Keppra solution for oral administration 100 mg/ml 300 ml bottle 1 pc. in Krasnodar

Keppra solution for oral administration 100 mg/ml 300 ml bottle 1 pc. in Krasnodar

Monotherapy

Adults and teenagers over 16 years of age.

Treatment should begin with a daily dose of 500 mg, divided into 2 administrations (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic dose of 1000 mg (500 mg 2 times a day). The maximum daily dose is 3000 mg (1500 mg 2 times a day).

The following solvents can be used:

• 0.9% sodium chloride solution for injection;
• lactated Ringer's solution for injection;
• 5% dextrose solution for injection.

The solution remains chemically stable at 15–25 °C for 24 hours in PVC bags.

However, from the point of view of microbiological purity, the drug must be used immediately after dilution.

If necessary, the solution can be stored at a temperature of 2 to 8 °C for 24 hours, provided that the dilution was carried out under aseptic conditions. In this case, responsibility for microbiological cleanliness lies with the user.

The use of the drug is not allowed if the color of the solution changes or mechanical inclusions appear.

As part of complex therapy

Children from 4 to 11 years old and adolescents 12–17 years old weighing up to 50 kg.

Treatment should begin with a daily dose of 20 mg/kg, divided into 2 administrations (10 mg/kg 2 times a day). The dose can be changed by 10 mg/kg every 2 weeks until the recommended daily dose is reached - 60 mg/kg (30 mg/kg 2 times a day). If the recommended daily dose is not tolerated, it may be reduced.

There is no clinical experience with the infusion of levetiracetam for periods exceeding 4 days.

The minimum effective dose should be used.

Recommended dosages for children (from 4 years old) and adolescents (up to 17 years old)

Adults and adolescents weighing more than 50 kg.

Treatment should begin with a daily dose of 1000 mg, divided into 2 administrations (500 mg 2 times a day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg (1500 mg 2 times a day). The dose can be changed to 500 mg 2 times a day every 2–4 weeks.

The duration of the course of treatment is determined by the doctor.

Inside,

regardless of food intake. The daily dose is divided into 2 doses of the same dose.

The tablets are taken with a sufficient amount of liquid.

The tablets are not intended for children under 6 years of age due to the impossibility of selecting the correct dose.

In the case of a solution, dosing is carried out using a measuring syringe included with the drug, with a nominal capacity of 10 ml (corresponding to 1000 mg of levetiracetam) with a division value of 25 mg (corresponding to 0.25 ml). The measured dose of the drug is diluted in a glass of water (200 ml).

Dosing of the solution is carried out using measuring syringes included in the delivery package of the drug. Syringes are available with nominal capacities:

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

- 3 ml (corresponds to 300 mg) with a division price of 0.1 ml (corresponds to 10 mg) for children from 6 months to 4 years;

- 1 ml (corresponds to 100 mg) and divided into 0.05 ml (corresponds to 5 mg) for children from 1 to 6 months.

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

Instructions for dosing the solution using a measuring syringe

1. Open the bottle: to do this, press the cap and turn it counterclockwise.

2. Insert the syringe adapter into the neck of the bottle, make sure it is well fixed, then take the syringe and place it in the adapter.

3. Turn the bottle upside down.

4. Fill the syringe with a small amount of solution by pulling the plunger down, then push the plunger up (to remove air bubbles).

5. By pulling the plunger, fill the syringe with the solution until the division corresponds to the number of ml of the solution prescribed by the doctor.

6. Turn the bottle upside down and remove the syringe from the adapter.

7. Introduce the contents of the syringe into a glass of water or a baby bottle, pressing the plunger all the way.

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

9. Rinse the syringe with water.

10. Close the bottle with a plastic cap.

Monotherapy

Adults and teenagers over 16 years of age.

The initial daily dose is 500 mg in 2 divided doses (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic dose of 1000 mg (500 mg 2 times a day). The maximum daily dose is 3000 mg (1500 mg 2 times a day).

