Composition, form of production and packaging
The tablets covered with a film shell of blue color, oval in shape, biconvex, with one-sided risk, on one side of which there is engraving "ucb", on the other - "250";on the fracture - homogeneous, white.
1 tab.
levetiracetam hydrochloride 250 mg
Excipients: croscarmellose sodium, macrogol 6000, silicon dioxide, magnesium stearate.
Composition of the film shell: opadrai 85F20694 (dye indigo carmine (E132), macrogol 3350, partially hydrolysed polyvinyl alcohol, talc, titanium dioxide (E171)).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
The tablets covered with a film membrane of light yellow color, oval in shape, biconvex, with one-sided risk, on one side of which there is engraving "ucb", on the other - "500"; on the fracture - homogeneous, white.
1 tab.
levetiracetam hydrochloride 500 mg
Excipients: croscarmellose sodium, macrogol 6000, silicon dioxide, magnesium stearate.
The composition of the film shell: opadray 85F32004 (iron dye oxide yellow (E172), macrogol 3350, partially hydrolysed polyvinyl alcohol, talc, titanium dioxide (E171)).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
The tablets covered with a film shell of white color, oval in shape, biconvex, with one-sided risk, on one side of which there is engraving "ucb", on the other - "1000"; on the fracture - homogeneous, white.
1 tab.
levetiracetam hydrochloride 1000 mg
Excipients: croscarmellose sodium, macrogol 6000, silicon dioxide, magnesium stearate.
The composition of the film shell: opadray 85F18422 (macrogol 3350, partially hydrolysed polyvinyl alcohol, talc, titanium dioxide (E171)).
10 pieces. - blisters (3) - packs of cardboard.
10 pieces. - blisters (6) - packs of cardboard.
The solution for oral administration is transparent, almost colorless, with a characteristic odor.
1 ml
levetiracetam 100 mg
Excipients: sodium citrate, citric acid monohydrate, methyl parahydroxybenzoate, propyl parahydroxybenzoate, ammonium glycyrrhizinate, glycerol 85%, maltitol, acesulfame potassium, grape flavor 501040A, purified water.
300 ml - bottles of dark glass (1) complete with a measuring syringe - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2012.
PHARMACHOLOGIC EFFECT
An antiepileptic drug, a pyrrolidone derivative (S-enantiomer of О±-ethyl-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from known antiepileptic drugs.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.
In vitro studies have shown that levetiracetam affects the intra-neuronal concentration of Ca 2+ ions , partially inhibiting the current of Ca 2+ through N-type channels and decreasing the release of calcium from intra-neuronal depots. In addition, levetiracetam partially restores the currents through GABA- and glycine-dependent channels, reduced by zinc and ОІ-carbolines.
One of the proposed mechanisms is based on proven binding to the glycoprotein of the synaptic SV2A vesicles contained in the gray matter of the brain and spinal cord. It is believed that in this way the anticonvulsant effect is realized, which is expressed in the counteracting of the hypersynchronization of neuronal activity. Does not change the normal neurotransmission, but suppresses the epileptiform neuronal outbreaks induced by the GABA agonist bicuculine, and the excitation of glutamate receptors. The activity of the drug has been confirmed with respect to both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).
PHARMACOKINETICS
Suction
After oral administration, levetiracetam is well absorbed from the digestive tract. Absorption is complete and linear, so the concentration in the blood plasma can be predicted based on the applied dose of the drug in mg / kg body weight. The degree of absorption is independent of the dose and time of ingestion. Bioavailability is about 100%.
After taking the drug at a dose of 1 g of C max in blood plasma is achieved after 1.3 hours and is 31 Ојg / ml, after repeated administration (2 times / day) - 43 Ојg / ml.
Distribution
The equilibrium state is reached after 2 days with a two-time intake of the drug. The binding to plasma proteins of levetiracetam and its main metabolite is less than 10%. V d of levetiracetam is about 0.5-0.7 l / kg.
Metabolism
The formation of the primary pharmacologically inactive metabolite (ucb L057) occurs without the participation of cytochrome P450 isoenzymes in the liver.Levetiracetam does not affect the enzymatic activity of hepatocytes.
Excretion
In adults, T 1/2 of plasma is 7 В± 1 h and does not vary with dose, route of administration, or repeated administration. The average clearance is 0.96 ml / min / kg. 95% of the dose is excreted by the kidneys. The renal clearance of levetiracetam and its inactive metabolite is 0.6 ml / min / kg and 4.2 ml / min / kg, respectively.
