LEVETIRACETAM

RECENT MAJOR CHANGES -----------------------------------RECENT MAJOR CHANGES--------------------------------- Warnings and Precautions ( 5.6) 4/2024

1 INDICATIONS AND USAGE Levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older ( 1 ) Levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION Initiate treatment with a dose of 1,000 mg once daily; increase by 1,000 mg every 2 weeks to a maximum recommended dose of 3,000 mg once daily ( 2 ) See full prescribing information for use in patients with impaired renal function ( 2.1 ) 2.1 Recommended Dosing For adults and adolescent patients, the recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below. Adults and Adolescents 12 Years of Age and Older Weighing 50 kg or More Initiate treatment with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg/day once daily. Administration Levetiracetam extended-release tablets are administered once daily. Levetiracetam extended-release tablets should be swallowed whole. The tablets should not be chewed, broken, or crushed. 2.2 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam extended-release tablets dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this, an estimate of the patient's creatinine clearance (CLcr) in mL/min must first be calculated using the following formula: [140-age (years)] x weight (kg) (x 0.85 for female patients) CLcr = ------------------------------------------------------------------------- 72 x serum creatinine (mg/dL) Then CLcr is adjusted for body surface area (BSA) as follows: CLcr (mL/min) CLcr (mL/min/1.73m2) = ---------------------------- x 1.73 BSA subject (m 2 ) Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment Group Creatinine Clearance (mL/min/1.73m 2 ) Dosage (mg) Frequency Normal > 80 1,000 to 3,000 Every 24 hours Mild 50 – 80 1,000 to 2,000 Every 24 hours Moderate 30 – 50 500 to 1,500 Every 24 hours Severe < 30 500 to 1,000 Every 24 hours 2.3 Discontinuation of Levetiracetam Extended-Release Tablets Avoid abrupt withdrawal from levetiracetam extended-release tablets in order to reduce the risk of increased seizure frequency and status epilepticus [see warnings and precautions (5.7) ] .

3 DOSAGE FORMS AND STRENGTHS 500 mg white, film-coated extended-release tablet ( 3 ) 750 mg white, film-coated extended-release tablet ( 3 ) Levetiracetam extended-release tablets, USP are white to off-white, capsule shaped, film coated tablets debossed with '1272' on one side and plain on other side and contain 500 mg levetiracetam. Levetiracetam extended-release tablets, USP are white to off-white colored, oval shaped, beveled edge, biconvex film coated tablets debossed with '1300' on one side and plain on other side and contain 750 mg levetiracetam.

4 CONTRAINDICATIONS Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 , 5.4 ) Levetiracetam extended-release tablets are contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [ see Warnings and Precautions ( 5.4 )].

6 ADVERSE REACTIONS Most common adverse reactions (incidence ≥5% more than placebo) include: somnolence and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. The following adverse reactions are discussed in more details in other sections of labeling: • Behavioral abnormalities and Psychotic Symptoms [see Warnings and Precautions ( 5.1 )] • Suicidal Behavior and Ideation [ see Warnings and Precautions ( 5.2 )] • Somnolence and Fatigue [see Warnings and Precautions ( 5.3 )] • Anaphylaxis and Angioedema [see Warnings and Precautions ( 5.4 )] • Serious Dermatological Reactions [ see Warnings and Precautions ( 5.5 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions ( 5.6 )] • Coordination Difficulties [see Warnings and Precautions ( 5.7 )] • Hematologic Abnormalities [see Warnings and Precautions ( 5.8 )] 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Levetiracetam Extended-Release Tablets In the controlled clinical study in patients with partial-onset seizures [see Clinical Studies ( 14.1 )], the most common adverse reactions in patients receiving levetiracetam extended-release tablets in combination with other AEDs, for events with rates greater than placebo, were irritability and somnolence. Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving levetiracetam extended-release tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either levetiracetam extended-release tablets or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in the Placebo-Controlled, Adjunctive Study in Patients Experiencing Partial-Onset Seizures Levetiracetam Extended-Release tablets (N=77) % Placebo (N=79) % Influenza 8 4 Somnolence 8 3 Irritability 7 0 Nasopharyngitis 7 5 Dizziness 5 3 Nausea 5 3 Discontinuation or Dose Reduction in the Levetiracetam Extended-Release Tablets Controlled Clinical Study: In the controlled clinical study, 5% of patients receiving levetiracetam extended-release tablets and 3% receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in discontinuation and that occurred more frequently in levetiracetam extended-release tablets-treated patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash, and respiratory failure. Each of these adverse reactions led to discontinuation in an levetiracetam extended-release tablets-treated patient and no placebo-treated patients. Immediate-Release Levetiracetam Tablets Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets in adult patients experiencing partial-onset seizures [see Clinical Studies ( 14.2 )] . Although the pattern of adverse reactions in the levetiracetam extended-release tablets study seems somewhat different from that seen in partial-onset seizure controlled studies for immediate-release levetiracetam tablets, this is possibly due to the much smaller number of patients in this study compared to the immediate-release tablet studies. The adverse reactions for levetiracetam extended-release tablets are expected to be similar to those seen with immediate-release levetiracetam tablets. Adults: In controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other AEDs in adults with partial-onset seizures, the most common adverse reactions, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Table 4 lists adverse reactions t …