As part of complex therapy

Children from 1 to 6 months.

The initial therapeutic dose is 7 mg/kg 2 times a day. Depending on clinical effectiveness and tolerability, the dose may be increased to 21 mg/kg 2 times a day. Dose changes should not exceed ±7 mg/kg 2 times a day every 2 weeks. The minimum effective dose should be prescribed.

Recommended dosages for children from 1 to 6 months

Children from 6 months to 11 years and adolescents from 12 to 17 years weighing less than 50 kg.

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

Recommended dosages for children (from 6 months) and adolescents (up to 17 years)

* For children weighing 25 kg or less, it is preferable to start treatment with Keppra®, oral solution, 100 mg/ml.

** The dosage for children and adolescents weighing more than 50 kg is the same as for adults.

Due to the lack of the required dosage, the tablets are not intended for the treatment of children weighing less than 25 kg, when a dose is prescribed less than 250 mg, as well as for patients who have difficulty swallowing them. In these cases, it is recommended to begin treatment by taking the drug in the form of an oral solution.

Adults and adolescents (from 12 to 17 years old) weighing more than 50 kg.

The initial daily dose is 1000 mg in 2 divided doses (500 mg 2 times a day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to a maximum of 3000 mg (1500 mg 2 times a day). The dose can be changed to 500 mg 2 times a day every 2–4 weeks.

Special patient groups

Renal dysfunction.

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

Creatinine clearance for men can be calculated from serum creatinine concentration using the following formula:

Cl creatinine, ml/min=(140−age, years)×body weight, kg/72×Cl serum creatinine, mg/dl

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

Creatinine clearance is then adjusted for body surface area (BSA) using the following formula:

Cl creatinine, ml/min/1.73 m2=Cl creatinine, ml/min×1.73/BSA of object, m2

Dose adjustment for adults

* On the first day of treatment with levetiracetam, a loading dose of 750 mg is recommended. After dialysis, an additional dose of 250–500 mg is recommended.

In children with renal failure, dose adjustment of levetiracetam should be made taking into account the degree of renal failure.

Creatinine clearance (ml/min/1.73 m2) can be estimated from serum creatinine (mg/dL) for adolescents, children and neonates using the following formula (Schwartz formula):

Cl creatinine, ml/min/1.73 m2=height, cm×ks/Cl serum creatinine, mg/dl

ks=0.45 for children under 1 year; ks=0.55 for children under 13 years of age and female adolescents; ks=0.7 for male adolescents.

Dose adjustment for newborns, children and adolescents weighing less than 50 kg

* On the first day of treatment with levetiracetam, a loading dose of 10.5 mg/kg (0.105 ml/kg) is recommended. After dialysis, an additional dose of 3.5–7 mg/kg (0.035–0.07 ml/kg) is recommended.

**On the first day of treatment with levetiracetam, a loading dose of 15 mg/kg (0.15 ml/kg) is recommended. After dialysis, an additional dose of 5–10 mg/kg (0.05–0.1 ml/kg) is recommended.

Liver dysfunction.

Patients with mild to moderate liver dysfunction do not require dosage adjustment. In patients with decompensated liver function and renal failure, the decrease in creatinine clearance may not fully reflect the severity of renal failure. In such cases, with creatinine clearance <60 ml/min/1.73 m2, it is recommended to reduce the daily dose by 50%.

Keppra®

The daily dose is divided into 2 equal doses.

Monotherapy

For adults and adolescents over 16
years of age
, the drug is prescribed in the form of tablets or oral solution at an initial dose of 500 mg, divided into 2 doses (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic dose of 1 g (500 mg 2 times a day). The maximum daily dose is 3 g (1.5 g 2 times a day).

As part of complex therapy

Children aged 1 month to 6 months

the drug is prescribed in the form of an oral solution. The initial therapeutic dose is 7 mg/kg 2 times/day. Depending on clinical effectiveness and tolerability, the dose may be increased to 21 mg/kg 2 times/day. Dose changes should not exceed plus or minus 7 mg/kg 2 times/day every 2 weeks. The minimum effective dose should be prescribed.

