Keppra oral solution 100mg/ml vials, 300ml

Composition

1 ml levetiracetam 100 mg

Auxiliary substances:

sodium citrate,

citric acid monohydrate,

methyl parahydroxybenzoate,

propyl parahydroxybenzoate,

ammonium glycyrrhizinate,

glycerol 85%,

maltitol,

acesulfame potassium,

grape flavor 501040 A,

purified water.

Pharmacological action

The antiepileptic drug, a derivative of pyrrolidone (the S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide), differs in chemical structure from most 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.

The results of an in vitro study showed that levetiracetam affects the intra-neuronal concentration of Ca2+ ions, partially inhibiting the flow of Ca2+ through N-type channels and reducing the release of calcium from intra-neuronal depots. In addition, levetiracetam partially restores currents through GABA-and glycine-dependent channels reduced by zinc and beta-carbolines.

One of the proposed mechanisms is based on the proven binding to the synaptic vesicle glycoprotein SV2A, which is 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 countering the hypersynchronization of neural activity. It does not alter normal neurotransmission, but it suppresses epileptiform neuronal bursts induced by the GABA – agonist bicuculin and the excitation of glutamate receptors. The activity of the drug was confirmed against both focal and generalized epileptic seizures (epileptiform manifestations/photoparoxysmal reaction).

Pharmacokinetics

Suction

After oral use, levetiracetam is well absorbed from the gastrointestinal tract. Absorption is complete and linear, so the concentration in blood plasma can be predicted based on the applied dose of the drug in mg/kg of body weight. The degree of absorption does not depend on the dose and time of food intake. Bioavailability is about 100%.

After taking the drug at a dose of 1 g, Cmax in blood plasma is reached in 1.3 hours and is 31 mcg / ml, after repeated use (2 times / day) – 43 mcg/ml.

Distribution

The equilibrium state is reached after 2 days with a double dose of the drug. The plasma protein binding of levetiracetam and its main metabolite is less than 10%. The 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 involvement of cytochrome P450 isoenzymes in the liver. Levetiracetam does not affect the enzymatic activity of hepatocytes.

Deduction

In adults, T1 / 2 from blood plasma is 7±1 h and does not change depending on the dose, method of use 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 is 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 insufficiency are recommended to adjust the dose depending on the creatinine clearance. In end-stage renal failure in adult patients, T 1/2 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 a 4-hour dialysis session,51% of levetiracetam is removed from the body.

No significant changes in levetiracetam clearance occur in patients with mild to moderate hepatic impairment. In severe hepatic impairment with concomitant renal failure, the clearance of levetiracetam decreases by more than 50%.

The pharmacokinetics of levetiracetam in children is linear in the dose range of 20 to 60 mg/kg/day. Cmax is achieved after 0.5-1 h. the T1/2 in children after a single oral dose of 20 mg/kg of body weight is 5-6 h. Total clearance of levetiracetam in children by approximately 40% higher than in adults and is in direct proportion to body mass.

Indications

As a monotherapy (the drug of first choice) 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 secondary generalization or without it in adults and children 4 years and older with epilepsy (for tablets);
• partial seizures with secondary generalization or without it in adults and children older than 1 month, epilepsy (for a solution);
• myoclonic seizures in adults and adolescents 12 years and older with juvenile myoclonic epilepsy;
• primary generalized convulsive (tonic-clonic) seizures in adults and adolescents 12 years and older with idiopathic generalized epilepsy.

Use during 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 extreme necessity.

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 baseline concentration in the period preceding pregnancy). Treatment with levetiracetam in pregnant women should be carried out under special supervision. 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 while taking the drug is not recommended. However, if treatment with levetiracetam is necessary during the feeding period, the ratio of risk to the child and the benefit of treatment to 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 under 1 month of age (for solution) (safety and efficacy of the drug have not been established);

Contraindications

• children under 4 years of age (for tablets) (safety and efficacy of the drug have not been established);
• children under 1 month of age (for solution) (safety and efficacy of the drug have not been established);
• violation of fructose tolerance (for solution);
• hypersensitivity to the components of the drug;
• hypersensitivity to other pyrrolidone derivatives.

With caution, the drug should be prescribed to elderly patients (older than 65 years), with liver diseases in the stage of decompensation, and renal failure.

Use in elderly patients

Caution should be exercised when prescribing the drug to elderly patients (over 65 years of age).

Side effects

Possible side effects are listed below by body system and frequency of occurrence: very common (>1/10), common (>1/100, >>

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

From the side of the visual organ:  often – diplopia, violation of accommodation.

Respiratory system disorders:  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, pruritus; in some cases-alopecia (in some cases, hair restoration was observed after discontinuation of the drug), Stevens-Johnson syndrome, erythema multiforme, toxic epidermal necrolysis.

From the hematopoietic system:  in some cases – leukopenia, neutropenia, pancytopenia (in some cases with suppression of bone marrow function), thrombocytopenia.

Other services:  in some cases – infections, nasopharyngitis, myalgia.

Interaction

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 change the pharmacokinetics of oral contraceptives (ethinyl estradiol and levonorgestrel).

Levetiracetam in a daily dose of 2 g does not change the pharmacokinetics of warfarin and digoxin.

Digoxin, oral contraceptives and warfarin do not affect the pharmacokinetics of levetiracetam.

When taken together with topiramate, the likelihood of developing anorexia is higher.

The complete absorption 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.

How to take, course of use and dosage

The daily dose is divided into 2 identical doses.

Monotherapy

Adults and adolescents over 16 years of age are prescribed the drug in the form of tablets or a solution for oral use in an initial dose of 500 mg, divided into 2 doses (250 mg 2 times a day). After 2 weeks, the dose can be increased to the initial therapeutic dose of 1 g (500 mg 2 times a day). The maximum daily dose is 3 g (1.5 g 2 times a day).

