Epitera - instructions for use, doses, side effects, contraindications

Composition:In 1 tablet 250 mg contains: active substance levetiracetam 250.0 mg; auxiliary substances: corn starch 34.0 mg, povidone (PVP K-30) 8.0 mg, croscarmellose sodium 37.0 mg, magnesium stearate 3.0 mg; film sheath Oiadrai 03F20667 blue 9.0 mg (hypromellose 6 cf (HPMC 2910) 5.63 mg, titanium dioxide (E171) 2.27 mg, macrogol-3350 0.56 mg, blue diamond dye (E133) 0.36 mg, indigo carmine (E132) 0.18 mg).
In 1 tablet 500 mg contains: active substance levetiracetam 500.0 mg; Excipients: corn starch 68.0 mg, povidone (PVP K-30) 16.0 mg, croscarmellose sodium 74.0 mg, magnesium stearate 6.0 mg; film sheath Opaprai 03B220001 yellow 18.0 mg (hypromellose 5 cf (HPMC 2910) 11.52 mg, titanium dioxide (E171) 5.2866 mg, macrogol-400 1.08 mg, iodicarbamine (EI32) 0.0054 mg, iron oxide dye yellow (E172) 0.108 mg).
In 1 tablet 1000 mg contains: the active substance levetiracetam 1000.0 mg; Excipients: corn starch 136.0 mg, povidone (PVP K-30) 32.0 mg, croscarmellose sodium 148.0 mg, magnesium stearate 12.0 mg; film sheath Opaprai 03F18435 white 36.0 mg (hypromellose 6 cf (HPMC 2910) 22.04 mg, titanium dioxide (E171) 6.62 mg, macrogol-3350 7.34 mg).

Description:Dosage of 250 mg. Oblong tablets covered with a film coating of blue color, engraved "7285" on one side and "9" and "3" on the other hand, separated by a risk.
Dosage of 500 mg. Oblong tablets covered with a yellow film cover, engraved with "7286" on one side and "9" and "3" on the other side, separated by a risk.
Dosage of 1000 mg. Oblong tablets covered with a white film shell, engraved "7493" on one side and "9" and "3" on the other hand, separated by a risk.
On the break, the tablets are white or almost white (all dosages).

Pharmacotherapeutic group:Antiepileptic agent.

ATX: & nbsp

N.03.A.X Other antiepileptic drugs

N.03.A.X.14 Levetiracetam

Pharmacodynamics:Levetiracetam is a derivative of pyrrolidone (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from known antiepileptic drugs.
The mechanism of action of levetiracetam has not been completely studied, but it is clear that it differs from the mechanism of action of known antiepileptic drugs. In vitro and in vivo studies have shown that levetiracetam does not affect the basic characteristics of cells and normal transmission.
In vitro studies have shown that levetiracetam affects the intra-neuronal concentration of Ca²⁺, partially inhibiting the current of Ca²⁺ through N-type channels and reducing the release of calcium from intra-neuronal depots. Besides, levetiracetam partially restores the ion currents through the gamma-aminobutyric acid (GABA) - and glycine-dependent channels, reduced zinc and 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 the anticonvulsant effect is realized in this way, which is expressed in counteracting the hypersynchronization of neuronal activity. Same levetiracetam affects the receptors of GABA and glycine receptors, modulating these receptors through various endogenous agents. It does not alter normal synaptic transmission, but inhibits neuronal epileptiform flash-induced GABA-agonist bikukulinom and excitement of glutamate receptors. Levetiracetam prevents the development of convulsions in various experimental models of focal and primary generalized seizures without a proconvulsive effect. In humans, the activity of levetiracetam has been confirmed both with focal,and in generalized epileptic seizures (epileptiform manifestations, photoparoximal reaction).

