Expiration date: 06/2025
Structure and Composition:
Tablets, film-coated. One tablet contains active substance:
500 mg levetiracetam
Excipients: Croscarmellose sodium - 21.5 mg macrogol 6000 - 5 mg of silicon dioxide - 10,375 mg of magnesium stearate - 0.625 mg Opadry 85F32004
shell film: Opadry 85F32004 (dye iron oxide yellow (E172), macrogol 3350, polyvinyl alcohol, partially hydrolyzed, talc, titanium dioxide (E171) - 16.125 mg
in blisters of 10 pieces. 3 a stack of cardboard or six packs.
Tablets, film-coated. One tablet contains:
active substance:
1000 mg of levetiracetam
excipients: Croscarmellose sodium - 43 mg Macrogol 6000 - silica 10 mg - magnesium stearate 20.75 mg - 1.25 mg
Film shell: Opadry 85F18422 (macrogol 3350, polyvinyl alcohol, partially hydrolyzed, talc, titanium dioxide (E171) - 32.25 mg
in blisters of 10 pieces. 3 a stack of cardboard or six packs.
Oral solution. 1 ml contains active substance:
100 mg levetiracetam
Excipients: sodium citrate - 1.05 mg of citric acid monohydrate - 0.06 mg methyl parahydroxybenzoate - propyl parahydroxybenzoate 2.7 mg - 0.3 mg of ammonium glycyrrhizate - 1.5 mg of glycerol 85% - 235.5 mg maltitol - 300 mg of acesulfame potassium - 4.5 mg flavor grape 501040A - 0.3 mg of purified water - 504 mg
in dark glass bottles, complete with a measured syringe in paper cartons 1 set.
Description pharmaceutical form:
Concentrate for infusion: clear, colorless solution.
Tablets 500 mg: light yellow, oval shaped, film-coated, biconvex with surfaces with a one-sided risk, on one side of which there is an engraving "ucb", on the other - "500" on a break - homogeneous, white color.
1000 mg tablets: white, oval-shaped, film-coated, biconvex with surfaces with a one-sided risk, on one side of which there is an engraving "ucb", on the other - "1000" on a break - homogeneous, white color.
Oral solution: clear, almost colorless, with a characteristic odor.
Pharmacokinetics:
The dose of levetiracetam 1500 mg at / in a bioequivalent dose of 1500 mg taken orally in pill form.
Levetiracetam - readily soluble substance with high penetrating power. Pharmacokinetic profile - linear low variability and is comparable in healthy volunteers and patients with epilepsy.
Time parameters independent pharmacokinetic profile of levetiracetam confirmed in / administration of 1500 mg (2 times per day) for 4 days. There were no pharmacokinetic depending on gender, race, and time of day.
Suction. After oral levetiracetam is well absorbed from the gastrointestinal tract. Absorption occurs completely and is linear, whereby the plasma concentration may be predicted based on the highest dose of levetiracetam, expressed in mg / kg body weight. Completeness levetiracetam absorption is not dose mealtime, but the rate of absorption is somewhat reduced. Bioavailability is approximately 100%. Cmax is reached after 1.3 hours after oral administration at a dose of levetiracetam and 1000 mg single dose of 31 ug / ml after repeated administration (2 times a day) - 43 mcg / mL after / in a single administration of 1,500 mg Cmax achieved through 15 min and was (51 ± 19) g / ml. The equilibrium state is reached after 2 days at twice the dose.
Pharmacokinetics of levetiracetam in children is linear at a dosage range from 20 to 60 mg / kg / day C max is reached after 0.5-1 hours.
Distribution. The binding of levetiracetam and its main metabolite plasma protein is less than 10%. Vd is about 0,5-0,7 liters / kg.
Metabolism. The main pathway (24% of dose) is an enzymatic hydrolysis of the acetamido group. Education primary pharmacologically inactive metabolite (ucb L057) occurs without the involvement of the cytochrome P450 liver. Levetiracetam has no effect on the enzymatic activity of hepatocytes.
Withdrawal. T1 / 2 of the blood plasma of adult human (7 ± 1) hours and does not depend on the route of administration and dosage regimen. The average value of the total clearance of 0.96 mL / min / kg. 95% of the drug is excreted by the kidneys. Renal clearance of levetiracetam and ucb L057 is 0.6 and 4.2 ml / min / kg, respectively.
Elderly patients T1 / 2 increased by 40% and amounts to 10-11 hours, which is associated with a decrease in renal function in these patients.
During the 4-hour dialysis session is removed up to 51% of levetiracetam.
In patients with impaired liver function mild to moderate severity significant change the clearance of levetiracetam does not occur. Most patients with severe hepatic impairment levetiracetam clearance is reduced by more than 50% due to the concomitant renal insufficiency.
