Levetiracetam Canon, 1000 mg 30 pcs

Pharmacodynamics

Levetiracetam is a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide) and differs from known antiepileptic drugs by chemical structure. 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 and in vivo experiments have shown that levetiracetam does not affect basic cell characteristics and normal transmission. In in vitro studies it has been shown to affect intraneuronal Ca2+ ion concentration by partially inhibiting Ca2+ ion current through N-type channels and reducing calcium release from intraneuronal depots.

In addition, it partially restores currents through GABA- and glycine-dependent channels reduced by zinc and carbolines. One putative mechanism is based on the proven binding to the synaptic glycoprotein SV2A vesicles contained in the gray matter of the brain and spinal cord. It is believed that this is the way the anticonvulsant effect is realized, which is expressed in the counteraction of hypersynchronization of neuronal activity.

Levetiracetam also acts on GABA receptors and glycine receptors, modulating these receptors through various endogenous agents. The drug does not alter normal neurotransmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculline and excitation of glutamate receptors.

The activity of the drug has been confirmed against both focal and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal response).

Pharmacokinetics

No dependence of pharmacokinetics on sex, race and time of day was observed.

Intake.

Levetiracetam is well absorbed from the gastrointestinal tract after oral administration. Levetiracetam is well soluble in water and has high permeability.

The absorption is complete and linear, so that plasma concentrations can be predicted based on the dose of levetiracetam taken, expressed in mg/kg body weight. The degree of absorption is independent of the dose and time of ingestion.

The bioavailability is approximately 100%. The maximum plasma concentration (Cmax) is reached 1.3 hours after oral administration of levetiracetam in a dose of 1000 mg and is 31 µg/ml in a single dose, after repeated administration (twice daily) – 43 µg/ml. The equilibrium state is reached after 2 days with twice-daily administration of the drug.

Distribution.

The binding of levetiracetam and its main metabolite to plasma proteins is less than 10%. The volume of distribution (Vd) is approximately 0.5-0.7 L/kg, which is approximately the volume of water in the body.

There are no data on the distribution of the drug in tissues.

Metabolism.

Levetiracetam is poorly metabolized in the human body.

The major metabolic pathway (24% of the dose taken) is enzymatic hydrolysis of the acetamide group. The formation of the primary metabolite (ucb L057) occurs without the participation of hepatic cytochrome P450. The metabolite ucb L057 is pharmacologically inactive. Levetiracetam does not affect the enzymatic activity of hepatocytes.

Under in vitro conditions, levetiracetam and its major metabolite did not inhibit major forms of cytochrome P450 (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1, 1A2) or glucuronyl transferase (UGT1A1, UGT1A6) and epoxide hydroxylase activity. Did not affect glucuronidation of valproic acid in vitro.

Elimination.

The elimination half-life (T1/2) from adult blood plasma is 7±1 h and is independent of the route of administration and dosing regimen. Mean value of the total clearance is 0.96 ml/min/kg. 95% of the drug is excreted by the kidneys. Renal clearance of levetiracetam and its metabolite is 0.6 and 4.2 ml/min/kg, respectively.

Pharmacokinetics in special clinical cases

Elderly patients

The T1/2 in elderly patients is increased by 40% and is 10-11 h, which is associated with impaired renal function in this category of people.

Renal impairment

In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with creatinine clearance. Therefore, in patients with renal impairment, it is recommended that the dose be adjusted according to creatinine clearance (see section “Dosage and administration”).

In end-stage renal failure in adult patients the T1/2 is 25 h between dialysis sessions and 3.1 h during dialysis. Up to 51% of levetiracetam is removed during a 4-hour dialysis session.

Hepatic impairment

In patients with mild to moderate hepatic impairment, there are no significant changes in the clearance of levetiracetam. In most patients with severe hepatic impairment with concomitant renal impairment, levetiracetam clearance is reduced by more than 50%.

Children aged 4-12 years

After a single dose of 20 mg/kg, the T1/2 in children aged 4-12 years is 6 hours. Total clearance of levetiracetam in children 4-12 years old is approximately 30% higher and is in direct correlation with body weight.

After repeated administration of the drug at a dose of 20-60 mg/kg body weight in children 4-12 years of age, the maximum plasma concentration is reached after 0.5-1.0 hours and increases linearly and in proportion to the dose.

Indications

As monotherapy (first choice drug) in the treatment

As part of complex therapy in the treatment of

Partial seizures with or without secondary generalization in adults and children over 6 years of age with epilepsy;

myoclonic seizures in adults and adolescents over 12 years of age with juvenile myoclonic epilepsy;

primary generalized seizures (tonic-clonic) in adults and adolescents over 12 years of age with idiopathic generalized epilepsy.

