Konvilept^® (Tablets) Instructions for Use

ATC Code

N03AX14 (Levetiracetam)

Active Substance

Levetiracetam (Rec.INN registered by WHO)

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Antiepileptic drug, a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine acetamide). It differs in chemical structure from known antiepileptic drugs. The mechanism of action of levetiracetam is not fully understood, but it is clearly different 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 neurotransmission.

In vitro and in vivo studies have shown that Levetiracetam affects the intraneuronal concentration of Ca²⁺ ions, partially inhibiting Ca²⁺ current through N-type channels and reducing calcium release from intraneuronal stores. Furthermore, Levetiracetam partially restores currents through GABA- and glycine-dependent channels, reduced by zinc and β-carbolines. Also, in vitro studies have determined that Levetiracetam binds to a specific site in brain tissue. The binding site is the synaptic vesicle protein 2A, which is presumably involved in vesicle fusion and neurotransmitter exocytosis. Levetiracetam and related analogs differ in their binding affinity for synaptic vesicle protein 2A, which correlates with the degree of antiepileptic protection in the audiogenic model of epilepsy in mice. This fact suggests that the interaction between levetiracetam and synaptic vesicle protein 2A apparently contributes to the anticonvulsant mechanism of action of the drug.

Levetiracetam induces antiepileptic protection in various animal models of partial and primary generalized seizures, without showing pro-convulsant action. The main metabolite of levetiracetam is inactive.

In humans, the activity of levetiracetam against epilepsy with both partial and generalized seizures (epileptiform discharges/photoparoxysmal response) confirms its broad pharmacological profile.

Pharmacokinetics

Levetiracetam is a well-soluble substance with high penetrating ability. Levetiracetam has linear pharmacokinetics with low intra- and inter-individual variability. The clearance of levetiracetam remains constant after repeated administration. The time-independent pharmacokinetic profile was also confirmed after IV administration of 1500 mg twice daily for 4 days. C_max after a single IV administration of 1500 mg was reached in 15 minutes and was 51±19 µg/ml.

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

After a dose of 1 g, C_max in plasma is reached in 1.3 hours and is 31 µg/ml, after repeated administration (twice daily) – 43 µg/ml.

The binding to plasma proteins of levetiracetam and its main metabolite is less than 10%. The V_d of levetiracetam is about 0.5-0.7 l/kg. Steady state is reached in 2 days when taken twice daily.

Levetiracetam is not actively metabolized in the human body. The main metabolic pathway (24% of the dose) is enzymatic hydrolysis of the acetamide group. The formation of the primary pharmacologically inactive metabolite occurs without the involvement of cytochrome P450 isoenzymes in the liver. Levetiracetam does not affect the enzymatic activity of hepatocytes.

In adults, the T_1/2 from plasma is 7±1 hour and does not change depending on dose, route of administration, or repeated administration. The average clearance value 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.

In elderly patients, T_1/2 increases by 40% and is 10-11 hours, which is associated with reduced renal function in this category of patients. In patients with impaired renal function, the clearance of levetiracetam and its primary metabolite correlates with CrCl. In the terminal stage of renal failure in adult patients, T_1/2 is 25 hours during the interdialytic period and 3.1 hours during dialysis. Up to 51% of levetiracetam is removed during a 4-hour dialysis session.

During a 4-hour dialysis session, 51% of levetiracetam is removed from the body.

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

The pharmacokinetics of levetiracetam in children (aged 4 to 12 years) is linear in the dose range from 20 to 60 mg/kg/day. C_max is reached in 0.5-1 hour. T_1/2 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 on body weight.

Indications

As monotherapy for the treatment of partial seizures with or without secondary generalization in patients from 16 years of age with newly diagnosed epilepsy.

As adjunctive therapy in the treatment of: partial seizures with or without secondary generalization in patients older than 1 month (in the appropriate pediatric dosage form) with epilepsy; myoclonic seizures in patients from 12 years of age with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures in patients from 12 years of age with idiopathic generalized epilepsy.