As part of complex therapy

For children aged from 1 month to 6 months, 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 can 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.

Weight melancholia dose: 7 mg/kg 2 times/setmaxvalue 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 a body weight of less than 50 kg, treatment should begin with a dose of 10 mg/kg of body weight divided into 2 doses (10 mg/kg of body weight 2 times/day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to 30 mg/kg 2 times / day. A dose change of 10 mg / kg of body weight can be made every 2 weeks. The minimum effective dose should be used.

The dosage for children weighing 50 kg or more is the same as for adults.

Recommended doses for children aged 6 months and older and adolescents are shown in the table.

Weight melancholia dose: 10 mg/kg 2 times/setmaxvalue 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/STOT 50 kg 500 mg 2 times/day to 1500 mg 2 times/day

Children over 4 years of age should start treatment with a daily dose of 20 mg / kg of body weight, divided into 2 doses (10 mg/kg of body weight 2 times/day). The dose can be changed by 20 mg/kg of body weight every 2 weeks until the recommended daily dose is 60 mg/kg of body weight (30 mg/kg of body weight 2 times/day). If you are intolerant to the recommended daily dose, it may be reduced. The minimum effective dose should be used.

The drug should be prescribed in the most appropriate dosage form and dose, depending on the patient’s body weight and the required therapeutic dose.

Children with a body weight of less than 20 kg are recommended to start treatment with the drug in the form of an oral solution.

Children with a body weight of > 50 kg are dosed 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 start treatment with a daily dose of 1 g, divided into 2 doses (500 mg 2 times / day). Depending on the clinical response and tolerability of the drug, the daily dose can be increased to a maximum of 3 g (1.5 g 2 times a 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 insufficiency, the dose should be adjusted depending on the creatinine clearance.

CC can be calculated based on the concentration of serum creatinine using the following formula.

For men:

CC (ml / min)= [140-age (years)] × body weight (kg)/72 × serum creatinine (mg / dl)

For women: the resulting value is x 0.85

Renal insufficiency CC (ml / min)Dose and multiplicity of Priemanorm>80500-1500 mg 2 times / Sutlatent 50-79500-1000 mg 2 times / Sutcompensated 30-49250-750 mg 2 times / Suttermitting 250-500 mg 2 times/Sutterminal stage (patients undergoing hemodialysis)*-500-1000 * *

* – 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 insufficiency, levetiracetam dose adjustment should be made taking into account the degree of renal insufficiency, using the recommendations given for adults.

Patients with mild to moderate hepatic impairment do not need to adjust the dosage regimen. In patients with decompensated hepatic impairment and renal insufficiency, the CC value may not reflect the true degree of renal impairment, so with CC,

Rules for the use of the drug

Tablets should be taken orally, washed down with a sufficient amount of liquid, regardless of food intake.

Dosage of the solution is carried out using a measuring syringe with a nominal capacity of 10 ml (corresponds to 1 g of levetiracetam) and with a division price of 25 mg (corresponds to 0.25 ml), which is included in the delivery package of the drug. The measured dose of the drug is diluted in a glass of water (200 ml).

To dispense the solution with a measuring syringe, open the bottle by pressing the cap and turning it counterclockwise. Insert the syringe adapter into the neck of the bottle, 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 plunger down, then push the plunger up to remove air bubbles. By pulling the plunger, fill the syringe with the solution to the division corresponding to the number of ml of solution prescribed by the doctor. Remove the syringe from the adapter. Insert the contents of the syringe into a glass of water, pressing the plunger until it stops. You should drink all the contents of the glass completely. Then rinse the syringe with water and close the bottle with a plastic lid.

Overdose

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

Treatment: in the acute period – artificial vomiting and gastric lavage followed by the appointment of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment is performed in a hospital setting using hemodialysis (the effectiveness of dialysis for levetiracetam is 60%, for its primary metabolite — 74%).

Special instructions

If you need to stop taking the drug, then it is recommended to cancel it gradually, reducing the single dose by 500 mg every 2-4 weeks. In children, the dose reduction should not exceed 10 mg / kg of body weight 2 times / day every 2 weeks.

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

Patients with kidney disease and decompensated liver disease are recommended to have their kidney function evaluated before starting treatment. If renal function is impaired, a dose adjustment may be required.

Due to reports of cases of suicide, suicidal intent, and attempted suicide during treatment with levetiracetam, patients should be cautioned to immediately inform the attending physician of any symptoms of depression or suicidal intent.

The oral solution contains maltitol, so patients with impaired fructose tolerance should not take Keppra® in the appropriate dosage form.

Use in pediatrics

The available data on the use of the drug in children do not indicate any negative effects on development and sexual maturity. However, the long-term effects of treatment on children’s learning ability, intellectual development, growth, endocrine function, sexual development, and fertility remain unknown.

Influence on the ability to drive motor vehicles and manage mechanisms

Effect of Keppra® the ability to drive motor vehicles and manage mechanisms was not specifically studied. However, due to different individual sensitivity to the drug on the part of the central nervous system during treatment, it is necessary to refrain from driving vehicles and engaging in potentially dangerous activities that require increased concentration of attention and speed of psychomotor reactions.

Form of production

The solution for oral use is transparent, almost colorless, with a characteristic odor.

Storage conditions

Tablets should be stored in a dry place at a temperature not exceeding 25°C. Oral solution should be stored in a place protected from light at a temperature not exceeding 30°C. Concentrate for preparation of solution for infusions should be stored in a protected place.

Shelf

life is 3 years. Concentrate for preparation of solution for infusions – 2 years.

Active ingredient

Levetiracetam

Conditions of release from pharmacies

By prescription

Dosage form

oral solution