Composition, form of production and packaging
Concentrate for the preparation of a solution for infusions in the form of a clear, colorless solution.
1 ml of 1 fl.
levetiracetam 100 mg 500 mg
Excipients: sodium acetate trihydrate 8.2 mg, sodium chloride 45 mg, acetic acid 10% (up to pH 5.5), water d / u (up to 5 ml).
5 ml - bottles of glass (5) - packings of cellular contour (2) - packs cardboard.
INSTRUCTION FOR THE SPECIALIST.
Description of the drug approved by the manufacturer for the printed edition of 2011.
PHARMACHOLOGIC EFFECT
Levetiracetam, the active substance of the Keppra preparation, is a derivative of pyrrolidone (the 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. An in vitro study showed that levetiracetam affects the intra-neuronal concentration of Ca 2+ ions , partially inhibiting the Ca 2+current 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 anti-somatic effect is realized, which is expressed in counteracting the hypersynchronization of neuronal activity. Similarly, levetiracetam affects GABA and glycine receptors, modulating these receptors through various endogenous agents. Does not change the normal neurotransmission, but suppresses epileptiform neuronal outbreaks induced by 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
The dose of levetiracetam 1500 mg with iv administration is bioequivalent to a dose of 1500 mg taken internally in the form of tablets.
Levetiracetam is a highly soluble substance with a high penetrating ability. The pharmacokinetic profile is linear with low variability and is comparable in healthy volunteers and patients with epilepsy.
The time parameters of the independent pharmacokinetic profile of levetiracetam have been confirmed in / in the administration of 1500 mg (2 times / day) for 4 days.There was no dependence of pharmacokinetics on sex, race and time of day.
Distribution
C max after iv injection of 1500 mg was achieved after 15 minutes and was 51 В± 19 Ојg / ml. The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. V d is about 0.5-
0.7 l / kg. There is no data on the distribution of levetiracetam on tissues.
Metabolism
The main metabolic pathway (24% of the dose) is the enzymatic hydrolysis of the acetamide group. The formation of the primary pharmacologically inactive metabolite (ucb L057) occurs without the involvement of liver cytochrome P450. Levetiracetam does not affect the enzymatic activity of hepatocytes.
Excretion
T 1/2 from the blood plasma of an adult human is 7 В± 1 h and does not depend on the mode of administration and dosing regimen. The average overall clearance is 0.96 ml / min / kg. 95% is excreted by the kidneys. The renal clearance of levetiracetam and its metabolite is 0.6 and 4.2 ml / min / kg, respectively.
In elderly patients T 1/2 increases by 40%, which is associated with a decrease in kidney function in this category of people.
In patients with impaired liver function of mild and moderate severity, no significant changes in the clearance of levetiracetam occur.
INDICATIONS
This dosage form can be used as a temporary alternative if oral dosage forms are not possible.
As a monotherapy (the drug of the first choice) 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 with epilepsy;
- 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 drug is administered as an infusion.
The transition from oral to intravenous administration and back can be carried out with preservation of the dose and the frequency of administration. One vial of concentrate for solution for infusion contains 500 mg levetiracetam (100 mg / ml).
The daily dose is divided into two injections in the same dose.
Before use, the concentrate must be diluted with a solvent of at least 100 ml. Enter into / in the drip for 15 minutes.
Instruction for dosing the solution
Dose Volume of preparation Volume of solvent Infusion time Frequency of administration Daily dose
250 mg 2.5 ml (1/2 amp 5 ml) 100 ml 15 min 2 times / day 500 mg / day
500 mg 5 ml (1 amp 5 ml) 100 ml 15 min 2 times / day 1000 mg / day
1000 mg 10 ml (2 amp 5 ml) 100 ml 15 min 2 times / day 2000 mg / day
1500 mg 15 ml (3 amp 5 ml) 100 ml 15 min 2 times / day 3000 mg / day
As solvents can be used: 0.9% solution of sodium chloride for injection; Ringer's lactate solution for injection; 5% dextrose solution for injection.
The solution retains its chemical stability at a temperature of 15-25 В° C for 24 hours in polyvinyl chloride bags. However, from the point of view of microbiological purity, the drug should be used immediately after dilution.
