Epiterra (Tablets) Instructions for Use

Marketing Authorization Holder

Teva Pharmaceutical Industries, Ltd. (Israel)

ATC Code

N03AX14 (Levetiracetam)

Active Substance

Levetiracetam

Dosage Forms

	Epiterra	Film-coated tablets, 250 mg: 30, 50, or 60 pcs.
		Film-coated tablets, 500 mg: 30, 50, or 60 pcs.
		Film-coated tablets, 1000 mg: 30, 50, or 60 pcs.

Dosage Form, Packaging, and Composition

Film-coated tablets blue, oblong, with an engraving “7285” on one side and “9” and “3” on the other side, separated by a score; white or almost white in the break.

Excipients: corn starch – 34 mg, povidone (PVP K-30) – 8 mg, croscarmellose sodium – 37 mg, magnesium stearate – 3 mg.

Film coating composition: Opadry 03F20667 blue – 9 mg (hypromellose 6 cp (HPMC 2910) – 5.63 mg, titanium dioxide (E171) – 2.27 mg, macrogol 3350 – 0.56 mg, brilliant blue dye (E133) – 0.36 mg, indigo carmine (E132) – 0.18 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets yellow, oblong, with an engraving “7286” on one side and “9” and “3” on the other side, separated by a score; white or almost white in the break.

Excipients: corn starch – 68 mg, povidone (PVP K-30) – 16 mg, croscarmellose sodium – 74 mg, magnesium stearate – 6 mg.

Film coating composition: Opadry 03B220001 – 18 mg (hypromellose 5 cp (HPMC 2910) – 11.52 mg, titanium dioxide (E171) – 5.2866 mg, macrogol 400 – 1.08 mg, indigo carmine (E132) – 0.0054 mg, iron oxide yellow dye (E172) – 0.108 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Film-coated tablets white, oblong, with an engraving “7493” on one side and “9” and “3” on the other side, separated by a score; white or almost white in the break.

Excipients: corn starch – 136 mg, povidone (PVP K-30) – 32 mg, croscarmellose sodium – 148 mg, magnesium stearate – 12 mg.

Film coating composition: Opadry 03F18435 white – 36 mg (hypromellose 6 cp (HPMC 2910) – 22.04 mg, titanium dioxide (E171) – 6.62 mg, macrogol 3350 – 7.34 mg).

10 pcs. – blisters (3) – cardboard packs.
10 pcs. – blisters (5) – cardboard packs.
10 pcs. – blisters (6) – cardboard packs.

Clinical-Pharmacological Group

Antiepileptic drug

Pharmacotherapeutic Group

Antiepileptic agent

Pharmacological Action

Antiepileptic drug, a pyrrolidone derivative (S-enantiomer of α-ethyl-2-oxo-1-pyrrolidine-acetamide), which 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 or in vivo studies have shown that Levetiracetam does not affect the basic characteristics of cells and normal neurotransmission.

In vitro studies have shown that Levetiracetam affects the intraneuronal concentration of Ca²⁺ ions, partially inhibiting Ca²⁺ current through N-type channels and reducing the release of calcium from intraneuronal stores. In addition, Levetiracetam partially restores ionic currents through GABA- and glycine-dependent channels, reduced by zinc and carbolines.

One of the proposed mechanisms is based on proven binding to the synaptic vesicle glycoprotein SV2A, found in the gray matter of the brain and spinal cord. It is believed that this is how the anticonvulsant effect is realized, which is expressed in counteracting the hypersynchronization of neuronal activity. Levetiracetam also acts on GABA receptors and glycine receptors, modulating these receptors through various endogenous agents. It does not alter normal synaptic transmission, but suppresses epileptiform neuronal bursts induced by the GABA agonist bicuculline and glutamate receptor excitation. The activity of levetiracetam has been confirmed in both focal and generalized epileptic seizures (epileptiform manifestations, photoparoxysmal response).

Pharmacokinetics

Absorption

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 of the drug in mg/kg body weight. The degree of absorption does not depend on the dose and time of food intake. Absolute bioavailability is about 100%.