Pharmacokinetics:There was no dependence of pharmacokinetics on sex, race and time of day.
A significant correlation was found between the concentrations of levetiracetam in plasma and in the saliva of adults and children (the ratio of salivary / plasma levetiracetam concentrations ranges from 1 to 1.7 for oral tablets and for oral administration 4 hours after ingestion).
Suction. After oral administration levetiracetam is well absorbed from the gastrointestinal tract (GIT). Absorption occurs completely and is linear in nature. so that the concentration in the blood plasma can be predicted based on the dose of levetiracetam taken, expressed in mg / kg of body weight. The degree of absorption of levetiracetam does not depend on the dose and time of ingestion. Absolute bioavailability is approximately 100%.
The maximum concentration of the drug in the blood plasma (C_max) is achieved after 1.3 hours after oral administration of levetiracetam in a dose of 1000 mg and at a single admission is 31 μg / ml, after repeated administration (2 times per day) -43 μg / ml.The equilibrium state is achieved after 2 days with a two-time intake of the drug.
After oral administration levetiracetam well absorbed from the gastrointestinal tract (GIT). 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. Biostability is about 100%.
After taking levetiracetam in a dose of 1 g, the maximum concentration in the blood plasma (C_max) is achieved after 1.3 hours and is 31 μg / ml, after repeated administration (2 times a day) - 43 μg / ml.
Distribution. Equilibrium concentration in the plasma is achieved after two days with a two-time administration of levetiracetam. The association with plasma proteins of levetiracetam and its main metabolite is less than 10%. The volume of distribution (V_d) levetiracetam is about 0.5-0.7 l / kg, which approximately corresponds to the volume of water in the body.
Metabolism. The formation of the primary pharmacologically inactive metabolite (ucb L057) occurs without the participation of cytochrome P450 isoenzymes. The main way of metabolism is the hydrolysis of the acetamide group (24% of the dose). Levetiracetam does not affect the enzymatic activity of hepatocytes.
In vitro, as well as in vivo levetiracetam and its primary metabolite did not suppress the activity of cytochrome P450 isoenzyme systems (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and IA2), glucuronyltransferase (UGT1A1 and UGT1A6), and epoxy hydroxylase. In addition, in vitro levetiracetam does not affect the glucuronidation of valproic acid.
In human hepatocyte culture levetiracetam had little or no effect on the activity of the isoenzymes СUR1А2, SULT1E1 and UGT1A1. Levetiracetam weakly induced the activity of isoenzymes SUR2B6 and SURZA4.
Data on the drug interaction with oral contraceptives, digoxin and warfarin in vitro and in vivo show that significant induction of enzymes in vivo is not expected. Therefore, the interaction of levetiracetam with other substances or the interaction of other substances with levstiracetam is unlikely.
Excretion. In adults, the half-life (T_1/2) from the blood plasma is 7 ± 1 h and does not change depending on the dose, method of administration or repeated administration. The average overall clearance is 0.96 ml / min / kg. 95% of the drug is excreted by the kidneys (of which 93% of the dose is excreted within 48 hours). Excretion with faeces is only 0.3% of the dose.
The total excretion of levetiracetam and its main metabolite is 66 and 24%, respectively, of the dose taken within the first 48 hours.The renal clearance of leucetiracetam and its metabolite ucb L057 is 0.6 and 4.2 ml / min / kg, respectively, which indicates the excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and the main metabolite, along with glomerular filtration by active tubular secretion.
Elimination of levetiracetam correlates with creatinine clearance (CC). 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 patients with renal insufficiency, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance (CC). Therefore, in patients with renal insufficiency, dose selection is recommended depending on the CK. In the terminal stage of renal failure in adult patients, T_1/2 is 25 hours between sessions and 3.1 hours during dialysis. In the course of 4-hour dialysis, 51% of levetiracetam is removed from the body.
In patients with malfunctioning liver function of light and moderate degree, no significant changes in the clearance of levetiracetam have been detected.If liver function is severely affected, the clearance of levetiracetam is reduced by more than 50% because of concomitant renal failure.
The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg / kg / day, C_max is achieved after 0.5-1 h. T_1/2 in children aged 4-12 years 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 in direct proportion to body weight.

