-0.14 ml / kg) once a day ⁽¹⁾ ⁽³⁾	10-20 mg / kg (0.10-0.20 ml / kg) once a day ^{(2) (4)}

⁽¹⁾ 10.5 mg / kg (0.105 ml / kg) the recommended loading dose on the first day of treatment

⁽²⁾ 15 mg / kg (0.15 ml / kg) the recommended loading dose on the first day of treatment

⁽³⁾ the recommended maintenance dose after dialysis is 3.5-7 mg / kg (0.035-0.07 ml / kg)

⁽⁴⁾ the recommended maintenance dose after dialysis is 5-10 mg / kg (0.05-0.10 ml / kg)

Patients with impaired hepatic function light and moderate degrees of gravity correction of the dosing regimen is not required. In patients with severe decompensated impairment of liver function and renal insufficiency the degree of decrease in the clearance of creatinine may not fully reflect the severity of renal failure. In such cases, when creatinine clearance is <60 ml / min / 1.73, a daily dose reduction of 50% is recommended.

Side effects:

The following profile of adverse events is based on an analysis of the results of placebo-controlled studies, as well as the experience of post-marketing use of levetiracetam. The most frequent adverse reactions were nasopharyngitis, snotty, headache,fatigue and dizziness. The safety profile of levetiracetam is generally similar for different age groups of adults and children.

Undesirable reactions are listed below for systems and organs and the frequency of occurrence: very often (≥1 / 10); often (≥1 / 100, <1/10); infrequently (≥1 / 1,000, <1/100); rarely (≥1 / 10,000, <1/1 000) and very rarely (<1/10 000).

MedDRA	Frequency Category
	Very Frequent	Frequent	Infrequent	Rare
Infections and invasions	Nasopharyngitis			Infections
On the part of the blood and lymphatic system			Thrombocytopestion, leukopenia	Pancytopenia, agranulocytosis, neutropenia
From the immune system				Drug reaction with eosinophilia and systemic manifestations (DRESS-syndrome)
From the side of metabolism		Anorexia	Weight loss, weight gain	Hyponatremia
Mental disorders		Depression, hostility / aggressiveness, anxiety, insomnia, nervousness, irritability	Attempts of suicide, suicidal intentions, psychotic disorders, behavioral disorders, hallucinations, anger, confusion, emotional lability, mood swings, agitation, panic attacks	Suicide, disorder personality, violation of thinking
Disturbances from the nervous system	Drowsiness, headache	Convulsions, imbalance, dizziness, lethargy, tremor	Amnesia, memory impairment, impaired coordination / ataxia, paresthesia, decreased concentration of attention	Choreoathetosis, dyskinesia, hyperkinesia
From the side of the organ of vision			Diplopia, blurred vision
From the side of the hearing organ		Vertigo
From the respiratory system		Cough
From the digestive system		Abdominal pain, diarrhea, indigestion, vomiting, nausea		Pancreatitis
From the liver and biliary tract			Changes in functional liver samples	Hepatic insufficiency, hepatitis
From the skin		Rash	Alopecia, eczema, itching	Toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme
From the musculoskeletal system			Myalgia, muscle weakness
General disorders		Asthenia / fatigue
Injuries, complications of procedures			Random Damage

The risk of anorexia is higher with simultaneous application of levetiracetam and then feast mat.

In a number of cases, restoration of the hair was observed after the removal of levetiracetam.

In some cases of pancytopenia, bone marrow depression was recorded.

The safety profile of children in placebo-controlled clinical trials was comparable to the safety profile of levetiracetam in adults. In children and adolescents aged 4 to 16 years, the following undesirable reactions were more frequent: vomiting (very often, 11.2%), excitation (often, 3.4%), moodiness (often 2.1%), emotional lability (often 1.7%), aggressiveness (often, 8.2%), behavioral disorders (often, 5.6%) and lethargy (often, 3.9%). In children aged 1 month to 4 years, the following adverse reactions were more often reported: irritability (very often 11.7%) and impaired coordination (often, 3.3%).

In a double-blind, placebo-controlled study whose goal was to show that the drug but safety was not inferior to placebo, the cognitive and neuropsychological effects of Keppre® in children from 4 to 16 years with partial seizures were evaluated. Based on the results of the study, it was concluded that Keppra® did not differ from placebo (not inferior to it) with respect to changes in the score of the "Attention and Memory" and "Combined Memory Screening" scales of the Leiter-R scaleLeiter-R) in patients who underwent a protocol study compared with the initial visit.