Dosing recommendations for Keppra® oral solution for children under 6 months of age

are presented in the table.

In children aged 6 months to 23 months, children aged 2 years to 11 years, and adolescents aged 12 years to 17 years weighing less than 50 kg

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

Doses for children weighing 50 kg

and more is the same as for adults.

Recommended dosage for children 6 months and older and adolescents

are presented in the table.

In children over 4 years old

treatment should begin with a daily dose of 20 mg/kg body weight, divided into 2 doses (10 mg/kg body weight 2 times a day). The dose can be changed by 20 mg/kg body weight every 2 weeks until the recommended daily dose is reached - 60 mg/kg body weight (30 mg/kg body weight 2 times a day). If the recommended daily dose is not tolerated, it may be reduced. The minimum effective dose should be used.

The drug should be prescribed in the most appropriate dosage form and dose depending on the patient’s body weight and the required therapeutic dose.

Children weighing ≤ 20 kg

It is recommended to begin treatment by taking the drug in the form of an oral solution.

Children weighing > 50 kg

dosing is carried out according to the scheme given for adults.

Adults and adolescents over 16 years of age weighing more than 50 kg

treatment should begin with a daily dose of 1 g, divided into 2 doses (500 mg 2 times a day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to a maximum of 3 g (1.5 g 2 times a day). The dose can be changed to 500 mg 2 times a day every 2-4 weeks.

Since levetiracetam is excreted by the kidneys when the drug is prescribed to elderly patients and patients with renal failure

the dose should be adjusted depending on the CC value.

CC can be calculated based on serum creatinine concentration using the following formula.

For men:

CC (ml/min)= [140-age (years)] × body weight (kg)/72 × serum creatinine (mg/dl)

For women:

obtained value x 0.85

* - on the first day of treatment with Keppra®, a loading dose of 750 mg is recommended.

** - after dialysis, it is recommended to take an additional dose of 250-500 mg.

Children with kidney failure

Dose adjustments of levetiracetam should be made based on the degree of renal impairment, using recommendations given for adults.

Patients with
mild to moderate liver dysfunction
do not require dosage adjustment.
In patients with decompensated liver dysfunction and renal failure,
the CC value may not reflect the true degree of renal dysfunction, therefore, when
CC <70 ml/min
a reduction in the daily dose by 50% is recommended.

Rules for using the drug

Pills

should be taken orally with sufficient liquid, regardless of meals.

Dosing the solution

carried out using a measuring syringe with a nominal capacity of 10 ml (corresponding to 1 g of levetiracetam) and with a division price of 25 mg (corresponding to 0.25 ml), included in the delivery package of the drug. The measured dose of the drug is diluted in a glass of water (200 ml).

To dispense the solution using a measuring syringe, open the bottle: to do this, press the cap and turn it counterclockwise. Insert the syringe adapter into the neck of the bottle, then take the syringe and place it in the adapter. Turn the bottle upside down. Fill the syringe with a small amount of solution by pulling the plunger down, then push the plunger up to remove any air bubbles. By pulling the plunger, fill the syringe with the solution until the division corresponds to the number of ml of solution prescribed by the doctor. Remove the syringe from the adapter. Introduce the contents of the syringe into a glass of water, pressing the plunger all the way. You should drink the entire contents of the glass. Then rinse the syringe with water and close the bottle with a plastic cap.

