Description
Latin name
Keppra
Dosage form
concentrate for preparation srd1rd65% srrd1rf75 solution for% rrd5575% srrd55 infrds75% rdrdsa% srrd65 Concentrate for solution for infusion in the form of a clear, colorless solution.
Packaging
5 ml – glass bottles (5) – blister strip packaging (2) – packs of cardboard.
Pharmacological action
antiepileptic drug, pyrrolidone derivative (S-enantiomer of -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 obvious 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 Ca2 + ions, partially inhibiting the flow of Ca2 + through N-type channels and decreasing the release of calcium from intra-neuronal depots. In addition, levetiracetam partially restores currents through the GABA- and glycine-dependent channels, reduced by zinc and β-carbolines.
One of the proposed mechanisms is based on the proven binding of the synaptic SV2A synaptic vesicles contained in the gray matter of the brain and spinal cord to the glycoprotein. Believed that in this way an anticonvulsant effect is realized, which is expressed in counteracting hypersynchronization of neural activity. It does not alter normal neurotransmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist biculin and excitation of glutamate receptors. The activity of the drug is confirmed in relation to both focal and generalized epileptic seizures (epileptiform manifestations / photoparoxysmal reaction).
Pharmacokinetics
Absorption
After oral administration, levetiracetam is well absorbed from the gastrointestinal tract. Absorption is complete and linear, so the plasma concentration can be predicted based on the dose of the drug used in mg / kg body weight. The degree of absorption does not depend on the dose and time of meal. Bioavailability is about 100%.
After taking the drug in a dose of 1 g of Cmax in plasma, it is reached after 1.3 hours and amounts to 31 μg / ml, after repeated administration (2 times / day) – 43 μg / ml.
Distribution of
An equilibrium state is reached after 2 days with a double dose of the drug. The binding to plasma proteins of levetiracetam and its main metabolite is less than 10%. Vd of levetiracetam is about 0.5-0.7 L / kg.
Metabolism
The formation of a 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 of
In adults, T1 / 2 from plasma is 7 ± 1 h and does not change depending on the dose, route of administration or repeated use. 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, T1 / 2 increases by 40% and amounts to 10-11 hours, which is associated with a decrease in renal 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 failure are recommended dose selection depending on the QC. In the terminal stage of renal failure in adult patients, T1 / 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.
During 4-hour dialysis, 51% of levetiracetam is removed from the body.
In patients with mild to moderate impaired liver function, significant changes in the clearance of levetiracetam do not occur. In severe hepatic impairment with concomitant renal failure, the clearance of levetiracetam is reduced by more than 50%.
The pharmacokinetics of levetiracetam in children is linear in the range of doses from 20 to 60 mg / kg / day. Cmax is achieved in 0.5-1 hours. T1 / 2 in children after a single oral 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 directly dependent by body weight.
Contraindications
children under 4 years of age (for tablets) (drug safety and efficacy not established)
children under 1 month of age (for solution) (drug safety and efficacy not established)
fructose tolerance impairment (for solution)
increased sensitivity to the components of the drug
hypersensitivity to other pyrrolidone derivatives.
With caution, the drug should be prescribed to elderly patients (over 65 years old), with liver diseases in the stage of decompensation, renal failure.
Use in children
Contraindicated: Children under 4 years of age (for tablets) (drug safety and efficacy not established) Children under 1 month of age (for solution) (drug safety and efficacy not established)
Use in elderly patients
Caution is advised to prescribe the drug to elderly patients (older 65 years old).
Use in pregnancy and lactation
Adequate and strictly controlled clinical studies on the safety of levetiracetam in pregnant women have not been conducted. Animal studies have revealed reproductive toxicity. Therefore, the drug should not be prescribed during pregnancy, except in cases of emergency.
Physiological changes in a woman’s body during pregnancy can affect the plasma concentration of levetiracetam, as well as other antiepileptic drugs. During pregnancy, a decrease in the concentration of levetiracetam in plasma was noted. This decrease is more pronounced in the first trimester (up to 60% of the base concentration in the period preceding pregnancy). Treatment with pregnant levetiracetam should be carried out under special control. Interruptions in antiepileptic therapy can 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 levetiracetam treatment is necessary during the feeding period, the risk ratio for the baby and the benefit of the treatment for the mother should be carefully weighed against
the importance of feeding.
Composition
1 ml1 vial
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).
Dosage and administration
The daily dose is divided into 2 identical doses.
