Levipil San (Tablets) Instructions for Use

Marketing Authorization Holder

Sun Pharmaceutical Industries, Ltd. (India)

ATC Code

N03AX14 (Levetiracetam)

Active Substance

Levetiracetam (Rec.INN registered by WHO)

Dosage Forms

	Levipil San	Extended-release film-coated tablets 500 mg: 30 or 60 pcs.
		Extended-release film-coated tablets 750 mg: 30 or 60 pcs.

Dosage Form, Packaging, and Composition

Extended-release film-coated tablets oval, biconvex, two-layer, with a blue layer having a laser-drilled hole and a white to off-white layer; one side is imprinted with “573” in black ink, the other side is smooth.

Excipients :

Drug-containing tablet layer povidone K90 – 8.34 mg, hypromellose 2208 – 23.40 mg, methacrylic acid – ammonium methacrylate copolymer – 9.332 mg, colloidal silicon dioxide – 2.168 mg, magnesium stearate (Liga Magnesium Stearate MF-2-V Vegetable) – 2.254 mg, talc – 2.42 mg.
Drug release layer of the tablet silicified microcrystalline cellulose 132.52 mg, crospovidone 24.862 mg, colloidal silicon dioxide 4.144 mg, sodium lauryl sulfate 1.658 mg, aluminum lake blue 0.414 mg, magnesium stearate 1.74 mg, talc 0.414 mg.
Functional coating ethylcellulose aqueous dispersion (Aquacoat ECD-30) 39.417 mg, dibutyl sebacate 9.854 mg, triethyl citrate 1.971 mg, polysorbate-20 0.142 mg, talc 5.709 mg.
Outer coating Opadry II 85F19250 clear (polyvinyl alcohol, partially hydrolyzed 52.260%, talc 30.000%, macrogol (polyethylene glycol) 14.740%, polysorbate-80 3.000%) 30.83 mg.
Printing ink composition Opacode black S-1-17823 (shellac glaze-45% (20% esterified) in ethanol 44.467%, isopropanol 26.882%, iron oxide black dye 23.409%, butanol 2.242%, propylene glycol 2.000%, ammonium hydroxide 28% 1.000%) q.s., isopropanol q.s.

10 pcs. – PVC/aluminum foil blisters (3) – cardboard packs.
10 pcs. – PVC/aluminum foil blisters (6) – cardboard packs.

Extended-release film-coated tablets oval, biconvex, two-layer, with a blue layer having a laser-drilled hole and a white to off-white layer; one side is imprinted with “576” in black ink, the other side is smooth.

Excipients :

Drug-containing tablet layer povidone K90 – 12.51 mg, hypromellose 2208 – 35.10 mg, methacrylic acid – ammonium methacrylate copolymer – 13.998 mg, colloidal silicon dioxide – 3.252 mg, magnesium stearate (Liga Magnesium Stearate MF-2-V Vegetable) – 3.381 mg, talc – 3.63 mg.
Drug release layer of the tablet silicified microcrystalline cellulose 198.78 mg, crospovidone 37.293 mg, colloidal silicon dioxide 6.216 mg, sodium lauryl sulfate 2.487 mg, aluminum lake blue 0.621 mg, magnesium stearate 2.61 mg, talc 0.621 mg.
Functional coating ethylcellulose aqueous dispersion (Aquacoat ECD-30) 59.126 mg, dibutyl sebacate 14.781 mg, triethyl citrate 2.956 mg, polysorbate-20 0.213 mg, talc 8.564 mg.
Outer coating Opadry II 85F19250 clear (polyvinyl alcohol, partially hydrolyzed 52.260%, talc 30.000%, macrogol (polyethylene glycol) 14.740%, polysorbate-80 3.000%) 46.246 mg.
Printing ink composition Opacode black S-1-17823 (shellac glaze-45% (20% esterified) in ethanol 44.467%, isopropanol 26.882%, iron oxide black dye 23.409%, butanol 2.242%, propylene glycol 2.000%, ammonium hydroxide 28% 1.000%) q.s., isopropanol q.s.

6 pcs. – PVC/aluminum foil blisters (5) – cardboard packs.
6 pcs. – PVC/aluminum foil blisters (10) – cardboard packs.

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). Its chemical structure differs 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 reverses currents through GABA- and glycine-dependent channels reduced by zinc and β-carbolines. In vitro studies have also 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 an audiogenic model of epilepsy in mice. This 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 activity. 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 highly soluble substance with high permeability. 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 dose of 1500 mg was reached in 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 from the administered dose in mg/kg body weight. The extent of absorption is independent of dose and food intake. Bioavailability is approximately 100%.

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

Plasma protein binding 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 after 2 days when taken twice daily.

Levetiracetam is not extensively 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 hepatic cytochrome P450 isoenzymes. 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 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.

In elderly patients, T_1/2 increases by 40% and is 10-11 h, 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 end-stage 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 to 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 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 aged 16 years and older 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 aged 12 years and older with juvenile myoclonic epilepsy; primary generalized tonic-clonic seizures in patients aged 12 years and older with idiopathic generalized epilepsy.

ICD codes

Dosage Regimen

Orally, IV.

Treatment can be started either orally or with IV administration.

Transition from oral to IV administration and vice versa can be done while maintaining the dose and frequency of administration.

Depending on the indication and patient age, the 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 attacks, emotional lability, agitation; rare – suicide, personality disorder, thinking abnormal, delusion.

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, gait disturbance, encephalopathy, convulsion aggravated.

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 creatine phosphokinase.

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

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 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 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 levetiracetam treatment 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 cell count is recommended for patients who develop severe weakness, hyperthermia, recurrent infections or coagulation disorders.

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

Abnormal and aggressive behavior: Levetiracetam may cause psychotic symptoms and behavioral disturbances, including irritability and aggressiveness. Patients receiving Levetiracetam should be monitored regularly for the development of certain psychiatric signs indicating significant changes in mood and/or personality. If such behavior is observed, potential treatment adaptation or gradual discontinuation should be considered. If discontinuation of levetiracetam therapy is considered, the dose should be changed according to the recommended dosing regimen.

Worsening of seizures: like other antiepileptic drugs, Levetiracetam may rarely increase the frequency or severity of seizures. This paradoxical effect has been most frequently reported during the first month after starting levetiracetam or increasing the dose, and it was reversible after drug withdrawal or dose reduction. Patients should consult their doctor immediately in case of worsening of the disease.

Prolonged 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 concomitantly 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, intelligence, growth, endocrine function, puberty and reproductive potential of children remain unknown.

Effect on ability to drive and operate machinery

Levetiracetam has minimal to moderate influence on the ability to drive and operate machinery. Due to possible differences in individual sensitivity, some patients may develop drowsiness or other central nervous system symptoms during treatment, especially at the beginning of treatment or after a dose increase. Therefore, such patients are advised to exercise caution when performing tasks requiring developed skills, such as driving a car or operating machinery. Patients should refrain from driving 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. However, the concentration of this metabolite remains low.

When levetiracetam and methotrexate were used concomitantly, a decrease in methotrexate clearance 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 medications, 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.