T1 / 2 in children after a single oral administration of 20 mg / kg of body weight of 5-6 hours. The total clearance of levetiracetam in children is about 40% higher than in adults and is a direct function of the body weight.
Description of the pharmacological actions:
Levetiracetam - Keppra drug active substance - a pyrrolidone derivative (S-enantiomer-ethyl-2-oxo-1-pyrrolidine acetamide), the chemical structure different from the known anti-epileptic drugs.
The mechanism of action of levetiracetam is not fully understood, but it is obvious that he is different from the known mechanism of action of anti-epileptic drugs. In vitro study showed that levetiracetam affects intraneuronal Ca2 + ion concentration, partially inhibiting Ca2 + current through N-channel type, and reducing the intraneuronal calcium release from the depot. In addition, levetiracetam partially restores currents through GABA and glycine-dependent channels, reduced zinc and p-carbolines.
One of the proposed mechanisms is based on evidence that binding to synaptic vesicle glycoprotein SV2A, contained in the gray matter of the brain and spinal cord. It is believed that in this way is realized anticonvulsant effect, which is expressed in countering gipersinhronizatsii neural activity. Levetiracetam also affects the GABA and glycine receptors, modulating the data through different receptors endogenous agents. It does not change the normal neurotransmission, but inhibits neuronal epileptiform flash, induced GABA-agonist bikukulinom and excitement of glutamate receptors. Drug activity was confirmed in respect of both focal and generalized seizures (epileptiform manifestations / fotoparoksizmalnaya reaction).
Indications:
- In monotherapy (the drug of first choice) in the treatment of the following conditions:
- partial seizures with secondary generalization or without in adults and adolescents over 16 years of age with newly diagnosed epilepsy.
- In the combined therapy in the treatment of the following conditions:
- partial seizures with secondary generalization or without adults and children over 4 years (for oral solution - older than 1 month), epilepsy
- myoclonic seizures in adults and adolescents over 12 years old suffering from juvenile myoclonic epilepsy
- primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years old suffering from idiopathic generalized epilepsy.
- Dosage form "concentrate for infusion" can be used as an interim alternative if you can not receive oral forms of the drug.
Contraindications:
- Hypersensitivity to levetiracetam or other pyrrolidone derivatives, as well as any components of the drug
- tolerance disorder fructose (Oral Solution)
- Children under 4 years - for tablets and up to 1 month - for the oral solution (safety and efficacy have not been established).
Precautions: older patients (over 65 years), severe liver function abnormalities (concentrate - decompensated) renal insufficiency.
Application of pregnancy and breastfeeding:
Common to all dosage forms
Adequate and well-controlled clinical studies on the safety of levetiracetam in pregnant women has been conducted, and the drug should not be administered during pregnancy except in cases of extreme necessity. Note that the breaks in the conduct of antiepileptic therapy may lead to worsening of the disease, which may harm the health of both mother and fetus.
Levetiracetam is excreted in breast milk, so if you need it, use during lactation breastfeeding at the time of taking the drug should be discontinued.
To further concentrate
However, if levetiracetam treatment is needed in the feeding period, the ratio of risk to the child and the treatment benefit to the mother must be carefully weighed against the importance of feeding.
Side effect:
Common to all dosage forms
Possible side effects are listed below by body system and frequency of occurrence: very common (& ge1 / 10), often (& ge1 / 100, <1/10).
From the nervous system: very often - drowsiness, fatigue, asthenia often - amnesia, ataxia, convulsion, dizziness, headache, hyperkinesia, tremor, imbalance, poor concentration, memory loss, agitation, depression, emotional lability, variability of mood, hostility / aggression, insomnia, nervousness, irritability, personality disorder, thinking violation of individual messages - paresthesias, behavioral disorders, anxiety, anger, confusion, hallucination, psychotic disorder, suicide, suicide attempt and suicidal intentions.
From a sight organ: often - diplopia, blurred vision.
With the respiratory system: often - increased cough, nasopharyngitis.
From the digestive system: often - abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight increase individual message body - pancreatitis, hepatic failure, hepatitis, weight loss.
For the skin: often - skin rash, eczema, pruritus individual messages - Alopecia (in some cases, recovery of hair was observed after discontinuation of the drug) individual messages - Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
Changes in laboratory parameters: often - individual messages thrombocytopenia - leukopenia, neutropenia, pancytopenia (in some cases with bone marrow suppression), changes in liver function tests.
Other: individual messages - infection, myalgia, vertigo, accidental damage.
Drug Interactions:
The drug does not interact with other antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, primidone).
Levetiracetam in a daily dose of 1000 mg did not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol, levonorgestrel) and a daily dose of 2000 mg - digoxin and warfarin.