Monotherapy
For adults and adolescents over 16 years of age, the drug is prescribed in the form of tablets or oral solution in an initial dose of 500 mg divided into 2 doses (250 mg 2 times / day). After 2 weeks, the dose can be increased to the initial therapeutic – 1 g (500 mg 2 times / day). The maximum daily dose is 3 g (1.5 g 2 times / day).
As part of
combination therapy, for children from 1 month to 6 months of age, the drug is prescribed in the form of an oral solution. The initial therapeutic dose is 7 mg / kg 2 times / day. Depending on the clinical efficacy and tolerability, the dose may 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 prescribed.
Dosing recommendations for Keppra ® in the form of an oral solution 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 / day84 mg (0.85 ml) 2 times / day
5 kg35 mg (0.35 ml) 2 times / day105 mg (1.05 ml) 2 times / day
7 kg49 mg (0.5 ml) 2 times / day147 mg (1.5 ml) 2 times / day
In children aged 6 months to 23 months, children aged 2 years to 11 years and adolescents from 12 years to 17 years with a body weight of less than 50 kg, treatment should be started with a dose of 10 mg / kg body weight divided into 2 doses (10 mg / kg body weight 2 times / day). Depending on the clinical reaction and tolerability of the drug, the daily dose may be increased to 30 mg / kg 2 times / day. A dose change of 10 mg / kg body weight can be carried out every 2 weeks. The minimum effective dose should be used.
Doses for children weighing 50 kg or more is the same as for adults.
Recommended doses for children from 6 months of age 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 over 4 years of age, treatment should be started with a daily dose of 20 mg / kg weight body divided into 2 doses (10 mg / kg body weight 2 times / day). A dose change of 20 mg / kg body weight can be carried out every 2 weeks until the recommended daily dose is reached – 60 mg / kg body weight (30 mg / kg body weight 2 times / day). If you are intolerant of the recommended daily dose, it may decrease. The minimum effective dose should be used.
Prescribe the drug in the most suitable dosage form and dose, depending on the patient’s body weight and the required therapeutic dose.
Children with body weight? 20 kg is recommended to begin treatment with the drug in the form of a solution for oral administration.
For children weighing> 50 kg, dosing is carried out 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 begin treatment with a daily dose of 1 g divided into 2 doses (500 mg 2 times / day). Depending on the clinical reaction and 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 prescribing the drug to elderly patients and patients with renal failure, the dose should be adjusted depending on the size of the CC.
KK can be calculated based on the concentration of serum creatinine, according to the following formula.
For men:
QC (ml / min) = [140-age (years)]? body weight (kg) / 72? serum creatinine (mg / dl)
For women: obtained value x 0.85
Renal failure KK (ml / min) Dose and frequency of administration of
Normal> 80500-1500 mg 2 times / day
Latent 50-79500-1000 mg 2 times / day
Compensated 30-49250-750 mg 2 times / day
Intermittent 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 ®, a saturating 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, using the recommendations given for adults.
Patients with impaired liver function of mild to moderate severity dosage adjustment is not required. In patients with decompensated impaired liver function and renal failure, the QC value may not reflect the true degree of renal dysfunction, therefore, with
KK Rules for the use of the drug
Tablets should be taken orally with a sufficient amount of liquid, regardless of food intake.
Dosing of the solution is 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), which is included in the delivery package. A measured dose of the drug is diluted in a glass of water (200 ml).
To dispense a solution using a measuring syringe, open the vial: to do this, click on the cap and turn it counterclockwise. 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 by pulling the piston down, then push the piston up to remove air bubbles. Pulling the piston, fill the syringe with the solution until the division corresponds to the number of ml of the solution prescribed by the doctor. Pull the syringe out of the adapter. Insert the contents of the syringe into a glass of water, pushing the piston all the way. You should drink all the contents of the glass. Then flush the syringe with water and close the bottle with a plastic cap.
Side effects of
Possible side effects are listed below on the body systems and frequency of occurrence: very often (> 1/10), often (> 1/100,
from the central nervous system: very often drowsiness, asthenic syndrome often amnesia, ataxia , convulsions, dizziness, headache, hyperkinesia, tremors, imbalance, decreased concentration, memory impairment, agitation, depression, emotional lability, moodiness, hostility / aggressiveness, insomnia, nervousness, irritability, frustration personalities, impaired 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, impaired accommodation.
From the respiratory system: often – increased coughing.
