Kepayra-vero^® (Tablets) Instructions for Use

Marketing Authorization Holder

Veropharm, JSC (Russia)

ATC Code

N03AX14 (Levetiracetam)

Active Substance

Levetiracetam (Rec.INN registered by WHO)

Dosage Forms

	Kepayra-vero®	Film-coated tablets, 250 mg: 30 or 60 pcs.
		Film-coated tablets, 500 mg: 30 or 60 pcs.
		Film-coated tablets, 1000 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets gray in color, oblong, biconvex, with a score; on the cross-section, the tablet core is white or almost white; on the cross-section, the tablet core is white or almost white.

Excipients: corn starch – 58 mg, povidone (polyvinylpyrrolidone) – 7 mg, colloidal silicon dioxide (aerosil) – 4 mg, talc – 5 mg, magnesium stearate – 0.5 mg.*

Film coating composition: gray film coating mixture – 10 mg [hypromellose (hydroxypropyl methylcellulose) – 28%, lactose monohydrate – 36%, macrogol (polyethylene glycol 4000) – 10%, titanium dioxide – 24.94%, iron oxide black – 0.25%, iron oxide yellow – 0.25%, aluminum lake based on indigo carmine dye – 0.56%].**

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

* to obtain a tablet core weighing 324.5 mg
** to obtain a film-coated tablet weighing 334.5 mg

Film-coated tablets yellow in color, oblong, biconvex, with a score; on the cross-section, the tablet core is white or almost white; on the cross-section, the tablet core is white or almost white.

Excipients: corn starch – 116 mg, povidone (polyvinylpyrrolidone) – 15 mg, colloidal silicon dioxide (aerosil) – 8 mg, talc – 10 mg, magnesium stearate – 1 mg.*

Film coating composition: yellow film coating mixture – 20 mg [hypromellose (hydroxypropyl methylcellulose) – 28%, lactose monohydrate – 36%, macrogol (polyethylene glycol 4000) – 10%, titanium dioxide – 22.87%, iron oxide red – 0.04%, aluminum lake based on quinoline yellow dye – 3.09%].**

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

* to obtain a tablet core weighing 650 mg
** to obtain a film-coated tablet weighing 670 mg

Film-coated tablets white in color, oblong, biconvex, with a score; on the cross-section, the tablet core is white or almost white; on the cross-section, the tablet core is white or almost white.

Excipients: corn starch – 232 mg, povidone (polyvinylpyrrolidone) – 30 mg, colloidal silicon dioxide (aerosil) – 16 mg, talc – 20 mg, magnesium stearate – 2 mg.*

Film coating composition: white film coating mixture – 40 mg [hypromellose (hydroxypropyl methylcellulose) – 28%, lactose monohydrate – 36%, macrogol (polyethylene glycol 4000) – 10%, titanium dioxide – 26%].**

10 pcs. – contour cell packaging (3) – cardboard packs.
10 pcs. – contour cell packaging (6) – cardboard packs.

* to obtain a tablet core weighing 1300 mg
** to obtain a film-coated tablet weighing 1340 mg

Clinical-Pharmacological Group

Anticonvulsant drug

Pharmacotherapeutic Group

Antiepileptic agents; other antiepileptic agents

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 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, while not exhibiting 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 after 15 min 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 applied dose in mg/kg body weight. The degree of absorption is independent of dose and food intake time. Bioavailability is about 100%.

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

Binding to plasma proteins of levetiracetam and its main metabolite is less than 10%. V_d of levetiracetam is about 0.5-0.7 l/kg. Steady state is reached after 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, T_1/2 from plasma is 7±1 h and does not change depending on dose, route of administration, or repeated intake. 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 h, which is associated with decreased 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 h during the interdialytic period and 3.1 h 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 after 0.5-1 h. T_1/2 in children after a single oral dose of 20 mg/kg body weight is 5-6 h. 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

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, the single dose is 250-750 mg. Frequency of application – 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 allergy with eosinophilia and systemic manifestations (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, seizure aggravation.

Eye disorders uncommon – diplopia, blurred vision.

Ear and labyrinth disorders common – vertigo.

Cardiac disorders rare – prolonged QT interval 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 CPK.

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

Adequate and strictly controlled clinical studies on the safety of levetiracetam use in pregnant women have not been conducted, therefore Levetiracetam should not be used 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 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 can lead to a worsening of the disease, which is harmful for both the mother and the fetus.

Levetiracetam is excreted in breast milk, so 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. In case of impaired renal function, dose adjustment may be required.

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 developing 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 disturbances, including irritability and aggression. Patients receiving Levetiracetam should be regularly monitored for the development of certain psychiatric signs indicating important changes in mood and/or personality. If such behavior is noticed, potential adaptation to 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 dosage regimen.

Increase in seizure severity: Like other antiepileptic drugs, Levetiracetam may rarely 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 in case of worsening of the disease.

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, intellectual ability, growth, endocrine function, puberty and reproductive potential of children remain unknown.

Effect on ability to drive vehicles and machinery

Levetiracetam has minimal or moderate influence on the ability to drive and use machines. 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 advised to exercise caution when performing tasks that require practiced skills, such as driving a vehicle 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 liver microsomal enzymes is 20% higher. Dose adjustment is not required.

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

When levetiracetam and methotrexate were used concomitantly, a decrease in the clearance of methotrexate was observed, leading to an increase in methotrexate blood concentration to potentially toxic levels or a prolongation of the period of maintaining such a 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.