Keppra (Levetiracetam)

Tablets, coated with a blue film shell, oval, with biconvex surfaces, one of which has an engraving "ucb 500"; at kink - uniform, white

 1 tablet of veletiracetam dihydrochloride 500 mg

Excipients:

croscarmellose sodium

macrogol 6000,

silicon dioxide

magnesium stearate.

The composition of the film shell:

 Opadry 85F32004 (yellow iron oxide dye (E172), macrogol 3350, partially hydrolyzed polyvinyl alcohol, talc, titanium dioxide (E171)).

Solution:

Levetiracetam 100mg

Auxiliary substances:

sodium acetate trihydrate - 8.2 mg,

sodium chloride - 45 mg,

acetic acid 10% (up to pH 5.5),

water (up to 5 ml).

The antiepileptic drug, a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from most of the known antiepileptic drugs. The study of the mechanism of action of levetiracetam is not yet complete, but it is obvious that it differs from the mechanism of action of known antiepileptic drugs.

An in vitro study showed that levetiracetam affects the intranurial concentration of Ca2 + ions, partially inhibiting the flow of Ca2 + through N-type channels and decreasing the release of calcium from intneuronal 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 vesicles SV2A to the glycoprotein contained in the gray matter of the brain and spinal cord. It is assumed that this is how the anticonvulsant effect is realized, which is expressed in counteracting hypersynchronization of neural activity.

It does not alter normal neurotransmission, but it suppresses epileptiform neuronal outbreaks 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

Suction

After oral administration, levetiracetam is well absorbed from the digestive tract. Absorption is complete and linear, therefore, the plasma concentration can be predicted based on the applied dose of the drug 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 achieved after 1.3 hours and amounts to 31 μg / ml, after repeated administration (2 times / day) - 43 μg / ml.

Distribution

The 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.

Breeding

In adults, T1 / 2 from blood plasma is 7 ± 1 h and does not change depending on the dose, method of application or repeated administration. 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 kidney 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 violations of liver function with concomitant renal failure, the clearance of levetiracetam is reduced by more than 50%.

The pharmacokinetics of levetiracetam in children is linear in the dose range 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.

As monotherapy (first-choice drug) in the treatment of:

• partial seizures with or without secondary generalization in adults and adolescents over 16 years of age with newly diagnosed epilepsy.

As part of complex therapy in the treatment of:

• partial seizures with or without secondary generalization in adults and children over 4 years of age suffering from epilepsy (for tablets);
• partial seizures with or without secondary generalization in adults and children older than 1 month suffering from epilepsy (for solution);
• myoclonic seizures in adults and adolescents over 12 years old with juvenile myoclonic epilepsy;
• primary generalized convulsive (tonic-clonic) seizures in adults and adolescents over 12 years of age with idiopathic generalized epilepsy.

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 levetiracetam in pregnant women 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.

Use in children

Contraindicated: children under 4 years of age (for tablets) (safety and efficacy of the drug have not been established); children's age up to 1 month (for solution) (safety and efficacy of the drug have not been established);

• children's age up to 4 years (for tablets) (safety and efficacy of the drug have not been established);
• children's age up to 1 month (for solution) (safety and efficacy of the drug have not been established);
• violation of tolerance to fructose (for solution);
• hypersensitivity 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 elderly patients

With caution, the drug should be prescribed to elderly patients (over 65 years old).

Possible side effects are given below by body systems and frequency of occurrence: very often (> 1/10), often (> 1/100,

From the side of the central nervous system: very often - drowsiness, asthenic syndrome; often - amnesia, ataxia, convulsions, dizziness, headache, hyperkinesia, tremor, imbalance, decreased concentration, memory impairment, agitation, depression, emotional lability, moodiness, hostility / aggressiveness, insomnia, nervousness, irritability, personality disorders, impaired thinking; in some cases - paresthesia, behavioral disorders, anxiety, anxiety, confusion, hallucinations, irritability, psychotic disorders, suicide, attempted suicide and suicidal intentions.

From the side of the organ of vision: often - diplopia, violation of accommodation.

From the respiratory system: often - increased cough.

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 - skin rash, eczema, itching; in some cases - alopecia (in some cases, restoration of the hairline 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.

Levetiracetam does not interact with anticonvulsants (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin, and primidone).