Indications:Monotherapy
Partial seizures with secondary generalization or without it in adults and children over 16 years old with newly diagnosed epilepsy.
In the complementary therapy
- Partial seizures with secondary generalization or without it in adults and children over 6 years with epilepsy.
- Myoclonic seizures in adults and children over 12 years with juvenile myoclonic epilepsy.
- Primary-generalized convulsive (tonic-clonic) seizures in adults and children over 12 years with idiopathic generalized epilepsy.

Contraindications:Hypersensitivity to levetiracetam, to derivatives of pyrrolidone or other components of the drug, children up to 6 years of age.

Carefully:Dysfunction of the liver of a severe degree; kidney failure; patients older than 65 years.

Pregnancy and lactation:In post-marketing data obtained from several prospective pregnancy registries, more than 1,000 cases of monotherapy of levetiracetam in the first trimester of pregnancy were recorded.
In general, these data do not indicate a significant increase in the risk of serious congenital malformations.
Teratogenic damage can not be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, so monotherapy in pregnant women is more appropriate. Adequate and strictly controlled clinical studies but safety of levetiracetam in pregnant women has not been carried out, therefore Epitera is used during pregnancy only if the expected benefit for the mother exceeds the possible risk to the fetus. Physiological changes in the body of a woman during pregnancy can affect the concentration of levetiracetam, like other antiepiletic drugs, in blood plasma.During pregnancy, there was a decrease in the concentration of levetiracetam in the blood plasma. This decrease was expressed in the third trimester of pregnancy (up to 60% of the baseline concentration during the third trimester). The use of levetiracetam in 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 can harm the health of both the mother and the fetus. Levetiracetam excreted in breast milk, so the use of Epitera during breastfeeding is not recommended. However, when levetiracetam is needed during breastfeeding, the benefit / risk ratio of treatment should be evaluated in view of the importance of breastfeeding.
In animal studies, levetiracetam has not been shown to affect fertility. Clinical evidence of the effect of levetiracetam on fertility is not available, the possible risk to humans is unknown.

Dosing and Administration:Inside, squeezed enough fluids, regardless of food intake. The daily dose is divided into 2 equal parts for reception 2 times a day.
Monotherapy
Adults and children over 16 years of age. The initial dose is 500 mg. divided into 2 doses (250 mg twice a day). After 2 weeks of therapy, depending on the individual response and tolerability, the daily dose can be increased to the initial therapeutic dose of 1 g (500 mg twice a day).
The maximum daily dose is 3 g (1.5 g twice a day).
In the complementary therapy
Adults and children over 12 years of age with a body weight of more than 50 kg. The initial dose is 1 g divided into 2 doses (500 mg twice a day
day). Depending on the clinical response and tolerability, the daily dose can be increased to a maximum dose of 3 g (1.5 g twice daily). A dose change of 500 mg 2 times a day can be carried out every 2-4 weeks.
Children older than 6 years with a body weight of less than 50 kg.
The initial dose of 20 mg / kg body weight divided into 2 doses (10 mg / kg body weight 2 times a day). Depending on the clinical response and tolerability, 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 a day). With intolerance of the recommended daily dose, it is possible to reduce it. The minimum effective dose should be used.The drug should be used in the most suitable dosage form and dosage depending on the patient's body weight and the required therapeutic dose.
In children weighing less than 25 kg, when a dose of less than 250 mg / day is needed and in patients who have difficulty swallowing, the use of levetiracetam in the form of a drug for oral administration is recommended.
In children with a body weight of more than 50 kg, the dosing of the drug is carried out according to the scheme for adults.