As a result of the analysis of behavioral and emotional status with the help of the validated tool - the Achenbach questionnaire (Achenbach) - aggressive behavior was revealed in the group of patients taking Keppra®. However, patients who took Keppru® during long-term follow-up in the open phase of the study did not show a worsening of the behavioral and emotional status, in particular, the indicators of aggressive behavior did not deteriorate compared to the baseline.

Overdose:

Symptoms: drowsiness, agitation, aggressiveness, oppression of consciousness, respiratory depression, coma.

Treatment: in the acute period - the artificial challenge of vomiting and gastric lavage followed by the appointment of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite - 74%).

Interaction:

Antiepileptic drugs

Levetiracetam does not affect the concentration in the plasma of antieleptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamira, gabapentin, topiramate and primidon) and these antiepileptic drugs do not affect the concentration of levetiracetam.

The clearance of levetiracetam was 22% higher in children taking anticonvulsants - inducers of microsomal liver enzymes, compared with children not taking them,

Probenecid

Reduction of renal secretion of the primary metabolite was observed with the administration of probenecid in a dose of 500 mg 4 times a day. The effect of levetiracetam with simultaneous administration with probenecid has not been studied, nor is it known when taken with such drugs as non-steroidal anti-inflammatory drugs, sulfonamides and methotrexate.

Contraceptive preparations and other pharmacokinetic interactions

Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of digoxin and warfarin.

Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of levetiracetam.

Antacids

There is no data on the effect of antacids on the absorption of levetiracetam.

Eating and drinking

Completeness of absorption of levetiracetam does not change under the influence of food, while the rate of absorption is somewhat reduced.

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

Special instructions:

Abolition of therapy

If it is required to stop taking the drug, it is recommended to cancel the treatment gradually (in adults and adolescents weighing more than 50 kg), reducing the single dose by 500 mg every 2-4 weeks. In children, the dose reduction should not exceed 10 mg / kg of body weight 2 times a day every 2 weeks, in children less than 6 months, the dose reduction should not exceed 7 mg / kg of body weight 2 times a day every 2 weeks.

Concomitant antiepileptic drugs (during the transfer of patients to receive levetiracetam) should be gradually phased out. The available information on the use of the drug in children does not indicate any of its negative effects on development and puberty. However, the long-term consequences of treatment on the ability of children to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

Diseases of the liver and kidneys

Patients with kidney disease and decompensated liver disease are recommended to study the function of the kidneys before treatment. If the kidney function is impaired, a dose adjustment may be required.

Suicidal intentions

Due to reports of cases of suicide, suicidal intentions and suicide attempts in the treatment with levetiracetam, patients should be warned to immediately notify the attending physician of any symptoms of depression or suicidal intentions.

The solution for oral ingestion contains maltitol, therefore, in patients with impaired tolerance to fructose, taking Keppra® in the appropriate dosage form is contraindicated.

The oral solution also contains methyl parahydroxybenzoate and propyl parahydroxybenzoate, which can cause allergic reactions (possibly delayed action).

Effect on the ability to drive transp. cf. and fur:

The effect of Keppra® on the ability to drive vehicles and control mechanisms has not been specifically studied. However, due to the different individual sensitivity to the drug from the central nervous system during the treatment period (some patients may experience drowsiness),it is necessary to refrain from driving motor vehicles and practicing potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Form release / dosage:

Solution for oral administration, 100 mg / ml.

Packaging:For 150 ml or 300 ml of solution in bottles of dark glass (type III, Hebrew F.) with a screw cap made of white polypropylene with "child protection".

For 1 bottle complete with a measuring syringe (polyethylene / polystyrene), along with instructions for use in a cardboard bundle.

Storage conditions:

At a temperature of no higher than 30 ° C, in a place protected from light.

Keep out of the reach of children.

Shelf life:

3 years.

Use the opened bottle for seven months.

Do not use after the expiration date.

Terms of leave from pharmacies:On prescription

Registration number:LSR-003170/09

Date of registration:24.04.2009

Expiration Date:Unlimited

The owner of the registration certificate: YUSB Farma S.A. YUSB Farma S.A. Belgium

Manufacturer: & nbsp

NEXTPHARMA, SAS France

Representation: & nbspYUSB FARMA LLC YUSB FARMA LLC Russia

Information update date: & nbsp25.09.2016

Illustrated instructions

Instructions

Keppra® (Keppra®)