Keppra in rational polytherapy of epilepsy in children

If two subsequent monotherapies are not effective, then rational polytherapy is used. Rational polytherapy consists of using several anticonvulsants (most often two), taking into account their pharmacodynamic interactions. In polytherapy, broad-spectrum drugs are usually used. Thus, a neurologist or psychiatrist quite often has to think about which AED he will prescribe to a patient if there is no effect from the first monotherapy. Moreover, a significant proportion of patients with epilepsy (25–30%) will be forced to take two AEDs simultaneously for quite a long time. It is believed that polytherapy should be based on the following rational principles: •• combinations of anticonvulsants with different mechanisms of action have advantages; •• the dose of the first prescribed drug should be adapted taking into account possible drug interactions when combined with the second drug; •• interactions of enzyme-inducing drugs (carbamazepine, phenytoin, phenobarbital) in terms of the effect on blood concentrations are largely unpredictable; •• the combination of anticonvulsants with pronounced sedative effects should be avoided. In the last few years, our practice has increasingly used the new antiepileptic drug levetiracetam (trade name Keppra. Manufacturer: USB S.A., Belgium) for alternative monotherapy or polytherapy of epilepsy in children. It should immediately be said about the rather complex issue of age restrictions in the use of this drug. In international practice, levetiracetam is approved for use as an additional therapy in the treatment of partial epileptic seizures with or without secondary generalization in adults and children 4 years of age and older; As a monotherapy, the drug is approved for use in Europe from 16 years of age. In Russia, both of these indications for use are still in the registration process, and formally we can use this drug only after 16 years of age. But, taking into account the extensive international experience of use, good tolerability and high effectiveness of the drug, in the Department of Psychoneurology and Epileptology of the Moscow Research Institute of Pediatrics, the drug has been prescribed for several years to children with epilepsy under 16 years of age. As a rule, these are patients in whom the first monotherapy was ineffective or poorly tolerated. A mandatory condition for prescribing the drug is to inform the patient’s parents about the “temporary” (related to the peculiarities of registration of the drug in Russia) age restrictions. It is no coincidence that we prefer this drug over other “new” antiepileptic drugs. Below are the reasons why we have been enthusiastic about using Keppra in the treatment of epilepsy in children for several years. 1. Keppra has a wide spectrum of therapeutic activity and can be used in almost all focal or generalized (both idiopathic and symptomatic) epileptic syndromes [1]. In terms of the breadth of the spectrum of therapeutic activity, it is second only to valproate, since it did not prove to be as effective in absence seizures [2]. Keppra has been proven effective in the treatment of myoclonus and generalized tonic-clonic seizures [2]. Therefore, the drug is successfully used abroad as monotherapy for the treatment of juvenile myoclonic epilepsy [3]. In focal epilepsy, Keppra is comparable in effectiveness to carbamazepine [4]. Keppra is quite actively used in the treatment of encephalopathies, such as infantile spasms, Lennox–Gastaut syndrome, electrical status epilepticus during slow-wave sleep, etc. [5–7]. The effectiveness of Keppra in the treatment of progressive myoclonus-epilepsy, in particular in Unferricht-Lundborg disease, has been proven [1]. On the other hand, Keppra can be successfully used not only for severe epileptic syndromes, but also for benign focal epilepsy with centrotemporal adhesions as the first monotherapy and in polytherapy for its resistant course [8]. 2. Keppra is effective in the treatment of epilepsy resistant to other AEDs. There are numerous open and double-blind studies proving the effectiveness of the drug in the treatment of resistant focal epilepsy in children [9–13]. Let us refer to only one of them, conducted by Franzoni E. et al. in 2006 [13]. In this study, which is similar to clinical practice, patients receiving Keppra at a daily dose of 8.3 to 56.6 mg per kg of body weight had a seizure remission rate of 24.4%. 