Active ingredient

Composition

1 film-coated tablet contains:

the active substance:

excipients:

calcium stearate 12.0 mg,

colloidal silicon dioxide 12.0 mg,

How to take, the dosage

Overly with plenty of fluid, regardless of meals, 2 times a day.

Adults and adolescents over 16 years old start dose of 500 mg 2 times daily, from the first day of treatment. Depending on clinical reaction and tolerability the daily dose can be increased up to 1500 mg 2 times per day (it is possible to increase the dose by 500 mg every 2-4 weeks).

Elderly persons and patients with CKD are recommended to choose the dose individually. In normal renal function and IQ over 80 ml/min the recommended dose and frequency of administration are from 500 to 1500 mg 2 times a day, in mild renal failure and IQ 50-79 ml/min – from 0.5 to 1 g 2 times a day, in moderate renal failure and IQ 30-49 ml/min – from 250 to 750 mg 2 times a day, in severe renal failure and IQ less than 30 ml/min – from 250 to 500 mg 2 times a day.

In terminal stage of CKD – from 0.5 to 1 g once daily, after dialysis an additional dose of 250 to 500 mg is recommended. For patients on dialysis, a saturation dose of 750 mg is recommended on the first day of treatment with levetiracetam.

In severe hepatic impairment and CK less than 70 ml/min, a 50% reduction in the daily consumed dose.

Interaction

Anticonvulsants

According to pre-registration clinical studies, levetiracetam has no effect on the serum concentrations of other anticonvulsant medications: phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone – and these anticonvulsant drugs do not affect the pharmacokinetics of levetiracetam.

However, there is evidence that the clearance of levetiracetam in children taking anticonvulsant drugs that induce microsomal liver enzymes is increased by 22%.

Probenecid

Probenecid (500 mg 4 times daily) is a blocker of renal tubular secretion and has been shown to inhibit renal clearance of the main metabolite but not levetiracetam. However, the concentration of the main metabolite remains low.

It is expected that other drugs that are excreted by active tubular secretion may decrease the renal clearance of the main

metabolite. The effect of levetiracetam on probenecid has not been studied; the effect of levetiracetam on other drugs that are excreted by active tubular secretion, including nonsteroidal anti-inflammatory drugs, sulfonamide and methotrexate, is not known.

Peroral contraceptives and other pharmacokinetic interactions

Levetiracetam at a dose of 1000 mg daily had no effect on the pharmacokinetics of oral contraceptives (ethinylestradiol and levonorgestrel); hormonal status (luteinizing hormone and progesterone levels) was not changed.

Levetiracetam at a dose of 2000 mg daily had no effect on the pharmacokinetics of digoxin and warfarin; prothrombin time was not altered. Concomitant use of digoxin, oral contraceptives and warfarin had no effect on the pharmacokinetics of levetiracetam.

Antacids

There are no data on the effect of antacids on the absorption of levetiracetam.

Food and alcohol

Food does not affect the degree of absorption of levetiracetam, but slightly reduces its rate. There are no data on the interaction of levetiracetam with ethanol.

Special Instructions

Cancellation of therapy

Cancellation of the drug is recommended to be done gradually. For example, in adults and adolescents with a body weight greater than 50 kg, the dose should be reduced in increments of 500 mg 2 times daily no more frequently than every 2-4 weeks; in children, the dose should be reduced in increments of no more than 10 mg/kg 2 times daily no more frequently than every two weeks.

The concomitant antiepileptic drugs (during transfer of patients to levetiracetam therapy) should preferably be withdrawn gradually.

Renal failure

The use of levetiracetam in patients with renal impairment may require dose adjustment. In patients with severe hepatic impairment, it is recommended that renal function be assessed prior to dose adjustment (see section Dosage and administration).

Suicide

Patients who have taken anticonvulsants (including levetiracetam) have reported suicide, suicide attempts, suicidal thoughts and behavior. Because of the above, patients with symptoms of depression or suicidal thoughts and behavior should be monitored and appropriate therapy should be prescribed.

Patients (and their caregivers) should be informed to seek care when they have symptoms of depression and/or suicidal thoughts and behaviors.

Children

The tablets are not intended for use in children under 6 years of age. For children under 6 years of age, the recommended dosage form is oral solution.

Levetiracetam is not reported to affect growth and puberty. However, long-term effects on learning, intelligence, growth, endocrine function, puberty and fertility in children are not known.

The effect of levetiracetam on driving and operating ability

The effect of levetiracetam on driving and operating ability has not been specifically studied.

Perhaps somnolence and other central nervous system disturbances may occur in some patients, particularly at the beginning of therapy and after increasing the dose, due to varying individual sensitivities to the drug.

Hence, it is recommended to refrain from driving and engaging in potentially hazardous activities requiring increased concentration and quick psychomotor reactions.

Contraindications

Hypersensitivity to levetiracetam or other pyrrolidone derivatives or to any of the drug components.