From the digestive system: often – abdominal pain, diarrhea, dyspepsia, nausea, vomiting, anorexia, weight gain in some cases – pancreatitis, liver failure, hepatitis, changes in functional liver tests, weight loss.
Dermatological reactions: often – a skin rash, eczema, itching in some cases – alopecia (in some cases, hair restoration was observed after drug withdrawal), Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.
From the hemopoietic system: in some cases – leukopenia, neutropenia, pancytopenia (in some cases with inhibition of bone marrow function), thrombocytopenia.
Other: in some cases – infections, nasopharyngitis, myalgia.
Drug Interaction
No clinically relevant interactions with other drugs have been identified. disopyramide) and class III (including amiodarone, sotalol, dofetilide, ibutilide), some neuroleptics (including thioridazine, chlorpromazine, levomepromazine, trifluoperazine, ciamemazine, sulpiride, thiapride, pimozide, other pimozide) drugs (including bepridil, cisapride, difemanil, erythromycin, misolastin, vincamine, halofantrine, sparfloxacin, gatifloxacin, moxifloxacin, pentamidine, spiramycin). The risk of ventricular arrhythmias is increased, especially the development of pirouette arrhythmias. If the combination of drugs can not be avoided, before the appointment to monitor the QT interval and begin monitoring the ECG. Ethanol enhances the sedative effects of neuroleptics. Consumption of alcoholic beverages and the use of medicines containing alcohol should be avoided.
Irbesartan
Based on in vitro studies, no interaction with the metabolites of which is carried out with the participation of isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2A4 or CYP2E4, should be expected.
Irbesartan is predominantly metabolised by the CYP2C9 isoenzyme, however, no significant pharmacokinetic interaction was observed during the interaction studies when irbesartan was administered concomitantly with warfarin metabolised by CYP2C9 isoenzyme.
The pharmacokinetic parameters of irbesartan do not change when co-administered with nifedipine and hydrochlorothiazide.
Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized by the CYP3A4 isoenzyme, or digoxin (a substrate of β-glycoprotein).
The combination of Aprovask ® with aliskiren containing medicinal products is contraindicated in patients with diabetes mellitus or moderate and severe renal failure (GFR <60 ml / min / 1.73 m2 body surface area) and is not recommended in other patients. The use of Aprovask ® in combination with ACE inhibitors is contraindicated in patients with diabetic nephropathy and not recommended for other patients. Based on the experience of using other drugs that affect RAAS, the concomitant use of potassium-sparing diuretics, potassium or salt containing potassium may increase serum potassium concentration. In elderly patients, patients with hypovolemia (due to diuretics) or with impaired renal function, concomitant use of NSAIDs, Irbesartan Based on in vitro studies, no interaction with the metabolites of which is carried out with the participation of isoenzymes: CYP1A1, CYP1A2, CYP2A6, CYP2B6, CYP2D6, CYP2A4 or CYP2E4, should be expected. Irbesartan is predominantly metabolised by the CYP2C9 isoenzyme, however, no significant pharmacokinetic interaction was observed during the interaction studies when irbesartan was administered concomitantly with warfarin metabolised by CYP2C9 isoenzyme. The pharmacokinetic parameters of irbesartan do not change when co-administered with nifedipine and hydrochlorothiazide. Irbesartan does not alter the pharmacokinetics of simvastatin, which is metabolized by the CYP3A4 isoenzyme, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone). Levetiracetam at a daily dose of 1 g does not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel). Levetiracetam at a daily dose of 2 g does not alter the pharmacokinetics of warfarin and digoxin. Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of levetiracetam. When co-administered with topiramate, anorexia is more likely to develop. The absorption completeness of levetiracetam does not change under the influence of food, with the absorption rate slightly decreasing. There are no data on the interaction of levetiracetam with alcohol. Overdose Symptoms: drowsiness, anxiety, aggressiveness, depression of consciousness, respiratory depression, coma. Treatment: in the acute period – an 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 is carried out in a hospital setting using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite – 74%). Storage conditions Tablets should be stored in a dry place at a temperature not exceeding 25 ° C The solution for oral administration should be stored in a dark place at a temperature not exceeding 30 ° C. Store the concentrate for the preparation of infusion solutions in a dark place at a temperature of no higher than 25 ° C. Keep out of the reach of children. Expiration 3 years. Concentrate for preparation of solution for infusions – 2 years. dosage form dosage form infusion solution YUSB Farma Belgium