Digoxin, oral contraceptives and warfarin did not affect the pharmacokinetics of levetiracetam.
When co-administered with topiramate more likely to develop anorexia.
There are no data on the interaction of levetiracetam with alcohol.
Completeness of absorption when administered levetiracetam does not change under the influence of the food, and the rate of absorption of several sigean.
Dosage and administration:
The transition from intravenous to oral use and can be carried back to the conservation dose and frequency of administration.
A bottle of concentrate for solution for infusion contains 500 mg of levetiracetam (100 mg / ml).
The daily dose is divided into two administration in the same dosage.
Before use, the concentrate must be diluted with a solvent, of not less than 100 ml.
Dosing solution Instructions
| Dose, mg | The volume of the drug | The volume of solvent, ml | infusion time, min | The frequency of administration, once a day | The daily dose, mg / day |
| 250 | 2.5 ml (half-ampoule 5 ml) | 100 | 15 | 2 | 500 |
| 500 | 5 ml (one ampule 5 ml) | 100 | 15 | 2 | 1000 |
| 1000 | 10 ml (2 to 5 ml ampule) | 100 | 15 | 2 | 2000 |
| 1500 | 15 ml (3 ampoules 5 ml) | 100 | 15 | 2 | 3000 |
The solvents can be used:
- 0.9% sodium chloride solution for injection
- Lactated Ringer's injection
- 5% dextrose solution for injection
The solution maintains chemical stability at a temperature of 15-25 ° C for 24 hours in PVC bags.
However, in terms of microbiological purity of the drug should be used immediately after dilution.
If necessary, the solution is allowed storage at 2 to 8 ° C for 24 hours provided the dilution was made under aseptic conditions. In this case, the responsibility for microbiological purity is the user.
Monotherapy
Adults and adolescents over 16 years of treatment should be started with a daily dose of 500 mg, divided into 2 injection (250 mg 2 times a day). After 2 weeks the dose may be increased to an initial therapeutic - 1000 mg (500 mg 2 times a day). The maximum daily dose is 3000 mg (1500 mg two times a day).
In the combined therapy
Children from 4 to 11 years and adolescents 12-17 years with a body weight up to 50 kg, treatment should begin with a daily dose of 20 mg / kg divided into 2 administration (10 mg / kg body weight 2 times a day). Changes in the dose of 10 mg / kg may be carried out every two weeks to achieve the recommended daily dose - 60 mg / kg (30 mg / kg two times a day). When intolerance recommended daily dose may decrease it.
It should use the minimum effective dose.
Adults and adolescents weighing more than 50 kg, treatment should begin with a daily dose of 1000 mg, divided into 2 injection (500 mg 2 times a day). Depending on the clinical response and tolerability daily dose may be increased to a maximum - 3000 mg (1500 mg two times a day). Change every 2-4 weeks the dose may be 500 mg 2 times a day.
The recommended dose for children and adolescents:
| Body Weight in kg | Starting dose - 10 mg / kg, 2 times per day | The maximum dose - 30 mg / kg, 2 times per day |
| 15 | 150 mg 2 times a day | 450 mg 2 times a day |
| 20 | 200 mg 2 times a day | 600 mg 2 times a day |
| 25 | 250 mg 2 times a day | 750 mg 2 times a day |
| from 50 | 500 mg 2 times a day | 1500 mg 2 times a day |
Since levetiracetam is excreted by the kidneys, when administering the drug to patients with renal failure and patients older dose should be adjusted depending on the magnitude of creatinine clearance.
Cl creatinine for males can be calculated from the serum creatinine concentration by the following formula (1):
Cl creatinine
Cl creatinine for women can be calculated by multiplying the resulting value by a factor of 0.85.
Then CC is adjusted for body surface area (BSA) as follows:
Cl creatinine (ml / min / 1,73m2) = (creatinine clearance (ml / min) / BSA object (m 2) × 1,73
| Kidney failure | Creatinine clearance ml / min / 1.72 m2 | Dosage |
| Norm | >80 | from 500 to 1500 mg 2 times a day |
| Latent | 50–79 | from 500 to 1000 mg 2 times a day |
| Compensated | 30–49 | from 250 to 750 mg 2 times a day |
| Intermittent | <30 | from 250 to 500 mg 2 times a day |
| Patients with end-stage renal failure on hemodialysis * | — | from 500 to 1000 mg 1 times a day** |
* On the first day of treatment levetiracetam recommended intake of 750 mg loading dose.
** When the dialysis is recommended to take extra doses of 250-500 mg.
Children with kidney failure correction of the dose of levetiracetam should be made taking into account the degree of renal insufficiency using the advice given to adults.