After taking levetiracetam at a dose of 1000 mg, C_max is reached in 1.3 h and is 31 µg/ml, after repeated administration (2 times/day) – 43 µg/ml.

Distribution

Steady-state plasma concentration is reached after 2 days when taking levetiracetam 2 times/day. 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, which approximately corresponds to the volume of water in the body.

Metabolism

The formation of the primary pharmacologically inactive metabolite (ucb L057) occurs without the involvement of cytochrome P450 isoenzymes. The main pathway of metabolism is hydrolysis of the acetamide group (24% of the dose). Levetiracetam does not affect the enzymatic activity of hepatocytes.

In vitro, as well as in vivo, Levetiracetam and its primary metabolite did not inhibit the activity of cytochrome P450 isoenzyme systems (CYP3A4, 2A6, 2C9, 2C19, 2D6, 2E1 and 1A2), glucuronyltransferase (UGT1A1 and UGT1A6) and epoxide hydrolase. Furthermore, in vitro, Levetiracetam does not affect the glucuronidation of valproic acid.

In human hepatocyte cultures, Levetiracetam had little or no effect on the activity of CYP1A2, SULT1E1 and UGT1A1 isoenzymes. Levetiracetam weakly induced the activity of CYP2B6 and CYP3A4 isoenzymes.

Data on drug interactions with oral contraceptives, digoxin and warfarin in vitro and in vivo indicate that significant enzyme induction in vivo is not expected. Therefore, interaction of levetiracetam with other substances or interaction of other substances with levetiracetam is unlikely.

Excretion

In adults, T_1/2 from plasma is 7±1 h and does not change depending on dose, route of administration or repeated administration. The mean total clearance value is 0.96 ml/min/kg. 95% of the drug is excreted by the kidneys (of which 93% of the dose is excreted within 48 hours). Fecal excretion is only 0.3% of the dose.

The total excretion of levetiracetam and its main metabolite is 66% and 24% of the administered dose, respectively, during the first 48 hours. The renal clearance of levetiracetam and its metabolite ucb L057 is 0.6 and 4.2 ml/min/kg, respectively, indicating excretion of levetiracetam by glomerular filtration followed by tubular reabsorption, and the main metabolite by glomerular filtration and active tubular secretion.

The elimination of levetiracetam correlates with CrCl.

Pharmacokinetics in special clinical cases.

No dependence of pharmacokinetics on gender, race or time of day was observed.

A significant correlation was found between levetiracetam concentrations in plasma and saliva in adults and children (the ratio of levetiracetam concentrations saliva/plasma ranges from 1 to 1.7 for oral tablets and for oral solution 4 hours after the last dose).

In elderly patients, T_1/2 increases by 40% and is 10-11 h, which is associated with decreased renal function.

In patients with renal failure, the clearance of levetiracetam and its primary metabolite correlates with CrCl. Therefore, in patients with renal failure, dose adjustment is recommended depending on CrCl. In end-stage renal failure in adult patients, T_1/2 is 25 h between sessions and 3.1 h during dialysis. During a 4-hour dialysis, 51% of levetiracetam is removed from the body.

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

The pharmacokinetics of levetiracetam in children is linear in the dose range from 20 to 60 mg/kg/day. C_max is reached in 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

Monotherapy

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

As adjunctive therapy

• Partial seizures with or without secondary generalization in epilepsy in adults and children over 6 years of age with epilepsy;
• Myoclonic seizures in adults and children over 12 years of age with juvenile myoclonic epilepsy;
• Primary generalized convulsive (tonic-clonic) seizures in adults and children over 12 years of age with idiopathic generalized epilepsy.

ICD codes

Dosage Regimen

Orally, with a sufficient amount of liquid, regardless of meals. The daily dose is divided into 2 equal parts for administration 2 times/day.

Monotherapy

Adults and children over 16 years: initial dose – 500 mg, divided into 2 doses (250 mg 2 times/day). After 2 weeks of therapy, depending on the individual response and tolerance, the daily dose can be increased to the initial therapeutic dose – 1 g (500 mg 2 times/day). Maximum daily dose – 3 g (1.5 g 2 times/day).