11% experienced a reduction in seizure frequency of 50% or more. Some patients were switched to Keppra monotherapy after achieving remission. Naturally, in double-blind studies the remission rate is lower than in those that are as close as possible to clinical practice. Thus, a study by Glauser T. et al. (2006) demonstrated that the remission rate for intractable partial epilepsy in children when Keppra was added to therapy was 7% (1% when adding placebo). In 40.6% of patients, the number of attacks was reduced by 50 percent or more with the addition of Keppra (with the addition of placebo - in 19.6%, respectively) [12]. Keppra may be effective where other AEDs do not due to its unique mechanism of action. Keppra's unique mechanism of action is that it binds to the glycoprotein SV2A of synaptic vesicles (this protein is essential for normal neurotransmission), regulating the release of neurotransmitters and reducing epileptic neuron activity [1]. In addition, Keppra has proven other additional mechanisms of action. These include enhancing GABA- and glycinergic inhibition and stabilizing the neuronal membrane, blocking epileptic discharges caused by activation of NMDA receptors, inhibition of high-voltage Ca2+ and K+ channels (suppression of paroxysmal polarization shifts), blocking epileptic gene expression in neurons (antiepileptogenic effect at the gene level ) and limiting the excitotoxic effect of NMDA receptor activation (neuroprotective effect). Another reason for Keppra's effectiveness in overcoming resistance in epilepsy may lie in the underlying mechanisms of resistance formation. Currently, one of the popular hypotheses for the formation of resistance in epilepsy is the hypothesis of disruption of the functioning of transport systems that ensure the transport and absorption of drugs in the intestinal wall and their transfer across the blood-brain barrier (the so-called “multiple drug resistance”). Transporter proteins have affinity for many antiepileptic drugs; they “bind” these drugs and do not allow them to pass further. Experimental studies have shown that P-glycoprotein and other carrier proteins have affinity for phenytoin, phenobarbital, carbamazepine, valproate, oxcarbazepine, lamotrigine, and topiramate. Keppra was the first antiepileptic drug that was not a substrate for transporter proteins [14]. Perhaps it is precisely because of all of the above that the outstanding English epileptologist S.P. Panayiotopoulos considers Keppra the first-line drug of choice in the treatment of resistant focal epilepsies [1]. 3. Keppra combines well with other AEDs. A big problem in rational polytherapy is the pharmacokinetic interactions of drugs. It is well known that some AEDs (carbamazepine, phenobarbital, phenytoin) are quite powerful inducers of liver enzymes. If we add another drug to such enzyme-inducing AEDs, then with chronic combined use the concentration of the second drug will decrease, sometimes quite significantly. Classic examples of such interactions are the combined use of carbamazepine and topiramate (the former can cause the concentration of the latter to decrease by approximately half). The same applies to the combination of carbamazepine and valproate (the concentration of valproate may be significantly reduced). Sometimes the opposite situation occurs, for example, when valproate and lamotrigine are used together. Valproate inhibits the metabolism of lamotrigine and increases its concentration in the blood, which is why in children under 12 years of age the use of half the daily dosage of lamotrigine in this combination is indicated. Fluctuations in the concentration of AEDs in the blood serum, both in the direction of increasing concentration and in the direction of decreasing it, are dangerous for a patient with epilepsy. A decrease in concentration can cause a low effect of antiepileptic therapy, while an increase can lead to the development of side effects. Unlike some other AEDs, Keppra does not affect the concentrations of other drugs. And the addition of other AEDs to Keppra does not cause clinically significant fluctuations in the concentration of the drug in the blood [15]. This positive pharmacokinetic characteristic is due to the fact that the metabolism of Keppra does not depend on hepatic cytochrome P450. Thus, it is possible to combine any antiepileptic drugs with Keppra. These same metabolic features of Keppra lead to the fact that it does not affect the concentrations of digoxin and warfarin and does not reduce the activity of antibiotics when used together in a patient [15]. 