8 USE IN SPECIFIC POPULATIONS Pregnancy: Plasma levels of levetiracetam may be decreased and therefore need to be monitored closely during pregnancy. Based on animal data, may cause fetal harm ( 5.10 , 8.1 ) 8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, during pregnancy. Encourage women who are taking levetiracetam extended-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Prolonged experience with levetiracetam tablets in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy registries and reflects experience over two decades [see Human Data] . In animal studies, levetiracetam produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral alterations in offspring) at doses similar to human therapeutic doses [see Animal Data] . In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of major birth defects and miscarriage for the indicated population is unknown. Clinical Considerations Levetiracetam extended-release tablets level may decrease during pregnancy [see Warnings and Precautions ( 5.10 )] . Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response. Data Human Data: While available studies cannot definitively establish the absence of risk, data from the published literature and pregnancy registries have not established an association with levetiracetam use during pregnancy and major birth defects or miscarriage. Animal Data When levetiracetam (0, 400, 1200, or 3600 mg/kg/day) was administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal developmental in rats (1200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3000 mg on a body surface area (mg/m 2 ) basis. Oral administration of levetiracetam (0, 200, 600, or 1800 mg/kg/day) to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately equivalent to the MRHD on a mg/m 2 basis. Oral administration of levetiracetam (0, 70, 350, or 1800 mg/kg/day) to female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations, reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no evidence of maternal toxicity. The no-effect dose for adverse effects on pre-and postnatal development in rats (70 mg/kg/day) is less than the MRHD on a mg/m2 basis. Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or …

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

11 DESCRIPTION Levetiracetam extended-release tablet USP is an antiepileptic drug available as 500 mg and 750 mg (white) extended-release tablets for oral administration. The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine acetamide, its molecular formula is C 8 H 14 N 2 O 2 and its molecular weight is 170.21. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula: Levetiracetam is a white to off-white crystalline powder with a faint odor and a bitter taste. It is very soluble in water (104.0 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7 g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.) Levetiracetam extended-release tablets USP contain the labeled amount of levetiracetam. Inactive ingredients: colloidal silicon dioxide, dibasic calcium phosphate anhydrous, hydrogenated vegetable oil, hypromellose, lactose anhydrous, magnesium stearate, polyvinyl alcohol, polyethylene glycol, talc and titanium dioxide. The imprinting ink contains shellac, iron oxide black and propylene glycol. The medication is combined with a drug release controlling agent that provides a drug release at a controlled rate. The biologically inert components of the tablet may occasionally remain intact during GI transit and will be eliminated in the feces as a soft, hydrated mass. Molecular Structure-Levetiracetam

10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The signs and symptoms for levetiracetam extended-release tablets overdose are expected to be similar to those seen with immediate-release levetiracetam tablets. The highest known dose of oral immediate-release levetiracetam tablets received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression and coma were observed with immediate-release levetiracetam tablets overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam extended-release tablets. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam extended-release tablets. 10.3 Hemodialysis Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient's clinical state or in patients with significant renal impairment.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Levetiracetam extended-release 500 mg tablets, USP are white to off-white, capsule shaped, film coated tablets debossed with '1272' on one side and plain on other side. Bottles of 60 NDC 13668-272-60 Bottles of 120 NDC 13668-272-12 Bottles of 250 NDC 13668-272-25 Bottles of 500 NDC 13668-272-05 Bottles of 1,000 NDC 13668-272-10 Levetiracetam extended-release 750 mg tablets, USP are white to off-white colored, oval shaped, beveled edge, biconvex film coated tablets debossed with '1300' on one side and plain on other side. Bottles of 60 NDC 13668-300-60 Bottles of 120 NDC 13668-300-12 Bottles of 250 NDC 13668-300-25 Bottles of 500 NDC 13668-300-05 16.2 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure.