Levetiracetam

Indications and Usage ( 1.1 ) 10/2019 Dosage and Administration ( 2.2 , 2.6 ) 10/2019

1 INDICATIONS & USAGE Levetiracetam oral solution is indicated for the treatment of partial-onset seizures in patients 1 month of age and older (1.1) Levetiracetam oral solution is indicated for adjunctive therapy for the treatment of: Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy (1.2) Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy (1.3) 1.1 Partial-Onset Seizures Levetiracetam oral solution is indicated for the treatment of partial-onset-seizures in patients 1 month of age and older. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam oral solution is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam oral solution is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

1.1 Partial-Onset Seizures Levetiracetam oral solution is indicated for the treatment of partial-onset-seizures in patients 1 month of age and older.

1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam oral solution is indicated as adjunctive therapy for the treatment of myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy.

1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam oral solution is indicated as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy.

2 DOSAGE AND ADMINISTRATION • Use the oral solution for pediatric patients with body weight ≤ 20 kg ( 2.1 ) • For pediatric patients, use weight-based dosing for the oral solution with a calibrated measuring device (not a household teaspoon or tablespoon) ( 2.1 ) Partial-Onset Seizures (monotherapy or adjunctive therapy) • 1 Month to ˂ 6 Months: 7 mg/kg twice daily; increase by 7 mg/kg twice daily every 2 weeks to recommended dose of 21 mg/kg twice daily ( 2.2 ) • 6 Months to ˂ 4 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 25 mg/kg twice daily ( 2.2 ) • 4 Years to ˂ 16 Years: 10 mg/kg twice daily; increase by 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.2 ) • Adults 16 Years and Older: 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to a recommended dose of 1500 mg twice daily ( 2.2 ) Myoclonic Seizures in Adults and Pediatric Patients 12 Years and Older • 500 mg twice daily; increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.3 ) Primary Generalized Tonic-Clonic Seizures • 6 Years to ˂ 16 Years: 10 mg/kg twice daily, increase in increments of 10 mg/kg twice daily every 2 weeks to recommended dose of 30 mg/kg twice daily ( 2.4 ) • Adults 16 Years and Older: 500 mg twice daily, increase by 500 mg twice daily every 2 weeks to recommended dose of 1500 mg twice daily ( 2.4 ) Adult Patients with Impaired Renal Function • Dose adjustment is recommended, based on the patient's estimated creatinine clearance ( 2.5 , 8.6 ) 2.1 Important Administration Instructions Levetiracetam Oral Solution USP is given orally with or without food. The Levetiracetam Oral Solution USP dosing regimen depends on the indication, age group, dosage form (tablets or oral solution), and renal function. Prescribe the oral solution for pediatric patients with body weight ≤ 20 kg. Prescribe the oral solution or tablets for pediatric patients with body weight above 20 kg. When using the oral solution in pediatric patients, dosing is weight-based (mg per kg) using a calibrated measuring device (not a household teaspoon or tablespoon). 2.2 Dosing for Partial-Onset Seizures The recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below. Adults 16 Years of Age and Older Initiate treatment with a daily dose of 1000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3000 mg. There is no evidence that doses greater than 3000 mg/day confer additional benefit. Pediatric Patients 1 Month to ˂ 6 Months Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group. 6 Months to ˂ 4 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily). If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group. 4 Years to ˂ 16 Years Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3000 mg/day. Levetiracetam Oral Solution USP Weight-Based Dosing Calculation For Pediatric Patients The following calculation should be used to determine the appropriate daily dose …

3 DOSAGE FORMS AND STRENGTHS Levetiracetam tablets USP, 250 mg are blue, film coated caplet shape tablets, scored on one side. Engraved "LVT" on left of the score line and "250" on the right, and engraved "TARO" on the other side. Levetiracetam tablets USP, 500 mg are yellow, film coated caplet shape tablets, scored on one side. Engraved "LVT" on left of the score line and "500" on the right, and engraved "TARO" on the other side. Levetiracetam tablets USP, 750 mg are peach, film coated caplet shape tablets, scored on one side. Engraved "LVT" on left of the score line and "750" on the right, and engraved "TARO" on the other side. Levetiracetam tablets USP, 1000 mg are white to off-white, film coated caplet shaped tablets, scored, engraved "LVT" on the left of the score line and "1000" on the right and engraved "TARO" on the other side. Levetiracetam oral solution USP, 100 mg/mL is a clear, to yellowish, grape-flavored liquid. 250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( 3 ) 100 mg/mL solution ( 3 )

4 CONTRAINDICATIONS Levetiracetam Oral Solution USP is contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [ see Warnings and Precautions ( 5.4 ) ] . Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred ( 4 , 5.4 )