If necessary, storage of the solution at a temperature of 2 to 8 В° C for 24 hours is allowed provided that the dilution was carried out under aseptic conditions. In this case, the responsibility for microbiological purity lies with the user.
Monotherapy
Adults and adolescents over 16 years of age should be treated with a daily dose of 500 mg divided into 2 injections (250 mg-2 times / day). After 2 weeks, the dose may be increased to the initial therapeutic dose of 1000 mg (500 mg Г— 2 times / day). The maximum daily dose is 3000 mg (1500 mg? 2 times / day).
As part of complex therapy
Children from 4 to 11 years and adolescents 12-17 years old with a body weight of up to 50 kg should begin treatment with a daily dose of 20 mg / kg body weight divided into 2 injections (10 mg / kg body weight? 2 times / day). A dose change of 10 mg / kg body weight can be done every 2 weeks until the recommended daily dose is 60 mg / kg body weight (30 mg / kg body weight Г— 2 times / day). With intolerance of the recommended daily dose, it is possible to reduce it.
The minimum effective dose should be used.
Adults and adolescents with a body weight of more than 50 kg should be treated with a daily dose of 1000 mg divided into 2 injections (500 mg Г— 2 times / 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-2 times / day). A dose change of 500 mg 2 times / day can be carried out every 2-4 weeks. Recommended dose for children and adolescents:
Body weight Initial dose: 10 mg / kg 2 times / day Maximum dose: 30 mg / kg 2 times / day
15 kg 150 mg 2 times / day 450 mg 2 times / day
20 kg 200 mg 2 times / day 600 mg 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
Since levetiracetam is excreted from the body by the kidneys, when administered to patients with renal insufficiency and elderly patients, the dose should be adjusted depending on the amount of creatinine clearance (CC).
The creatinine clearance for men can be calculated based on the serum creatinine concentration, according to the following formula:
KK (ml / min) = [140 - age (years)]? body weight (kg) / 72? KK syu-ki (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 corrected taking into account the body surface area (PPT) according to the following formula: KK (ml / min / 1.73 m 2 ) = KK (ml / min) / PPT of the object (m 2 )? 1.73
Kidney Failure (ml / min / 1.73 m 2 ) Dosing regimen
Norm> 80 500 to 1500 mg 2 times / day
Latent 50-79 from 500 to 1000 mg 2 times / day
Compensated 30-49 from 250 to 750 mg 2 times / day
Intermittent <30 from 250 to 500 mg 2 times / day
Terminal stage (patients on dialysis *) - 500 to 1000 mg 1 time / day **
* On the first day of treatment, the administration of a saturating dose of 750 mg is recommended.
** 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, using recommendations given for adults.
Patients with a malfunction of the liver of mild and moderate severity of the correction of the dosing regimen is not required. In patients with decompensated impairment of liver function and renal failure, a decrease in creatinine clearance may not fully reflect the severity of renal failure. In such cases, with a creatinine clearance of <60 ml / min / 1.73 m 2 , a daily dose reduction of 50% is recommended.
The duration of the course of treatment is determined by the doctor.
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 nervous system: very often - drowsiness, fatigue, asthenia; 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, disturbance of thinking; separate messages - paresthesia, behavioral disorders, anxiety, anger, confusion, hallucinations, psychotic
disorders, suicide, suicide attempts and suicidal intentions.
From the side of the organ of vision: often - diplopia, impaired vision.
From the respiratory system: often - increased cough, nasopharyngitis.
From the digestive system: often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight gain; individual reports - pancreatitis, hepatic insufficiency, hepatitis, weight loss.
From the skin: often - skin rash, eczema, itching; individual reports - alopecia (in some cases, the restoration of the hair was observed after the drug was withdrawn), Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
Changes in laboratory indicators: often - thrombocytopenia; isolated reports - leukopenia, neutropenia, pancytopenia (in some cases with bone marrow suppression), changes in functional liver samples.
Other: often - infections, myalgia, vertigo, accidental lesions.
CONTRAINDICATIONS
- hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as to any components of the drug;
- children under 4 years of age (safety and efficacy - not
installed).
With caution : patients of advanced age (over 65 years); liver disease in the stage of decompensation; renal insufficiency.