As adjunctive therapy

Adults and children over 12 years of age weighing more than 50 kg initial dose – 1 g, divided into 2 doses (500 mg 2 times/day). Depending on the clinical response and tolerance, the daily dose can be increased to the maximum dose – 3 g (1.5 g 2 times/day). Dose changes of 500 mg 2 times/day can be made every 2-4 weeks.

Children over 6 years of age weighing less than 50 kg: initial dose 20 mg/kg body weight, divided into 2 doses (10 mg/kg body weight 2 times/day). Depending on the clinical response and tolerance, the dose can be changed by 20 mg/kg body weight every 2 weeks until the recommended daily dose of 60 mg/kg body weight (30 mg/kg body weight 2 times/day) is reached. If the recommended daily dose is not tolerated, it can be reduced. The minimum effective dose should be used. The drug should be used in the most appropriate dosage form and dosage depending on the patient’s body weight and the required therapeutic dose.

In children weighing less than 25 kg when it is necessary to use a dose of less than 250 mg/day and in patients who have difficulty swallowing, it is recommended to use levetiracetam in the dosage form of an oral solution. In children weighing more than 50 kg, dosing of the drug is carried out according to the scheme for adults.

Elderly patients and patients with renal failure the dose should be adjusted depending on CrCl according to the following formula

CrCl can be calculated based on serum creatinine concentration using the following formula

For men

For women multiply the obtained value by 0.85

Then CrCl is adjusted for body surface area (BSA) using the following formula

CrCl (ml/min/1.73 m²) = CrCl (ml/min)/BSA (m²)

Doses for use in adults and children weighing more than 50 kg

¹On the first day of treatment with Epiterra, a loading dose of 750 mg is recommended.

²After dialysis, an additional dose of 250-500 mg is recommended.

In children with renal failure, dose adjustment is carried out taking into account the degree of renal failure, using recommendations obtained from studies of adult patients with renal failure.

CrCl can be estimated based on the determination of creatinine concentration (mg/dl) for children, using the Schwartz formula

Ks = 0.55 for children under 13 years of age and female children over 13 years of age;
Ks = 0.7 for male children over 13 years of age.

Doses for use in children weighing less than 50 kg

¹ On the first day of treatment with Epiterra, a loading dose of 15 mg/kg is recommended.

² After dialysis, an additional dose of 5-10 mg/kg is recommended.

Patients with mild to moderate hepatic impairment do not require dosage adjustment. In patients with severe hepatic impairment, the CrCl value may not reflect the true degree of renal impairment, therefore, if CrCl is less than 60 ml/min/1.73 m², a 50% reduction in the daily dose is recommended.

Adverse Reactions

The safety profile presented below is based on an analysis of clinical trial results and post-registration experience.

The most common adverse reactions were nasopharyngitis, somnolence, headache, fatigue and dizziness. The profile of levetiracetam is generally similar across different age groups of adults and children.

Definition of frequency categories of adverse reactions: very common (≥1/10), common (≥1/100, <1/10), uncommon (≥1/1000, <1/100), rare (≥1/10,000, <1/1000), very rare (<1/10,000).

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

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

Immune system disorders: rare – drug reaction with eosinophilia and systemic symptoms (DRESS syndrome).

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, emotional lability/mood swings, agitation, panic attack; rare – suicide, personality disorder, thinking abnormal.

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

Eye disorders: uncommon – diplopia, blurred vision.

Ear and labyrinth disorders: common – vertigo.

Respiratory, thoracic and mediastinal disorders: common – cough.

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

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

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

Musculoskeletal and connective tissue disorders: uncommon – myalgia, muscle weakness.

General disorders and administration site conditions: common – asthenia/fatigue; uncommon – accidental injury.

The risk of anorexia is higher with concomitant use of levetiracetam and topiramate.

There are reports of hair regrowth after discontinuation of levetiracetam.

Some cases of pancytopenia were accompanied by bone marrow suppression.