ICD codes

Dosage Regimen

Tablets

Orally, IV.

Treatment can be started either with oral administration or with IV administration.

The transition from oral to IV administration and vice versa can be carried out while maintaining the dose and frequency of administration.

Depending on the indication and the patient’s age, a single dose is 250-750 mg. Frequency of application is 2 times/day.

In children, Levetiracetam should be used in the appropriate dosage form depending on age.

Adverse Reactions

Infections and infestations very common – nasopharyngitis; rare – infections.

Blood and lymphatic system disorders uncommon – thrombocytopenia, leukopenia; rare – agranulocytosis, pancytopenia, neutropenia.

Immune system disorders rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome), hypersensitivity (including angioedema and anaphylaxis).

Metabolism and nutrition disorders common – anorexia; uncommon – weight increased, weight decreased; rare – hyponatremia.

Psychiatric disorders common – depression, hostility/aggression, anxiety, insomnia, nervousness/irritability; uncommon – suicide attempt, suicidal ideation, psychotic disorder, behavioral disorder, hallucinations, anger, confusion, panic attack, emotional lability, agitation; rare – suicide, personality disorder, thinking abnormal, delusion.

Nervous system disorders very common – somnolence, headache; common – convulsion, disturbance in attention, dizziness, lethargy, tremor; uncommon – amnesia, memory impairment, coordination abnormal/ataxia, paresthesia, attention disturbance; rare – choreoathetosis, dyskinesia, hyperkinesia, gait disturbance, encephalopathy, convulsion aggravated.

Eye disorders uncommon – diplopia, vision blurred.

Ear and labyrinth disorders common – vertigo.

Cardiac disorders rare – QT prolonged on ECG.

Respiratory, thoracic and mediastinal disorders common – cough.

Gastrointestinal disorders common – abdominal pain, diarrhea, dyspepsia, vomiting, nausea; rare – pancreatitis.

Hepatobiliary disorders uncommon – liver function test abnormal; rare – hepatic failure, hepatitis.

Renal and urinary disorders rare – acute renal failure.

Skin and subcutaneous tissue disorders common – rash; uncommon – alopecia, eczema, pruritus; rare – toxic epidermal necrolysis, Stevens-Johnson syndrome, erythema multiforme.

Musculoskeletal and connective tissue disorders uncommon – muscle weakness, myalgia; rare – rhabdomyolysis and increased blood creatine phosphokinase.

General disorders and administration site conditions common – asthenia/fatigue, injuries, poisoning and procedural complications; uncommon – accidental injury.

Contraindications

Hypersensitivity to levetiracetam or other pyrrolidone derivatives, children under 1 month of age.

With caution

Elderly patients (over 65 years); decompensated liver disease; renal failure.

Use in Pregnancy and Lactation

There are no adequate and strictly controlled clinical studies on the safety of levetiracetam use in pregnant women, therefore Levetiracetam should not be used during pregnancy, except in cases of extreme necessity.

Physiological changes in a woman’s body during pregnancy may affect the plasma concentration of levetiracetam, as well as other antiepileptic drugs. During pregnancy, a decrease in the plasma concentration of levetiracetam has been noted. This decrease is more pronounced in the first trimester (up to 60% of the baseline concentration in the period preceding pregnancy).

Treatment of pregnant women with levetiracetam should be carried out under special supervision. It should be taken into account that interruptions in antiepileptic therapy may lead to a worsening of the disease, which is harmful for both the mother and the fetus.

Levetiracetam is excreted in breast milk, therefore breastfeeding during treatment is not recommended. However, if treatment with levetiracetam is necessary during lactation, the risk/benefit ratio of treatment relative to the importance of breastfeeding should be carefully weighed.

Use in Hepatic Impairment

Use with caution in decompensated liver disease.

Use in Renal Impairment

Use with caution in renal failure.

Pediatric Use

Contraindicated for use in children under 1 month of age.

Intended for use in children over 1 month of age in the appropriate dosage form.