6 ADVERSE REACTIONS The following adverse reactions are discussed in more details in other sections of labeling: Behavior 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 (5.9) ] Increase in Blood Pressure [ see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥ 5% more than placebo) include: Adult patients: somnolence, asthenia, infection and dizziness ( 6.1 ) Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Bionpharma Inc. at 1-888-235-BION or 1-888­235-2466 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 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. Partial-Onset Seizures Adults In controlled clinical studies in adults with partial-onset seizures [ see Clinical Studies (14.1) ] , the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection, and dizziness. Of the most common adverse reactions in adults experiencing partial-onset seizures, asthenia, somnolence, and dizziness occurred predominantly during the first 4 weeks of treatment with levetiracetam. Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults Experiencing Partial-Onset Seizures Levetiracetam (N = 769) % Placebo (N = 439) % Asthenia 15 9 Somnolence 15 8 Headache 14 13 Infection 13 8 Dizziness 9 4 Pain 7 6 Pharyngitis 6 4 Depression 4 2 Nervousness 4 2 Rhinitis 4 3 Anorexia 3 2 Ataxia 3 1 Vertigo 3 1 Amnesia 2 1 Anxiety 2 1 Cough Increased 2 1 Diplopia 2 1 Emotional Lability 2 0 Hostility 2 1 Paresthesia 2 1 Sinusitis 2 1 In controlled adult clinical studies, 15% of patients receiving levetiracetam and 12% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. Table 4 lists the most common (> 1%) adverse reactions that resulted in discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients. Table 4: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Placebo-Controlled Studies in Adult Patients Experiencing Partial-Onset Seizures Adverse Reaction Levetiracetam (N = 769) % Placebo (N = 439) % Somnolence 4 2 Dizziness 1 0 Pediatric Patients 4 Years to < 16 Years The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies in pediatric patients 4 years to 16 years of age with partial-onset seizures. The most common adverse reactions in pediatric patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 year …

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 ( 5.11 , 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, during pregnancy. Encourage women who are taking levetiracetam 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 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 blood levels may decrease during pregnancy [see Warnings and Precautions (5.11) ] . 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 mg/kg/day, 400 mg/kg/day, 1,200 mg/kg/day, or 3,600 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 (1,200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of 3,000 mg on a body surface area (mg/m 2 ) basis. Oral administration of levetiracetam (0 mg/kg/day, 200 mg/kg/day, 600 mg/kg/day, or 1,800 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 mg/kg/day, 70 mg/kg/day, 350 mg/kg/day, or 1,800 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/m 2 basis. Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no …

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 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 is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow), 750 mg (peach), and 1000 mg (white to off-white) tablets and as a clear to yellowish, grape-flavored liquid (100 mg/mL) 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 Tablets, USP contain the labeled amount of levetiracetam. Inactive ingredients: colloidal silicon dioxide, corn starch, magnesium stearate, povidone, talc and additional ingredients listed below: 250 mg tablets: opadry blue 03B20463 (contains FD&C Blue #2/indigo carmine aluminum lake, hypromellose, polyethylene glycol and titanium dioxide) 500 mg tablets: opadry yellow 03B32441 (contains hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, and titanium dioxide) 750 mg tablets: opadry pink 03B34672 (contains hypromellose, iron oxide black, iron oxide red, iron oxide yellow, polyethylene glycol, and titanium dioxide) 1000 mg tablets: opadry white Y-1-7000 (contains hypromellose polyethylene glycol and titanium dioxide) Levetiracetam Oral Solution, USP contains 100 mg of levetiracetam per mL. Inactive ingredients: acesulfame potassium, citric acid monohydrate, glycerin, grape flavor, maltitol solution, methylparaben, mono ammonium glycyrrhizinate, propylparaben, purified water, and sodium citrate dihydrate. Meets USP Dissolution Test 2. Chemical Structure

10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage In Humans The highest known dose of levetiracetam received in the clinical development program was 6000 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 levetiracetam overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. 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. 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.

10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage In Humans The highest known dose of levetiracetam received in the clinical development program was 6000 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 levetiracetam overdoses in postmarketing use.

10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam. 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.

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 Tablets USP, 250 mg are blue, film coated caplet shape tablets, scored on one side, engraved with "LVT" on the left of the score and "250" on the right, and "TARO" on the other side. They are supplied in white HDPE bottles containing: 30 Tablets (NDC 51672-4141-6); 120 Tablets (NDC 51672-4141-1); 1000 Tablets (NDC 51672-4141-3); and Blisters of 100 (10 × 10) (NDC 51672-4141-0). Levetiracetam Tablets USP, 500 mg are yellow, film coated caplet shape tablets, scored on one side, engraved with "LVT" on the left of the score and "500" on the right, and "TARO" on the other side. They are supplied in white HDPE bottles containing: 30 Tablets (NDC 51672-4142-6); 120 Tablets (NDC 51672-4142-1); 1000 Tablets (NDC 51672-4142-3); and Blisters of 100 (10 × 10) (NDC 51672-4142-0). Levetiracetam Tablets USP, 750 mg are peach, film coated caplet shape tablets, scored on one side, engraved with "LVT" on the left of the score and "750" on the right, and "TARO" on the other side. They are supplied in white HDPE bottles containing: 30 Tablets (NDC 51672-4143-6); 120 Tablets (NDC 51672-4143-1); 1000 Tablets (NDC 51672-4143-3); and Blisters of 100 (10 × 10) (NDC 51672-4143-0). Levetiracetam Tablets USP, 1000 mg are white to off-white, film coated caplet shaped tablets, scored on one side, engraved with "LVT" on the left of the score and "1000" on the right, and "TARO" on the other side. They are supplied in white HDPE bottles containing: 30 Tablets (NDC 51672-4137-6); 60 Tablets (NDC 51672-4137-4); and 750 Tablets (NDC 51672-4137-8). Levetiracetam Oral Solution USP, 100 mg/mL is a clear to yellowish, grape-flavored liquid. It is supplied in HDPE bottles: 100 mL (NDC 51672-4136-7); 473 mL (NDC 51672-4136-9); and 3785 mL (NDC 51672-4136-0). 16.2 Storage Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].