With caution:

decompensated liver disease;

renal failure (creatinine clearance less than 50 ml/min).

Side effects

Safety Profile Summary

The adverse event profile presented below is based on an analysis of pooled placebo-controlled clinical trials of levetiracetam for all indications, as well as post-registration data.

The most commonly reported adverse reactions were nasopharyngitis, drowsiness, headache, fatigue, and dizziness. The safety profile of levetiracetam generally did not differ by age (in adults and children).

WHO classification of the incidence of side effects:

very common – ≥1/10 prescriptions (>10%)

frequent – ≥1/100 to < 1/10 appointments (>1% and <10%)

infrequent – ≥1/1000 to <1/100 appointments (>0.1% and <1%)

rarely – ≥1/10000 to <1/1000 appointments (>0.01% and <0.1%)

very rarely – <1/10000 appointments (<0.01%)

Infectious and parasitic diseases

Very common: nasopharyngitis.

Rarely: infections.

Blood and lymphatic system disorders

Infrequent: thrombocytopenia, leukopenia.

Rarely: pancytopenia, agranulocytosis, neutropenia.

Immune system disorders

Rarely: drug reaction with eosinophilia and systemic manifestations (DRESS).

Metabolic and nutritional disorders

Often: anorexia.

Infrequent: decrease or increase in body weight.

Rarely: hyponatremia.

Mental disorders

Often: depression, hostility/aggressiveness, insomnia, nervousness, irritability.

Infrequent: suicide attempts, suicidal ideation, psychotic disorders, behavioral disorders, hallucinations, anger, confusion, emotional lability/mood changes, agitation, panic attacks.

Rarely: suicide, personality disorder, impaired thinking.

Nervous system disorders

Very common: drowsiness, headache.

Often: seizures, dizziness, tremor, loss of balance, lethargy.

Infrequent: impaired coordination of movements or ataxia, amnesia, attention deficit disorder, memory impairment, paresthesia.

Rarely: choreoathetosis, dyskinesia, hyperkinesia.

Visual disorders

Infrequent: diplopia, accommodation disorder.

Hearing organ and labyrinth disorders

Often: vertigo.

Respiratory system disorders

Often: cough.

Gastrointestinal disorders

Often: abdominal pain, diarrhea, dyspepsia, nausea, vomiting.

Rarely: pancreatitis.

Liver and biliary tract disorders

Infrequent: changes in liver function tests.

Rarely: liver failure, hepatitis.

Skin and subcutaneous tissue disorders

Often: skin rash.

Infrequent: eczema, itching, alopecia.

Rarely: toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Muscular and connective tissue disorders

Infrequent: muscle weakness, myalgia.

General disorders:

Often: asthenia/fatigue

Injuries, complications of procedures:

Infrequent: accidental injury

Description of individual adverse reactions

The risk of anorexia increases when topiramate and levetiracetam are used concomitantly.

In some cases, alopecia has reversed after withdrawal of levetiracetam.

In some patients with pancytopenia, bone marrow suppression has been detected.

Children

The profile of adverse events of levetiracetam does not generally differ by age (in adults and children), nor does it depend on the approved indication for use (epilepsy variants).

With the exception of behavioral and psychiatric adverse reactions, which occurred more often in children than in adults, the safety profile of levetiracetam in children was comparable to that of adults in placebo-controlled studies.

In children aged 4-16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood changes (common, 2.1%), emotional lability (common, 1.7%), aggression (common, 8.2%), conduct disorder (common, 5.6%) and lethargy (common, 3.9%) were reported more frequently than in other age groups and the overall safety profile. In children aged 1 month to 4 years, irritability (very common, 11.7%) and impaired movement coordination (common, 3.3%) were reported more frequently than in other age groups and the overall safety profile.

The cognitive and neuropsychological effects of levetiracetam in children 4-16 years of age with partial seizures were evaluated in double-blind, placebo-controlled safety profile studies. Levetiracetam was shown to be no different (no less safe) than placebo in changes from baseline on the Leiter-R Attention and Memory scale, Memory Screen Composite scale

in patients subjected to the protocol analysis. Behavioral and emotional findings confirming that levetiracetam causes aggressive behavior were obtained using a standardized method using a validated instrument, the Achenbach Child Behavior Checklist.

However, patients who took levetiracetam long-term in open-label studies did not show abnormal behavioral or emotional functioning, and in particular aggressive behavior did not differ from baseline.

Overdose

Symptoms: drowsiness, agitation, aggressiveness, anxiety, depression of consciousness, respiratory depression, coma.

Treatment: in the acute period – artificial vomiting and gastric lavage, followed by administration of activated charcoal.

There is no specific antidote for levetiracetam. If necessary, symptomatic treatment under hospital conditions with hemodialysis is carried out (dialysis efficiency for levetiracetam is 60%, for its primary metabolite -74%).

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