4. Keppra has a rapid and sometimes very rapid therapeutic effect. It is an antiepileptic drug with a rapid rate of administration. It is known that a starting dose of Keppra 500 mg twice a day is effective on the first day of administration in most adult patients [16]. The recommended dosing regimen and dose titration of Keppra in children is slightly different from that in adults. So, if a child weighs from 20 to 40 kg, then Keppra is prescribed at a dose of 250 mg 2 times a day, then during the 3rd–4th week - 500 mg 2 times a day and, if necessary, further 750 mg 2 times per day. Already at the first therapeutic dose of 500 mg, we often see a clinical effect in the form of a decrease in the frequency of attacks, that is, the starting dose of the drug may be therapeutic. In children weighing from 40 to 60 kg, Keppra is prescribed immediately at 500 mg 2 times a day, then for two weeks at 1000 mg 2 times a day. Of course, the exact dose is determined by the specific clinical situation and ranges from 20 to 60 mg per kg of body weight per day. Based on our clinical experience, we can confirm the common belief that Keppra often begins to work from the first day of treatment. It is probably unnecessary to prove what benefits such a rapid therapeutic effect provides both the patient and the doctor. 5. Keppra is one of the most well tolerated antiepileptic drugs. As a rule, the incidence of side effects with Keppra is slightly higher than that with placebo [16]. Over a fairly long period of use in the treatment of epilepsy, no life-threatening side effects have been described. When using Keppra, side effects such as drowsiness, asthenia, nausea, and headache may occur (they are dose-dependent and reversible). Zaccara G. et al. in 2006, they assessed the results of double-blind studies, which made it possible to compare the tolerability of new antiepileptic drugs (data from 31 studies were summarized). The frequency of 4 side effects was compared: drowsiness, tremor, negative effects on cognitive function and vestibulocerebellar disorders when levetiracetam (Keppra), oxcarbazepine and topiramate were used in patients with epilepsy. Least often (with a frequency of just over 5%), these side effects were observed when taking Keppra. Only fairly high daily doses of Keppra (2000 mg or more) were more often accompanied by the development of side effects from the central nervous system [18]. It is also necessary to note the extremely important property of levetiracetam to maintain its effectiveness for a long time. According to a number of authors, the retention rate on Keppra after more than 12 months of treatment for resistant forms of epilepsy was 49%, which is comparable and even higher than that of other modern AEDs [10,21]. Two aspects of Keppra's good tolerability are extremely attractive and significant for the practitioner: it does not impair liver function and does not have a negative effect on the cognitive functions of patients with epilepsy (in particular, memory and attention). Thus, a study by Mari F. et al. (2006) on the use of Keppra in patients with epilepsy and liver diseases (hepatitis C and acute toxic hepatitis) showed both the high effectiveness of the drug against epileptic seizures and the improvement of liver function in patients. Patients were transferred to monotherapy with Keppra from other AEDs; the daily dose of Keppra ranged from 1000 to 3000 mg. There are several studies on the positive effects of Keppra on cognitive function in patients with epilepsy [18–21]. Thus, one of them assessed attention and speech speed in patients with partial epilepsy before treatment with Keppra (as an additional therapy) and 7 weeks after its administration. Patients in the control group who received other AEDs (except Keppra) were also examined and underwent neuropsychological testing at the same time interval. The results showed a significant improvement in attention and speaking speed in the study group compared to the control group. This article is more devoted to the use of Keppra in combination therapy for resistant epilepsy. Of course, Keppra seems to be a very promising AED, which can be widely used in monotherapy for epilepsy. Therefore, we are looking forward to the registration of this indication in Russia and the lifting of age restrictions on the use of this drug. References 1. Panayiotopoulos S.P. The Epilepsies. Seizures, Syndromes and Management; 2005; Bladon Medical Publishing; Oxfordshire; UK; P. 506–508. 