Massa bodiesa

Initiallydose

10 mg / kg twice daily

The maximum dose

30 mg / kg 2 times a day

25-50 kg

125 mg twice daily

375 mg twice daily

More than 50 kg

250 mg twice a day

750 mg twice a day

Elderly patients and patients with renal insufficiency should be adjusted for dose depending on QC.
QA can be calculated from the serum creatinine concentration, according to the following formula.
For men:
CK (ml / min) = [140-yr (years)] x body weight (kg) / 72 x creatinine concentration (mg / dl)
For women: multiply that value by 0.85.
Then, the SC is correlated with the body surface area (PPT) according to the following formula:

KK (ml / mn / 1.73 m²) = KK (ml / min) / PPT (m²)

Doses for use in adults and children weighing more than 50 kg

Renal failure	QC (ml / min)	Dose and multiplicity of admission
Norm	more than 80	500-1500 mg 2 times a day
Easy degree	50-79	500-1000 mg twice daily
Average degree	30-49	250-750 mg 2 times a day
Heavy Degree	less than 30	250-500 mg 2 times a day
Terminal stage (patients on hemodialysis)		500-1000 mg once a day²

¹On the first day of treatment with the drug Epitera, a saturating dose of 750 mg is recommended.

²After dialysis, an additional 250-500 mg dose is recommended.

In children with kidney failure, dose adjustment is performed taking into account the degree of renal failure, using the recommendations obtained in studies of adult patients with renal insufficiency.
QC can be assessed by determining the creatinine concentration (mg / dL) for children using the Schwartz formula:

KK (ml / min / 1,73 m²) = Height (cm) x ks / creatinine concentration (mg / dl)

ks = 0.55 for children under 13 and for females over 13;
ks = 0.7 for male children over 13 years of age.
Doses for use in children weighing less than 50 kg

Renal failure	QC (ml / min / 1.73 m²)	Dose and multiplicity of admission
Norm	more than 80	10-30 mg / kg 2 times a day
Lightweight power	50-79	10-20 mg / kg 2 times a day
Average power	30-49	5-15 mg / kg 2 times per day
Heavy power	less than 30	5-10 mg / kg 2 times a day
Terminal stage (Patients, on hemodialysis)	-	10-20 mg / kg once a day^1,2

¹ On the first day of treatment with Epitera, a saturating dose of 15 mg / kg is recommended.
²After dialysis, an additional dose of 5-10 mg / kg is recommended.
Patients with a mild or moderate liver function disorder are not required to adjust the dosing regimen. In patients with impaired hepatic function, the severity of QA may not reflect the true extent of renal dysfunction, so with a CC of less than 60 ml / min / 1.73 m² it is recommended to reduce the daily dose by 50%.

