levetiracetam

Dosage and Administration ( 2.1 ) 06/2025

1 INDICATIONS AND USAGE Levetiracetam tablets for oral suspension are indicated for the treatment of partial-onset seizures in patients 4 years of age and older weighing more than 20 kg ( 1.1 ) Levetiracetam tablets for oral suspension are 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 tablets for oral suspension are indicated for the treatment of partial-onset seizures in patients 4 years of age and older weighing more than 20 kg. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam tablets for oral suspension are 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 tablets for oral suspension are 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 Levetiracetam tablets for oral suspension are intended to disintegrate in the mouth when taken with a sip of liquid. Swallow only after the tablet disintegrates. Do not swallow tablet(s) intact. Partial tablet(s) should not be administered ( 2.1 ) Alternately, add whole Levetiracetam tablet(s) for oral suspension to a small volume of liquid in a cup (one tablespoon or enough to cover the medicine). Allow the tablet(s) to disperse prior to consuming entire contents immediately ( 2.1 ) Levetiracetam tablets for oral suspension may also be administered via nasogastric or gastrostomy feeding tubes ( 2.1 ) Recommended dosage ( 2.2 ): Age and Body Weight Initial Dosage Titration Regimen Maximum or Recommended Dosage Adults and pediatric patients weighing over 40 kg 500 mg twice daily Increase by 500 mg twice daily every 2 weeks Partial-Onset Seizures Maximum dosage of 1,500 mg twice daily Myoclonic ± and PGTC ± Recommended dosage of 1,500 mg twice daily Pediatric patients weighing 20 kg to 40 kg 250 mg twice daily Increase by 250 mg twice daily every 2 weeks Maximum 750 mg twice daily Adult Patients with Renal Impairment Dose adjustment is recommended based on creatinine clearance ( 2.3 , 8.6 ) 2.1 Important Preparation and Administration Instructions The Levetiracetam tablets for oral suspension dosing regimen depends on the indication, age group, and renal function. Administer Levetiracetam tablets for oral suspension with or without food. Do not administer partial tablets. Patients should be instructed not to push the tablet through the foil. The foil should be peeled away from the blister by bending up and lifting the peel tab around the blister seal. Oral Administration Levetiracetam tablets for oral suspension are intended to disintegrate in the mouth when taken with a sip of liquid, one tablet at a time. As a primary method of administration, place one tablet on the tongue with a dry hand, follow with a sip of liquid and swallow only after the tablet disintegrates. Repeat this step, if needed, until the full dose has been administered. Do not swallow tablet(s) intact. Levetiracetam tablets for oral suspension disintegrate in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth when taken with a sip of liquid. Alternately, add whole Levetiracetam tablet(s) for oral suspension to a small volume of liquid in a cup (one tablespoon or enough liquid to cover the medicine). Allow the tablet(s) to fully disperse, then immediately consume the entire contents by mouth using the cup or an oral syringe. After administration of the suspension, re-suspend any residue by adding an additional small volume of liquid to the cup, swirl, then swallow the entire contents. Nasogastric Tube (NG Tube) or Gastrostomy Tube (G-Tube) Administration For patients who have a NG tube or G tube (French size 10 to 14) in place, administer Levetiracetam tablets for oral suspension as follows: Place the number of whole tablets needed for the prescribed dose in a small dosing cup, Add approximately 10 mL of room temperature water. Gently swirl the cup until the tablet(s) disperse. Draw up the mixture into a 10 mL oral catheter-tip syringe, hold the syringe in a vertical position, and administer immediately via feeding tube. After administration, flush the feeding tube twice, as follows: Add another 10 mL of room temperature water to the dosing cup that contained the dispersion. Swirl the cup to re-suspend any tablet residue. Draw up the mixture into the same oral syringe and immediately push through the feeding tube. 2.2 Recommended Dosage See Table 1 for the recommended dosage for patients with partial-onset seizures, myoclonic seizures with juvenile myoclonic epilepsy, and primary generalized tonic-clonic seizures. Table 1: Recommended Dosage for Patients with: Partial-Onset Seizures (4 years age and older)*, Myoclonic Seizures (12 years of age and older), and Primary Generalized Tonic-Clonic Seizures (PGTC) (6 year …

3 DOSAGE FORMS AND STRENGTHS Tablet(s) for oral suspension: 250 mg: round, white to off-white, spearmint-flavored, marked with " " on one side 500 mg: round, white to off-white, spearmint-flavored, marked with " " on one side Tablets for oral suspension: 250 mg and 500 mg ( 3 ) Imprint Marking Imprint Marking

4 CONTRAINDICATIONS Levetiracetam tablets for oral suspension are 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 serious adverse reactions are described below and elsewhere in the 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 (5.9) ] Increase in Blood Pressure [see Warnings and Precautions (5.10) ] Most common adverse reactions (incidence ≥ 5% more than placebo) include: Adults: somnolence, asthenia, infection, and dizziness ( 6.1 ) Pediatrics: fatigue, aggression, nasal congestion, decreased appetite, and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Aprecia Pharmaceuticals, LLC at 1-844-882-7732 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 4 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 4: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults with Partial- Onset Seizures Adverse Reaction 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 5 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 5: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Pooled Placebo- Controlled Studies in Adults with Partial-Onset Seizures Adverse Reaction Levetiracetam (N=769) % Placebo (N=439) % Somnolence 4 2 Dizziness 1 0 Pediatric Patients 4 Years to Less Than 16 Years of Age The adverse reaction data presented below was obtained from a pooled analysis of two controlled clinical studies in pediatric patients 4 to less than 16 years of age with partial-onset seizures. The most common adverse reactions in pediatric patients 4 to less than 16 years of age receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability. Table 6 lists adverse reactions from the pooled pediatric controlled studies …

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 tablets for oral suspension, during pregnancy. Encourage women who are taking Levetiracetam tablets for oral suspension 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 2-4% and 15-20%, 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 do …

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 tablets for oral suspension are an antiepileptic drug available as 250 mg and 500 mg, round, white to off-white, spearmint-flavored tablets for oral suspension. 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. 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 for oral suspension contain 250 mg and 500 mg levetiracetam. Each tablet also contains the following inactive ingredients: colloidal silicon dioxide, glycerin, mannitol, microcrystalline cellulose, polysorbate 20, povidone, sucralose, butylated hydroxyanisole, and natural and artificial spearmint flavor. Levetiracetam tablets for oral suspension are unitary porous structures produced by a three-dimensional printing process that binds the powders without compression. Levetiracetam tablets for oral suspension disintegrate in a mean time of 11 seconds (ranging from 2 to 27 seconds) in the mouth, when taken with a sip of liquid, to produce small particles that may be swallowed. 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 tablets for oral suspension. 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 tablets for oral suspension. 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 tablet(s) for oral suspension are supplied in child-resistant blisters as follows: 250 mg: round, white to off-white, spearmint-flavored tablets, marked with “ ” on one side Commercial Use: 60 tablets per carton (6 tablets per blister card x 10 cards) (NDC 66993-100-60) Institutional Use: 6 tablets per carton (6 tablets per blister card x 1 card) (NDC 66993-100-06) 500 mg: round, white to off-white, spearmint-flavored tablets, marked with “ ” on one side Commercial Use: 60 tablets per carton (6 tablets per blister card x 10 cards) (NDC 66993-101-60) 11 12 16.2 Storage Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].