PREGNANCY AND LACTATION
Adequate and strictly controlled clinical trials on the safety of levetiracetam in pregnant women have not been conducted. Studies in animals have revealed reproductive toxicity. Therefore, the drug should not be administered during pregnancy, except in cases of extreme 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 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. 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.
Levetiracetam is excreted in breast milk, so if it is necessary to use it during lactation, breastfeeding when taking the drug is not recommended. However, if treatment with levetiracetam is necessary during the period of feeding, the risk ratio for the child and the benefit of the treatment for the mother should be carefully weighed against
importance of feeding.
APPLICATION FOR FUNCTIONS OF THE LIVER
With caution : kidney failure.
Since levetiracetam is excreted from the body by the kidneys, when administered to patients with renal insufficiency and elderly patients, the dose should be adjusted depending on the amount of creatinine clearance (CC).
The creatinine clearance for men can be calculated based on the serum creatinine concentration, according to the following formula:
KK (ml / min) = [140 - age (years)]? body weight (kg) / 72? KK syu-ki (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 corrected taking into account the body surface area (PPT) according to the following formula: KK (ml / min / 1.73 m 2 ) = KK (ml / min) / PPT of the object (m 2 )? 1.73
Kidney Failure (ml / min / 1.73 m 2 ) Dosing regimen
Norm> 80 500 to 1500 mg 2 times / day
Latent 50-79 from 500 to 1000 mg 2 times / day
Compensated 30-49 from 250 to 750 mg 2 times / day
Intermittent <30 from 250 to 500 mg 2 times / day
Terminal stage (patients on dialysis *) - 500 to 1000 mg 1 time / day **
* On the first day of treatment, the administration of a saturating dose of 750 mg is recommended.
** After dialysis, an additional 250-500 mg dose is recommended.
APPLICATION FOR VIOLATIONS OF THE FUNCTION OF KIDNEYS
With caution : liver disease in the stage of decompensation.
Patients with a malfunction of the liver of mild and moderate severity of the correction of the dosing regimen is not required. In patients with decompensated impairment of liver function and renal failure, a decrease in creatinine clearance may not fully reflect the severity of renal failure. In such cases, with a creatinine clearance of <60 ml / min / 1.73 m 2 , a daily dose reduction of 50% is recommended.
APPLICATION FOR CHILDREN
Contraindicated in children under 4 years.
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.
APPLICATION IN ELDERLY PATIENTS
With caution : patients of advanced age (over 65 years).
SPECIAL INSTRUCTIONS
If it is required to stop taking the drug, it is recommended to cancel the treatment 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 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 on children's ability to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.
The risk of anorexia increases with simultaneous use with topiramate.
Patients with kidney disease and decompensated liver disease are recommended. Investigation of kidney function before treatment, if the kidney function is impaired, dose adjustment may be required.
The drug contains 0.83 mmol (or 19 mg) of sodium per ampoule. This should be taken into account for patients on a diet with sodium restriction.
Due to reports of cases of suicide, suicidal intentions and suicide attempts with levetiracetam, patients should be warned to immediately notify the attending physician of any symptoms of depression or suicidal intentions.
Clinical experience of infusion application of levetiracetam in the period exceeding 4 days is absent.
Do not use the drug when changing the color of the solution or the appearance of mechanical inclusions.
Impact on the ability to drive vehicles and manage mechanisms
The effect of Keppra's preparation on the ability to drive vehicles and control mechanisms has not been specifically studied. Nevertheless, due to the different individual sensitivity to the drug from the side of the central nervous system during the treatment period, 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.
OVERDOSE
Symptoms: drowsiness, agitation, aggressiveness, depression of consciousness, respiratory depression, coma.
Treatment: 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%).
DRUG INTERACTION
The drug does not interact with antiepileptic drugs (phenitbin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone).
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 did not influence the pharmacokinetics of levetiracetam.
When co-administered with topiramate more likely to develop anorexia.
Data on the interaction of levetiracetam with alcohol are not present.
TERMS OF RELEASE FROM PHARMACY
The drug is released by prescription.
TERMS AND CONDITIONS OF STORAGE
Store in a dark place at a temperature not higher than 25 В° C. Keep out of the reach of children. Shelf life - 2 years.