The safety profile of levetiracetam in children is comparable to that in adults. In children aged 4 to 16 years, vomiting (very common, 11.2%), agitation (common, 3.4%), mood swings (common, 2.1%), emotional lability (common, 1.7%), aggressiveness (common, 8.2%), behavioral disorders (common, 5.6%), lethargy (common, 3.9%) were more frequently reported. In children from 1 month to 4 years, irritability (very common, 11.7%) and coordination abnormal (common, 3.3%) were more frequently reported.

In a double-blind, placebo-controlled study of levetiracetam use in children aged 4 to 16 years with partial seizures, which aimed to show that Levetiracetam is not inferior to placebo in terms of safety, cognitive and neuropsychological effects were evaluated. It was concluded that Levetiracetam is not different from placebo (is not inferior to it) regarding changes in the sum of scores for the “Attention and Memory” and “Combined Memory Screening” sections of the Leiter-R scale in patients who completed the study according to the protocol, compared to the baseline visit.

As a result of the analysis of behavioral and emotional status using the validated Achenbach questionnaire tool, aggressive behavior was identified in the group of patients taking Levetiracetam. However, patients taking Levetiracetam during long-term follow-up in the open-label phase of the study did not demonstrate a worsening of behavioral and emotional status, in particular. Indicators of aggressive behavior did not worsen compared to baseline.

Contraindications

• Hypersensitivity to levetiracetam, pyrrolidone derivatives, or other components of the drug;
• Children under 6 years of age.

With caution: severe hepatic impairment, renal failure, elderly patients over 65 years of age.

Use in Pregnancy and Lactation

In post-marketing data obtained from several prospective pregnancy registries, more than 1000 cases of levetiracetam use as monotherapy in the first trimester of pregnancy were recorded. Overall, these data do not indicate a significant increase in the risk of major congenital malformations. Teratogenic damage cannot be completely ruled out. Therapy with several antiepileptic drugs is associated with a higher risk of congenital malformations than monotherapy, so monotherapy in pregnant women is more appropriate.

Adequate and strictly controlled clinical studies on the safety of levetiracetam use in pregnant women have not been conducted, therefore the drug Epiterra is used during pregnancy only if the expected benefit to the mother outweighs the potential risk to the fetus.

Physiological changes in a woman’s body during pregnancy can affect the concentration of levetiracetam, as well as other antiepileptic drugs, in the blood plasma. A decrease in levetiracetam plasma concentration was noted during pregnancy. This decrease was pronounced in the third trimester of pregnancy (up to 60% of the baseline concentration during the third trimester). The use of levetiracetam in pregnant women 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 can harm the health of both the mother and the fetus.

Levetiracetam is excreted in breast milk, therefore the use of the drug Epiterra during breastfeeding is not recommended. However, if it is necessary to use levetiracetam during breastfeeding, the benefit/risk ratio of treatment should be assessed taking into account the importance of breastfeeding.

Animal studies have not revealed any effect of levetiracetam on fertility. Clinical data on the effect of levetiracetam on fertility are lacking, the possible risk to humans is unknown.

Use in Hepatic Impairment

Use with caution in severe hepatic impairment.

No dose adjustment is required for patients with mild to moderate hepatic impairment. In patients with severe hepatic impairment, the CrCl value may not reflect the true degree of renal impairment, therefore, if CrCl is less than 50 ml/min, a 50% reduction in the daily dose is recommended.

Use in Renal Impairment

Use with caution in severe renal impairment.

Pediatric Use

Contraindicated in children under 6 years of age.

Geriatric Use

Use with caution in patients over 65 years of age.

Special Precautions

If it is necessary to discontinue therapy, withdrawal of the drug Epiterra is recommended to be carried out gradually, reducing the single dose by 500 mg every 2-4 weeks. In adults weighing less than 50 kg, it is recommended to reduce the dose by 20 mg/kg every 2 weeks. In children weighing 25-50 kg, it is recommended to reduce the dose by 10 mg/kg every 2 weeks.

The use of the drug Epiterra by patients with impaired renal function may require dose adjustment.

In patients with severe hepatic impairment, it is recommended to examine renal function before treatment.