Pharmacokinetics in special clinical cases
In elderly patients T 1/2 increases by 40% and is 10-11 hours, which is associated with a decrease in kidney function in this category of people.
In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, patients with renal insufficiency is recommended to select a dose depending on the CK. In the terminal stage of renal failure in adult patients, T 1/2 is 25 hours between dialysis sessions and 3.1 hours during dialysis. During a 4-hour dialysis session, up to 51% of levetiracetam is removed.
In the course of 4-hour dialysis, 51% of levetiracetam is removed from the body.
In patients with mild and moderate violations of liver function, significant changes in the clearance of levetiracetam do not occur. In severe violations of liver function with concomitant renal failure, the clearance of levetiracetam decreases by more than 50%.
The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg / kg / day. C max is achieved in 0.5-1 hour. T 1/2 in children after a single oral intake at a dose of 20 mg / kg body weight is 5-6 hours. The total clearance of levetiracetam in children is approximately 40% higher than in adults and is in direct dependence on body weight.
INDICATIONS
As a monotherapy (the first drug) in the treatment:
- partial seizures with secondary generalization or without it in adults and adolescents over 16 years with newly diagnosed epilepsy.
As part of complex therapy in the treatment of:
- partial seizures with secondary generalization or without it in adults and children older than 4 years suffering from epilepsy (for tablets);
- partial seizures with secondary generalization or without it in adults and children older than 1 month suffering from epilepsy (for solution);
- Myoclonic seizures in adults and adolescents over 12 years with juvenile myoclonic epilepsy;
- primary generalized convulsive (tonic-clonic) seizures in adults and adolescents older than 12 years with idiopathic generalized epilepsy.
DOSING MODE
The daily dose is divided into 2 identical doses.
Monotherapy
Adults and adolescents over 16 years of age the drug is prescribed in the form of tablets or a solution for ingestion in an initial dose of 500 mg divided into 2 divided doses (250 mg twice daily). After 2 weeks, the dose may be increased to the initial therapeutic dose - 1 g (500 mg 2 times / day). The maximum daily dose is 3 g (1.5 g 2 times / day).
As part of complex therapy
Children aged from 1 month to 6 months of the drug is prescribed in the form of a solution for oral administration. The initial treatment dose is 7 mg / kg 2 times / day. Depending on the clinical efficacy and tolerability, the dose can be increased to 21 mg / kg 2 times / day. The dose change should not exceed plus or minus 7 mg / kg 2 times / day every 2 weeks. The minimum effective dose should be given.
Recommendations for dosing Keppra В® in the form of a solution for oral administration for children under 6 months of age are presented in the table.
Body weight Initial dose: 7 mg / kg 2 times / day Maximum dose: 21 mg / kg 2 times / day
4 kg 28 mg (0.3 ml) 2 times / day 84 mg (0.85 ml) 2 times / day
5 kg 35 mg (0.35 ml) 2 times / day 105 mg (1.05 ml) 2 times / day
7 kg 49 mg (0.5 ml) 2 times / day 147 mg (1.5 ml) 2 times / day
In children aged 6 months to 23 months, children aged 2 to 11 years and adolescents from 12 to 17 years with a body weight of less than 50 kg, treatment should begin with a dose of 10 mg / kg body weight divided into 2 divided doses (10 mg / kg body weight 2 times / day). Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to 30 mg / kg 2 times / day. A dose change of 10 mg / kg body weight can be done every 2 weeks. The minimum effective dose should be used.
Doses for children weighing 50 kg or more are the same as for adults.
Recommended doses for children aged 6 months and adolescents are presented in the table.
Body weight Initial dose: 10 mg / kg 2 times / day Maximum dose: 30 mg / kg 2 times / day
6 kg 60 mg (0.6 ml) 2 times / day 180 mg (1.8 ml) 2 times / day
10 kg 100 mg (1 ml) 2 times / day 300 mg (3 ml) 2 times / day
15 kg 150 mg (1.5 ml) 2 times / day 450 mg (4.5 ml) 2 times / day
20 kg 200 mg (2 ml) 2 times / day 600 mg (6 ml) 2 times / day
25 kg 250 mg 2 times / day 750 mg 2 times / day
from 50 kg 500 mg 2 times / day 1500 mg 2 times / day
In children older than 4 years, treatment should begin with a daily dose of 20 mg / kg body weight divided into 2 doses (10 mg / kg body weight 2 times / day). A dose change of 20 mg / kg body weight can be performed every 2 weeks until the recommended daily dose is 60 mg / kg body weight (30 mg / kg body weight 2 times / day). With intolerance of the recommended daily dose, it is possible to reduce it. The minimum effective dose should be used.