Geriatric Use

Use with caution in elderly patients over 65 years of age.

Special Precautions

Patients with kidney disease and decompensated liver disease are recommended to have their renal function examined before starting treatment. Dose adjustment may be required in case of impaired renal function.

In very rare cases, the use of levetiracetam has been accompanied by acute kidney injury, developing from several days to several months.

Cases of decreased blood cell counts (neutropenia, agranulocytosis, leukopenia, thrombocytopenia and pancytopenia) have been described in connection with the use of levetiracetam. A blood test with a count of blood cells is recommended for patients who develop severe weakness, hyperthermia, recurrent infections or coagulation disorders.

During treatment with antiepileptic drugs, in particular levetiracetam, reports of completed suicides, suicide attempts, suicidal thoughts and behavior have been received. A meta-analysis of randomized placebo-controlled studies of antiepileptic drugs revealed a small increase in the risk of suicidal thoughts and behavior. The mechanism of the increased risk is not known. Therefore, during treatment with levetiracetam, monitoring for signs of depression and/or suicidal thoughts and behavior should be carried out and appropriate treatment should be provided if necessary. Patients (and their caregivers) should be warned that if signs of depression and/or suicidal thoughts or behavior appear, they should consult a doctor.

Abnormal and aggressive behavior: Levetiracetam can cause psychotic symptoms and behavioral disorders, including irritability and aggression. Patients receiving Levetiracetam should be regularly monitored for the development of certain psychiatric signs indicating significant changes in mood and/or personality. If such behavior is noticed, potential adaptation of treatment or its gradual discontinuation should be considered. If discontinuation of levetiracetam therapy is considered, the dose should be changed in accordance with the recommended dosing regimen.

Increased seizure frequency: Like other antiepileptic drugs, Levetiracetam may in rare cases increase the frequency or severity of seizures. This paradoxical effect was most often reported during the first month after starting levetiracetam or increasing the dose, and it was reversible after discontinuation of the drug or dose reduction. Patients should immediately consult their doctor if the course of the disease worsens.

Prolongation of the QT interval on ECG: Levetiracetam should be used with caution in patients with prolonged corrected QT interval or with pre-existing relevant heart disease, as well as concurrently with drugs affecting the corrected QT interval.

Use in pediatrics

Available data on the use of levetiracetam in children indicate no effect of this drug on growth and puberty. However, the long-term effects on learning ability, mental abilities, growth, endocrine function, puberty and reproductive potential of children remain unknown.

Effect on ability to drive and operate machinery

Levetiracetam has minimal or moderate influence on the ability to drive and operate machinery. Due to possible differences in individual sensitivity, some patients may develop drowsiness or other symptoms from the central nervous system during treatment, especially at the beginning of treatment or after a dose increase. Therefore, such patients are recommended to exercise caution when performing tasks that require developed skills, for example, when driving a car or operating machinery. Patients should refrain from driving a car or operating machinery until they are sure that their ability to perform the listed tasks is not impaired.

Drug Interactions

According to available data, the clearance of levetiracetam in children receiving treatment with anticonvulsant drugs that are inducers of hepatic microsomal enzymes is 20% higher. Dose adjustment is not required.

Probenecid, a tubular secretion blocker (500 mg 4 times/day), has been shown to inhibit the renal clearance of the main metabolite of levetiracetam, but not of levetiracetam itself. Nevertheless, the concentration of this metabolite remains low.

With simultaneous use of levetiracetam and methotrexate, a decrease in methotrexate clearance was noted, leading to an increase in methotrexate blood concentration to potentially toxic levels or prolongation of the period of maintaining such concentration. In patients receiving both drugs, plasma levels of methotrexate and levetiracetam should be monitored.

Storage Conditions

Store at 2°C (36°F) to 25°C (77°F). Keep in original packaging, protected from light. Keep out of reach of children.

Dispensing Status

Rx Only

Important Safety Information

This information is for educational purposes only and does not replace professional medical advice. Always consult your doctor before use. Dosage and side effects may vary. Use only as prescribed.