2. Labate A., Colosimo E., Gambardella A. et al. Levetiracetam in patients with generalized epilepsy and myoclonic seizures: an open label study. Seizure; 2006; V.15(3); P. 214–8. 3. Specchio LM, Gambardella A., Giallonardo AT et al Open label, long–term, pragmatic study on levetiracetam in the treatment of juvenile myoclonic epilepsy. Epilepsy Res.; 2006; V.71(1); P.32–9. 4. Brodie MJ, Perucca E, Ryvlin P et al. Comparison of levetiracetam and controlled–release carbamazepine in newly diagnosed epilepsy. Neurology; 2007; V. 68(6); P. 402–8. 5. Lawlor KM, Devlin AM Levetiracetam in the treatment of infantile spasms. Eur. J. Paediatr. Neurol.; 2005; V9(1); P. 19–22. 6. De los Reyes EC, Sharp GB, Williams JP, Hale SE Levetiracetam in the treatment of Lennox–Gastaut syndrome. Pediatr. Neurol; 2004; V.30; P. 254–256. 7. Kossoff EH, Boatman D., Freeman JM Landau–Kleffner syndrome responsive to levetiracetam. Epilepsy Behav.; 2003; V.4(5); P. 571–5. 8. Verrotti A., Coppola G., Manco R. et al. Levetiracetam monotherapy for children and adolescents with benign rolandic seizures. Seizure; 2007; V. 16; P. 271-275. 9. Grosso S., Franzoni E., Coppola G. et al. Efficacy and safety of levetiracetam: an add-on trial in children with refractory epilepsy. Seizure; 2005; V.14(4); P. 248–53. 10. Mandelbaum DE, Bunch M, Kugler SL, Venkatasubramanian A, Wollack JB. Efficacy of levetiracetam at 12 months in children classified by seizure type, cognitive status, and previous anticonvulsant drug use. Child Neurol 2005;20(July (7)):590–4. 11. Opp J., Tuxhorn I., May T. et al. Levetiracetam in children with refractory epilepsy: a multicenter open label study in Germany. Seizure; 2005; V. 14(7); P.476–84. 12. Glauser TA, Ayala R., Elterman RD Double-blind placebo-controlled trial of adjunctive levetiracetam in pediatric partial seizures. Neurology; 2006; V. 66(11); P.1654–60. 13. Franzoni E., Sarajlija J., Carone C. et al. Levetiracetam: Two Years Experience with Children. Abstracts from the 7th European Congress on Epileptology. Helsinki; 2006; P. 184 14. Sisodiya SM, Lin WR, Harding BN, Squier MV, Thom M. Drug Resistance in Epilepsy: Expression of Drug-Resistance Proteins in Common Causes of Refractory Epilepsy. Brain; 2002; V.125; P.22–31. 15. Otoul S., De Smedt H., Stockis A. Lack of Pharmacokinetic Interaction of Levetiracetam on Carbamazepine, Valproic Acid, Topiramate, and Lamotrigine in Children with Epilepsy. Epilepsy; 2007; V. 48(11); P. 2111–2115. 16. French J., Eldrich P., Cramer JA A systematic review of the safety profile of levetiracetam: a new antiepileptic drug. Epilepsy Res.; 2001; V.47; P.77–90 17. Zaccara G, Messori A, Cincotta M, Burchini G. Comparison of the efficacy and tolerability of new antiepileptic drugs: what can we learn from long–term studies? Acta Neurol. Scand.; 2006; V.114(3); P.157–68. 18. Mari F., Di Bonaventura C., Egeo G. et al. Long-term effectiveness of Levetiracetam in the Treatment of Epilepsy associated with Liver Diseases. Abstracts from the 7th European Congress on Epileptology. Helsinki; 2006; P. 132. 19. Gomer B., Wagner K., Frings L. et al. The influence of antiepileptic drugs on cognition: A comparison of levetiracetam with topiramate. Epilepsy & Behavior; 2007; V.10; P. 486–494. 20. Kossoff EH, Los JG, Boatman DF. A pilot study transitioning children onto levetiracetam monotherapy to improve language dysfunction associated with benign rolandic epilepsy. Epilepsy Behav.; 2007; Oct 11; 21. Peacke D., Mordekar S., Gosalakkal J. et al. Retention rate of levetiracetam in children with intractable epilepsy at 1 year. seizure; 2007; 16; P. 185–189 22. Piazzini A., Chifari R., Canevini MP et al. Levetiracetam: an improvement of attention and of oral fluency in patients with partial epilepsy. Epilepsy Res.; 2006; V.68(3); P.181–8.