Side effects:The safety profile presented below is based on an analysis of the results of clinical trials and the experience of post-marketing use. The most frequent adverse reactions were nasopharyngitis, drowsiness, headache, fatigue and dizziness. The profile of levetiracetam is generally similar for different age groups of adults and children.
Side effects are classified according to the following frequency: very often (≥ 1/10); often (≥1 / 100, <1/10); infrequently (≥1 / 1000, <1/100); rarely (≥1 / 10000, <1/1000); very rarely (<1/10000).
Infections and infestations: very often nasopharyngitis; rarely - infection.
From the side of the blood and lymphatic system: infrequently - leukopenia, thrombocytopenia; rarely - nantitopenia, neutropenia, agranulocytosis.
From the immune system: rarely a drug reaction with eosinophilia and systemic manifestations (DRESS-syndrome).
From the side of metabolism and nutrition: often - anorexia; infrequently - weight gain, weight loss; rarely hiponatremia.
Mental disturbance: often - depression, hostility / aggressiveness, anxiety, insomnia, nervousness / irritability; infrequently - suicidal attempt, suicidal ideation, psychotic disorder, behavioral disorder, hallucinations, anger, confusion, emotional lability / mood swings, agitation, panic attack; rarely - suicide, personality disorder, violation of thinking.
From the nervous system: very often - drowsiness, headache; often - convulsions, imbalance, dizziness, lethargy, tremor; infrequently - amnesia, memory impairment, impaired coordination / ataxia, paresthesia, decreased concentration of attention; rarely choreoathetosis, dyskinesia, hyperkinesia.
From the side of the organ of vision: infrequently, diplopia, blurred vision.
From the organ of hearing: often - vertigo.
From the respiratory system: often - a cough.
From the digestive tract: often - abdominal pain, diarrhea, indigestion, vomiting, nausea; pancreatitis.
From the liver and bile ducts: infrequently - change of functional samples; rarely - hepatic insufficiency, hepatitis.
From the skin and subcutaneous tissues: often - skin rash: infrequently - itching. eczema, alopecia; rarely - toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.
From the side of the musculoskeletal and connective tissue: infrequently - myalgia, muscle weakness.
Other: often asthenia / fatigue; infrequently - accidental damage.
The risk of anorexia is higher with the simultaneous use of levetiracetam and topiramate.
There are reports of the restoration of the hair follicle after the cancellation of levetiracetam. Some cases of pancytopenia were accompanied by oppression of bone marrow function. The safety profile of levetiracetam in children is comparable to that of adults. Vomiting was more frequent in children aged 4 to 16 years (very often, 11.2%), excitation (often.3.4%), mood swings (often, 2.1%), emotional lability (often, 1.7%), aggressiveness (often, 8.2%), behavioral disorders (often 5.6%), lethargy (often, 3.9%). In children from 1 month to 4 years old, irritability (very often, 11.7%) and impaired coordination (often, 3.3%) were more often recorded.
In a double-blind, controlled trial of levetiracetam in children with partial seizures aged 4 to 16 years, whose goal was to show that levetiracetam on safety is not inferior to placebo, cognitive and neuropsychological effects were evaluated. It was concluded that levetiracetam does not differ from placebo (not inferior to it) with respect to changes in the sum of scores in the "Warning and Memory" and "Combined Memory Screening" sections of the Leiter-R scale in patients who underwent a protocol study compared to the baseline visit.
As a result of the analysis of behavioral and emotional status with the help of a tool validated by Achenbach (Achenbach), aggressive behavior in the group of patients taking levetiracetam. However, patients receiving levetiracetam during long-term follow-up in the open phase of the study, did not demonstrate a worsening of the behavioral and emotional status, in particular. The indicators of aggressive behavior did not deteriorate compared to the baseline.

Overdose:Symptoms: drowsiness, agitation, aggression, oppression of consciousness, respiratory depression, coma.
Treatment: in the acute period - induction of vomiting, gastric lavage, reception of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment in a hospital using hemodialysis (dialysis efficiency for levetiracetam - 60%, for the primary metabolite - 74%).

Interaction:Levetiracetam does not affect the concentration of antiepileptic drugs (phenytoin, carbamazepine, valproic acid. phenobarbital, lamotrigine, gabapentin and primidon) in the blood plasma. In turn, these antiepileptic drugs do not affect the concentration of levetiracetam in the blood plasma. There are no data on clinically significant drug interactions in children who received levetiracetam in a dose of 60 mg / kg / day.A retrospective analysis of pharmacokinetic interactions in children aged 4-17 years with epilepsy confirmed that additional administration of levetiracetam does not affect the equilibrium plasma concentrations of concurrently taken carbamazepip and valproic acid. Nevertheless, the data show that the clearance of levetiracetam is 20% higher in children taking enzyme-induced antiepileptic drugs. Correction of the dose in these cases is not required.
Levetiracetam in a daily dose of 1000 mg does not change the pharmacokinetics of oral contraceptives of ethinylestradiol and levonorgestrel.
Levetiracetam in a daily dose of 2000 mg does not change the pharmacokinetics of warfarin and digoxin.
Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of levetiracetam.
Probenecid (500 mg 4 times a day) reduces the renal clearance of the primary metabolite of levetiracetam. It is assumed that drugs that are excreted from the body due to active renal secretion, are also able to reduce the clearance of the metabolite. The effect of levetiracetam on the propeptide and other drugs with a similar mechanism of induction(non-steroidal anti-inflammatory drugs, sulfonamides, methotrexate etc.) remains unclear.
There is no data on the effect of antacids on the absorption of levetiracetam.
Single reports were received on the reduction in the efficacy of levetiracetam when used simultaneously with osmotic laxatives macrogol. Macrogol should not be taken within 1 hour before and within 1 hour after taking levetiracetam.
The degree of absorption of levetiracetam does not change under the influence of food, while the rate of absorption is somewhat reduced.
Data on the interaction of levetiracetam with alcohol are absent.

