LEVETIRACETAM solution

1 INDICATIONS AND USAGE Levetiracetam is indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) Levetiracetam 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 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 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 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 80 500 to 1,500 Every 12 hours Mild 50 – 80 500 to 1,000 Every 12 hours Moderate 30 – 50 250 to 750 Every 12 hours Severe < 30 250 to 500 Every 12 hours ESRD patients using dialysis ---- 500 to 1,000 * Every 24 hours * * Following dialysis, a 250 to 500 mg supplemental dose is recommended. "Image Description" "Image Description" 2.6 Discontinuation of Levetiracetam Avoid abrupt withdrawal from levetiracetam in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions ( 5.8 )] .

3 DOSAGE FORMS AND STRENGTHS Levetiracetam Oral Solution 100 mg/mL is a clear, colorless, grape-flavored liquid. 100 mg/mL solution ( 3 )

4 CONTRAINDICATIONS Levetiracetam 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 Chartwell RX, LLC. at 1-845-232-1683 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 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 to 16 years of age) that occurred …

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 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, 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/m 2 basis. Oral administration of levetiracetam to rats during the latter part of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis). 8.2 Lactation Risk Summary Levetiracetam is excreted in human milk. There are no data on the effects of levetiracetam on the breastfed infant, or the effects on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for levetiracetam and any potential adverse effects on the breastfed infant from levetiracetam or fro …

11 DESCRIPTION Levetiracetam Oral Solution, USP is an antiepileptic drug available as a clear, colorless, 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 Oral Solution contains 100 mg of levetiracetam per mL. Inactive ingredients: acesulfame potassium, citric acid, grape flavor, glycerin, methylparaben, propylparaben, purified water, sodium citrate, and sorbitol solution. "Image Description"

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.

16 HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied Levetiracetam Oral Solution, USP 100 mg/mL, is a clear, colorless, grape-flavored liquid, and supplied as follows: 5 mL Unit Dose Cup (NDC 68999-548-45) 20 Unit Dose Cups of 5 mL (NDC 68999-548-24) 16.2 Storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].