During treatment with the drug Epiterra, CNS disorders may occur, including drowsiness, weakness, fatigue, psychotic and non-psychotic behavioral changes, especially during the first month of therapy. Therefore, patients should be monitored particularly carefully at the beginning of treatment.

In patients receiving treatment with antiepileptic drugs (including Levetiracetam), cases of suicide, suicide attempts, suicidal thoughts and behavior have been reported. A meta-analysis of randomized, placebo-controlled trials of antiepileptic drugs showed a small increase in the risk of suicidal thoughts and behavior. The mechanism of this risk is unknown.

Thus, it is necessary to monitor patients for signs of depression and/or suicidal thoughts and behavior, and to consider appropriate treatment. Patients (and patient caregivers) should be advised to seek medical attention if signs of depression and/or suicidal thoughts or behavior occur.

If signs of depression and suicide attempts are present, patients and their caregivers should consult a specialist.

Gradual withdrawal of concomitant anticonvulsant drugs is recommended during the transition of the patient to treatment with the drug Epiterra.

In patients with partial seizures, a slight but statistically significant decrease in red blood cell parameters was observed during treatment with the drug, which does not require active clinical intervention.

Use in Pediatrics

In children under 6 years of age, it is recommended to use levetiracetam in the oral solution dosage form.

Available data on the use of the drug in children do not indicate any negative impact on development and puberty. However, the long-term consequences of treatment on children’s learning ability, intellectual development, growth, endocrine gland function, sexual development and fertility remain unknown.

Effect on Ability to Drive and Operate Machinery

No studies on the effect on the ability to drive vehicles and operate machinery have been conducted. Due to possible varying individual sensitivity, some patients may experience drowsiness or other CNS symptoms, especially at the beginning of treatment or after a dose increase. Thus, such patients must exercise caution when performing tasks such as driving a vehicle or operating machinery.

Patients are advised not to drive vehicles or operate machinery until the absence of an effect on the ability to engage in potentially hazardous activities is established.

Overdose

Symptoms drowsiness, agitation, aggression, loss of consciousness, respiratory depression, coma.

Treatment in the acute period – induction of vomiting, gastric lavage, administration of activated charcoal. There is no specific antidote for levetiracetam. If necessary, symptomatic treatment is carried out in a hospital setting using hemodialysis (dialysis efficiency for levetiracetam is 60%, for the primary metabolite – 74%).

Drug Interactions

Levetiracetam does not affect the plasma concentrations of antiepileptic drugs (phenytoin, carbamazepine, valproic acid, phenobarbital, lamotrigine, gabapentin and primidone). In turn, these antiepileptic drugs do not affect the plasma concentration of levetiracetam.

There are no data on clinically significant drug interactions in children receiving Levetiracetam at a dose of 60 mg/kg/day. A retrospective analysis of pharmacokinetic interactions in children aged 4 to 17 years with epilepsy confirmed that concomitant oral administration of levetiracetam does not affect the steady-state plasma concentrations of concurrently taken carbamazepine and valproic acid. However, the data suggest that the clearance of levetiracetam is 20% higher in children taking enzyme-inducing antiepileptic drugs. Dose adjustment in these cases is not required.

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

Levetiracetam at 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.

Probenecid (500 mg 4 times/day) reduces the renal clearance of the primary metabolite of levetiracetam. It is assumed that drugs that are eliminated from the body due to active renal secretion may also reduce the clearance of the metabolite. The effect of levetiracetam on probenecid and other drugs with a similar elimination mechanism (including NSAIDs, sulfonamides, methotrexate) remains unclear.

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

Isolated reports have been received of a decrease in the effectiveness of levetiracetam when used concomitantly with the osmotic laxative macrogol. Macrogol should not be taken within 1 hour before and within 1 hour after taking levetiracetam.

The extent of absorption of levetiracetam is not affected by food, although the rate of absorption is somewhat reduced.

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

Storage Conditions

The drug should be stored out of the reach of children at a temperature not exceeding 25°C (77°F).

Shelf Life

Shelf life is 3 years.

Dispensing Status

The drug is dispensed by prescription.

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.