Special instructions:In children younger than 6 years, the use of levetiracetam in the form of a drug for oral administration is recommended.
If it is necessary to discontinue therapy, it is recommended to cancel Epiterra preparation gradually, reducing the single dose by 500 mg every 2-4 weeks. In adults weighing less than 50 kg, it is recommended to reduce the dose by 20 mg / kg every 2 weeks. In children with a body weight of 25 to 50 kg, it is recommended to reduce the dose by 10 mg / kg every 2 weeks. The use of Epiterra in patients with impaired renal function may require a dose adjustment (seeSee "How to use"). In patients with severe hepatic dysfunction, it is recommended that a study of renal function before treatment be performed.
During the reception of the drug Epitera, there may be abnormalities from the CNS, including drowsiness, weakness, fatigue, psychotic and behavioral changes, especially in the first month of therapy. Therefore, at the beginning of the treatment, patients should be monitored especially carefully.
In patients receiving treatment with antiepileptic drugs (including levetiracetam), cases of suicide, suicidal attempts, suicidal thinking and behavior were reported. A meta-analysis of randomized trials of antiepileptic drugs under the control of placebo showed a slight increase in the risk of suicidal thoughts and behavior. The mechanism of this risk is unknown.
Thus, it is necessary to observe patients for signs of depression and / or suicidal thinking and behavior, and to consider suitable treatment. Patients (and caregivers) should be advised to seek medical help if there is evidence of depression and / or suicidal thinking or behavior.
When signs of depression and suicide attempts, patients and caregivers should consult a specialist.
It is recommended to gradually phase out concomitant anticonvulsant drugs during the period of transfer of the patient to Epitera.
In patients with partial seizures during treatment with the drug, there was a slight but statistically significant decrease in red blood counts, which does not require active clinical intervention. 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 of treatment on the ability of children to learn, their intellectual development, growth, endocrine gland functions, sexual development and fertility remain unknown.

Effect on the ability to drive transp. cf. and fur:There have been no studies on the impact on the ability to drive vehicles and work with mechanisms. Due to the possible varying individual sensitivity, some patients may experience drowsiness or other symptoms from the central nervous system, especially at the beginning of treatment or after increasing the dose.Thus, such patients need to be cautious in performing tasks such as driving a vehicle or a mechanism. Patients are advised not to drive the vehicle and do not use the mechanisms until the absence of influence on their ability is established.

Form release / dosage:Tablets, film-coated, 250 mg, 500 mg, 1000 mg.

Packaging:For 10 tablets in a blister of PVC / PVDC / aluminum foil.
3, 5 or 6 blisters together with instructions for use in a cardboard box.

Storage conditions:Store at a temperature not exceeding 25 ° C.
Keep out of the reach of children.

Shelf life:3 years.
Do not use after expiry date.

Terms of leave from pharmacies:On prescription

Registration number:LP-002104

Date of registration:17.06.2013

Expiration Date:17.06.2018

The owner of the registration certificate:Teva Pharmaceutical Enterprises Co., Ltd.Teva Pharmaceutical Enterprises Co., Ltd. Israel

Manufacturer: & nbsp

TEVA Pharmaceutical Industries, Ltd. Israel

Representation: & nbspTeva Teva Israel

Information update date: & nbsp2016-10-21

Illustrated instructions

Instructions

Epitera (Epiterra)