Levetiracetam in a daily dose of 1 g does not alter the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Levetiracetam in 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 combined with topiramate, the likelihood of developing anorexia is higher.

The absorption capacity of levetiracetam does not change under the influence of food, while the rate of absorption decreases slightly.

There are no data on the interaction of levetiracetam with alcohol.

The tablets should be taken orally with a sufficient amount of liquid, regardless of the meal. The daily dose is divided into 2 identical doses.

In quality, 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 complex therapy

For children aged 1 month to 6 months, the drug is prescribed in the form of a solution for oral administration. 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.

Recommendations for the dosage of 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 / day 84 mg (0.85 ml) 2 times / day 5 kg 35 mg (0.35 ml) 2 times / day 105 mg (1.05 ml) 2 times / day 7 kg 49 mg (0.5 ml) 2 times / day 147 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 body weight 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 50 kg 500 mg 2 times / day 1500 mg 2 times / day

In children over 4 years of age, treatment should begin with a daily dose of 20 mg / kg body weight, 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.

The drug should be prescribed in the most suitable dosage form and dose, depending on the patient's body weight and the necessary therapeutic dose.

Children with body weight ≤ 20 kg are recommended to begin treatment with the drug in the form of a solution for oral administration.

For children with body weight> 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.

QC 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 Norm> 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 in 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.

For children with renal insufficiency, 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 regimen is not required. In patients with decompensated impaired liver function and renal failure, the value of CC may not reflect the true degree of impaired renal function, therefore, with CC

Rules for the use of the drug

The tablets should be taken orally with a sufficient amount of liquid, regardless of the meal.

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 of the drug. A measured dose of the drug is diluted in a glass of water (200 ml).

To dispense the solution using a measuring syringe, open the bottle: 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 rinse the syringe with water and close the bottle with a plastic cap. For monotherapy, adults and adolescents over 16 years of age are prescribed 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 complex therapy in children over 4 years of age, treatment should begin with a daily dose of 20 mg / kg body weight, 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.

* - for children weighing more than 50 kg, dosing is carried out according to the scheme for adults.

In children with a body weight of less than 25 kg, as well as more than 25 kg, but less than 50 kg, it is recommended to use levetiracetam in the form of an oral solution, which provides a more accurate dosage of the drug in this category of patients.

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 2-3 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 creatinine clearance.

* - 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.

Patients with impaired liver function of mild to moderate severity do not need to adjust the dosage regimen. In patients with severe hepatic impairment, the QC value may not reflect the true degree of impaired renal function, therefore, with creatinine clearance <70 ml / min, a daily dose reduction of 50% is recommended.

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

Treatment: in the acute period - artificial induction 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 using hemodialysis (dialysis efficiency for levetiracetam is 60%, for its primary metabolite - 74%).

If you want to stop taking the drug, then the cancellation is recommended to be carried out gradually, reducing a single dose by 500 mg every 2-4 weeks. In children, the dose reduction should not exceed 10 mg / kg body weight 2 times / day every 2 weeks.

Concomitant antiepileptic drugs (during the transfer of patients to levetiracetam) should preferably be withdrawn gradually.

Patients with kidney disease and decompensated liver disease are recommended to study kidney function before starting treatment. In case of impaired renal function, a dose adjustment may be required.

Due to reported cases of suicide, suicidal intent, and suicide attempts in the treatment of levetiracetam, patients should be warned about the need to immediately inform the attending physician of any symptoms of depression or suicidal intent.

The oral solution contains maltitol, therefore, for patients with impaired fructose tolerance, taking Keppra® in an appropriate dosage form is contraindicated.

Pediatric Use

Available information on the use of the drug in children does not indicate any negative effect on development and puberty. However, the long-term effects of treatment on children's learning ability, their intellectual development, growth, endocrine gland function, sexual development and fertility remain unknown.

Influence on the ability to drive vehicles and control mechanisms

The effect of Keppra® on the ability to drive vehicles and control mechanisms has not been specifically studied. Nevertheless, due to the different individual sensitivity to the drug by the central nervous system during the treatment period, it is necessary to refrain from driving vehicles and engaging in potentially dangerous activities that require an increased concentration of attention and speed of psychomotor reactions.

Pills