Prescribe the drug in the most appropriate dosage form and dose, depending on the patient's body weight and the required therapeutic dose.
Children with a body weight? 20 kg is recommended to begin treatment with taking the drug in the form of a solution for oral administration.
Children weighing> 50 kg are dosed according to the scheme given for adults.
Adults and adolescents over 16 years of age with a body weight of more than 50 kg should be treated with a daily dose of 1 g divided into 2 divided doses (500 mg 2 times / day). Depending on the clinical response and the tolerability of the drug, the daily dose can be increased to a maximum of 3 g (1.5 g 2 times / day). A dose change of 500 mg 2 times / day can be carried out every 2-4 weeks.
Since levetiracetam is excreted by the kidneys when the drug is administered to elderly patients and patients with renal insufficiency, the dose should be adjusted depending on the magnitude of the CC.
QA can be calculated from the serum creatinine concentration, according to the following formula.
For men:
KK (ml / min) = [140-years (years)]? body weight (kg) / 72? serum creatinine (mg / dL)
For women: the value obtained is x 0.85
Renal insufficiency KK (ml / min) Dose and frequency of admission
Norm> 80 500-1500 mg 2 times / day
Latent 50-79 500-1000 mg 2 times / day
Compensated 30-49 250-750 mg 2 times / day
Intermittent <30 250-500 mg 2 times / day
Terminal stage (patients on hemodialysis) * - 500-1000 mg 1 time / day **
* - on the first day of treatment with Keppra В® , a saturation dose of 750 mg is recommended.
** - after dialysis, an additional dose of 250-500 mg is recommended.
Children with renal insufficiency correction of the dose of levetiracetam should be made taking into account the degree of renal failure, using recommendations given for adults.
Patients with impaired liver function of mild to moderate severity do not need to adjust the dosage regimen. In patients with decompensated hepatic impairment and renal insufficiency, the value of QC may not reflect the true extent of renal dysfunction, therefore, at a CC <70 ml / min , a daily dose reduction of 50% is recommended.
Application rules
Tablets should be taken orally, with a sufficient amount of liquid, regardless of food intake.
Dosage of the solution is carried out using a measuring syringe with a nominal capacity of 10 ml (corresponds to 1 g of levetiracetam) and with a 25-mg division (corresponding to 0.25 ml), which is supplied with the preparation. The metered dose of the drug is diluted in a glass of water (200 ml).
To dispense the solution with a syringe, you need to open the bottle: to do this, press the cap and turn it counter-clockwise. Insert the syringe adapter into the neck of the vial, then take the syringe and place it in the adapter. Turn the bottle upside down. Fill the syringe with a small amount of solution, pulling the piston down, then push the plunger upward to remove air bubbles. Pulling the plunger, fill the syringe with the solution until it divides, corresponding to the number of ml of the solution prescribed by the doctor. Remove the syringe from the adapter. The contents of the syringe enter into a glass with water, pushing the piston to the stop. You should drink completely the entire contents of the glass. Then rinse the syringe with water and close the bottle with a plastic lid.
SIDE EFFECT
Possible side effects are given below for body systems and frequency of occurrence: very often (> 1/10), often (> 1/100, <1/10).
From the side of the central nervous system: very often - drowsiness, asthenic syndrome; often amnesia, ataxia, convulsions, dizziness, headache, hyperkinesia, tremor, imbalance, decreased concentration, memory impairment, agitation, depression, emotional lability, mood swings, hostility / aggressiveness, insomnia, nervousness, irritability, personality disorders, violation of thinking; in some cases - paresthesia, behavioral disorders, anxiety, anxiety, confusion, hallucinations, irritability, psychotic disorders, suicide, suicide attempts and suicidal intentions.
From the side of the organ of vision: often - diplopia, a violation of accommodation.
From the respiratory system: often - increased cough.
From the digestive system: often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight gain; in some cases - pancreatitis, hepatic insufficiency, hepatitis, changes in functional liver samples, weight loss.
Dermatological reactions: often - skin rash, eczema, itching; in some cases - alopecia (in some cases, the restoration of the hair was observed after the drug was withdrawn), Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
On the part of the hematopoiesis system: in some cases - leukopenia, neutropenia, pancytopenia (in some cases with oppression of bone marrow function), thrombocytopenia.
Other: in some cases - infections, nasopharyngitis, myalgia.