Patients with impaired liver function mild to moderate severity correct dosing regimen is required. In patients with decompensated hepatic impairment and renal impairment decreased creatinine clearance may not fully reflect the severity of renal failure. In such cases, the creatinine clearance <60 mL / min / 1.73 m2 recommended daily dose reduction by 50%.
The duration of treatment is determined by the doctor.
Inside, drinking plenty of fluids, regardless of the meal. The daily dose is divided into 2 equal reception.
In the case of dosing solution is performed by measuring syringe, the included drug, nominal capacity of 10 ml (corresponding to 1000 mg of levetiracetam) with a scale of 25 mg (corresponding to 0.25 mL). A metered dose of the drug is diluted in a glass of water (200 ml).
Instructions for dosing solution using the measuring syringe
- Open the bottle: it click on the cap and turn it counterclockwise.
- Insert the syringe adapter into the neck of the bottle, then take the syringe and put it in the adapter.
- Turn the bottle upside down.
- Fill the syringe with a small amount of solution by pulling the piston down, and then push the plunger upwards (to remove air bubbles).
- Pull the plunger to fill the syringe to rasvorom division corresponding to the number of ml of the dose prescribed by the doctor.
- Remove the syringe from the adapter.
- The contents of the syringe put into a glass of water by pushing the plunger until it stops.
- Drink the entire contents of the glass.
- Rinse the syringe with water.
- Close the vial with a plastic lid.
Monotherapy
Adults and adolescents over 16 years of the initial daily dose - 500 mg in 2 divided doses (250 mg 2 times a day). After 2 weeks the dose may be increased to an initial therapeutic - 1000 mg (500 mg 2 times a day). The maximum daily dose - 3000 mg (1500 mg 2 times a day).
In the combined therapy
Children over 4 years of initial daily dose - 20 mg / kg in two divided doses (10 mg / kg two times a day). Changes in the dose of 20 mg / kg may be carried out every two weeks to achieve the recommended daily dose - 60 mg / kg (30 mg / kg two times a day). When intolerance recommended daily dose may decrease it. It should use the minimum effective dose. The physician must assign the most suitable drug dosage form and the dosage, depending on the patient's weight and the required therapeutic dose.
Children weighing 20 kg or less is recommended to begin treatment with the drug in the form of a solution for oral administration.
Children weighing more than 50 kg dosing is carried out according to the scheme described for adults.
Adults and adolescents over 16 years weighing more than 50 kg initial daily dose - 1000 mg in two divided doses (500 mg 2 times a day). Depending on the clinical response and tolerability daily dose may be increased to a maximum - 3000 mg (1500 mg two times a day). Change every 2-4 weeks the dose may be 500 mg 2 times a day.
As mentioned above, since the levetiracetam is excreted by the kidneys, when administering the drug to patients with renal failure and patients older dose should be adjusted depending on the value of Cl creatinine.
Cl creatinine for men and women can be calculated from the serum creatinine concentration using the formula (1) above.
Overdose:
Symptoms: drowsiness, anxiety, aggressiveness, depression of consciousness, respiratory depression, coma.
Treatment: In acute period - induction of vomiting and gastric lavage, followed by the appointment of activated carbon (with an overdose of oral forms). Specific antidote for levetiracetam not. If necessary, symptomatic treatment in a hospital with dialysis (dialysis efficiency for levetiracetam was 60% for its primary metabolite - 74%).
Special instructions:
If you want to stop taking the drug, the abolition of the treatment recommended to gradually (by reducing a single dose of 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.
Concomitant antiepileptic drugs (during the transfer of patients receiving levetiracetam) is desirable to be lifted gradually.
Available data on drug use among children do not show any negative impact on its development and puberty. However, long-term effects on children's ability to learn, their intellectual development, growth, endocrine function, sexual development and fertility are unknown.
The risk of anorexia is increasing while the use of topiramate.
In the application of the concentrate for infusion in patients with kidney disease and decompensated liver disease it is recommended that the study of renal function prior to initiation of treatment, in violation of renal function may require dosage adjustment. The preparation contains 0.83 mmol (or 19 mg) of sodium per 1 vial. This should be considered for patients who are on restricted sodium diet.
In connection with current 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 intent.
Clinical experience infusion use of levetiracetam in a period longer than 4 days absent.
Do not use the drug in the solution or change in color appearance of mechanical impurities.
Oral solution contains maltitol, so patients with impaired tolerance to fructose intake Keppra drug in the appropriate dosage form is contraindicated.
Effects on ability to drive vehicles and management mechanisms. Not been specifically studied. However, due to different individual sensitivity to the drug in the CNS period of treatment should refrain from driving motor vehicles and activities potentially hazardous activities that require high concentration and psychomotor speed reactions.