CONTRAINDICATIONS
- Children's age to 4 years (for tablets) (safety and efficacy of the drug are not established);
- Children's age up to 1 month (for solution) (safety and efficacy of the drug are not established);
- impaired tolerance to fructose (for solution);
- hypersensitivity to the components of the drug;
- hypersensitivity to other pyrrolidone derivatives.
With caution should prescribe the drug elderly patients (over 65 years), with liver disease in the stage of decompensation, kidney failure.
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical trials on the safety of levetiracetam in pregnant women have not been conducted, so the drug should not be administered during pregnancy, except in cases of extreme need.
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 I trimester (up to 60% of the baseline concentration in the period preceding the pregnancy).
Treatment with levetiracetam pregnant women should be carried out under special supervision. It should be borne in mind that interruptions in antiepileptic therapy may lead to a worsening of the course of the disease, which is harmful for both the mother and the fetus.
Levetiracetam is excreted in breast milk, so breastfeeding during treatment with the drug is not recommended. However, if treatment with levetiracetam is necessary during lactation, the risk / benefit ratio of treatment should be carefully weighed against the importance of breastfeeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
Patients with renal insufficiency are selected individually according to the recommendations given in the table.
Renal failure Creatinine clearance (ml / min) Dose and multiplicity of admission
Norm> 80 500-1500 mg 2 times / day
Light degree 50-79 500-1000 mg 2 times / day
Average degree 30-49 250-750 mg 2 times / day
Severe degree <30 250-500 mg 2 times / day
Terminal stage on the background of hemodialysis * - 500-1000 mg 1 time / day **
* On the first day of treatment with Keppra, a saturating dose of 750 mg is recommended.
** after dialysis, an additional dose of 250-500 mg is recommended
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With light and moderate violations of liver function, dose adjustment is not required.
With caution should prescribe the drug for liver disease in the decompensation stage.
APPLICATION FOR CHILDREN
Contraindicated: children under 4 years (for tablets) (safety and efficacy of the drug are not established); Children's age up to 1 month (for solution) (safety and efficacy of the drug are not established);
APPLICATION IN ELDERLY PATIENTS
With caution should prescribe the drug to elderly patients (over 65 years).
SPECIAL INSTRUCTIONS
If you want to stop taking the drug, then it is recommended to cancel cancellation gradually, 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 / day every 2 weeks.
Concomitant antiepileptic drugs (during transfer in patients receiving levetiracetam) desirably lifted gradually.
Patients with kidney disease and decompensated liver disease recommended study of renal function prior to treatment. With impaired renal function may require dosage adjustment.
In connection with the available reports of cases of suicide, suicidal ideation and suicide attempts in the treatment of levetiracetam should warn patients about the need to be reported immediately to your doctor about any symptoms of depression or suicidal ideation.
Oral solution comprising maltitol, so patients with impaired fructose tolerance to the drug receiving Keppra В® the appropriate dosage form is contraindicated.
Use in Pediatrics
Available data on drug use among children do not show any of its negative impact on the development and puberty. However, long-term effects of treatment on the children's ability to learn, their intellectual development, growth, endocrine function, sexual development and fertility are unknown.
Impact on the ability to drive vehicles and manage mechanisms
The influence of the drug Keppra В® on the ability to drive vehicles and management mechanisms have not been studied specifically. However, due to different individual sensitivity to the drug from the CNS in the period of treatment should refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions.
OVERDOSE
Symptoms: drowsiness, anxiety, aggressiveness, depression of consciousness, respiratory depression, coma.
Treatment: in the acute period - an artificial challenge of vomiting and gastric lavage with activated charcoal followed by the appointment. Specific antidote for levetiracetam not. If necessary symptomatic treatment is carried out in a hospital environment using dialysis (dialysis efficiency for levetiracetam is 60%, to its primary metabolite - 74%).
DRUG INTERACTION
Levetiracetam does not interact with anticonvulsants (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone).
Levetiracetam in a daily dose of 1 g does not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).
Levetiracetam in a daily dose of 2 g does not alter the pharmacokinetics of digoxin and warfarin.
Digoxin, oral contraceptives and warfarin did not influence the pharmacokinetics of levetiracetam.
When co-administered with topiramate more likely to develop anorexia.
Completeness of absorption of levetiracetam does not change under the influence of the food, the rate of absorption is somewhat reduced.
Data on the interaction of levetiracetam with alcohol are absent.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Tablets should be stored in a dry place at a temperature not higher than 25 В° C. Shelf life - 3 years.
The solution should be stored for receiving inward in the dark place at a temperature not higher than 30 В° C. Shelf life - 3 years.
