LEVETIRACETAM

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

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.

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 years of age and older) Age and Body Weight Initial Dosage Titration Regimen Maximum or Recommended Dosage Adults and pediatric patients weighing over 40 kg 500 mg twice daily (1,000 mg daily) Increase by 500 mg twice daily (1,000 mg daily) every 2 weeks Partial-Onset Seizures** Maximum dosage of 1,500 mg twice daily (3,000 mg daily)** Myoclonic ± and PGTC ± Recommended dosage of 1,500 mg twice daily (3,000 mg daily) Pediatric patients weighing 20 kg to 40 kg 250 mg twice daily (500 mg daily) Increase by 250 mg twice daily (500 mg daily) every 2 weeks Maximum dosage of 750 mg twice daily (1,500 mg daily) * The recommended dosing for monotherapy and adjunctive therapy is the same. ** There is no evidence that doses greater than 3,000 mg daily confer additional benefit. ± The effectiveness of doses lower than 3,000 mg daily has not been adequately studied. 2.3 Dosage Adjustments in Adult Patients with Renal Impairment Levetiracetam tablets for oral suspension dosing must be individualized according to the patient’s renal function status. Recommended dosage adjustments for adults are shown in Table 2 . 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: Then CLcr is adjusted for body surface area (BSA) as follows: Table 2: Dosing Regimen For Adult Patients With Renal Impairment 1 Following dialysis, a 250 to 500 mg supplemental dose is recommended. Group Creatinine Clearance (mL/min/1.73m 2 ) Levetiracetam Tablets for Oral Suspension Dosage (mg) Frequency Normal >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 1 Every 24 hours 1 Recommended Dosage Adjustment Formula Recommended Dosage Adjustment Formula 2.4 Discontinuation of Levetiracetam Tablets for Oral Suspension Avoid abrupt withdrawal of Levetiracetam tablets for oral suspension in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.8) ].

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 )

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 (4 to less than 16 years of age) that occurred in at least 2% of pediatric levetiracetam-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either levetiracetam or placebo was added to concurrent AED therapy. Table 6: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients 4 to 16 Years of Age with Partial-Onset Seizures Adverse Reaction Levetiracetam (N=165) % Placebo (N=131) % Headache 19 15 Nasopharyngitis 15 12 Vomiting 15 12 Somnolence 13 9 Fatigue 11 5 Aggression 10 5 Cough 9 5 Nasal Congestion 9 2 Upper Abdominal Pain 9 8 Decreased Appetite 8 2 Abnormal Behavior 7 4 Dizziness 7 5 Irritability 7 1 Pharyngolaryngeal Pain 7 4 Diarrhea 6 2 Lethargy 6 5 Insomnia 5 3 Agitation 4 1 Anorexia 4 3 Head Injury 4 0 Altered Mood 3 1 Constipation 3 1 Contusion 3 1 Depression 3 1 Fall 3 2 Influenza 3 1 Affect Lability 2 1 Anxiety 2 1 Arthralgia 2 0 Confusional State 2 0 Conjunctivitis 2 0 Ear Pain 2 1 Gastroenteritis 2 0 Joint Sprain 2 1 Mood Swings 2 1 Neck Pain 2 1 Rhinitis 2 0 Sedation 2 1 In the controlled pooled pediatric clinical studies in patients 4 years to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse reaction. Myoclonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures. In the controlled clinical study in patients 12 years of age and older with myoclonic seizures, [see Clinical Studies (14.2) ] , the most common adverse reactions in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis. Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Table 7: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Patients 12 Years of Age and Older with Myoclonic Seizures Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Somnolence 12 2 Neck pain 8 2 Pharyngitis 7 0 Depression 5 2 Influenza 5 2 Vertigo 5 3 In the placebo-controlled study, 8% of patients receiving levetiracetam and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 8 . Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy Adverse Reaction Levetiracetam (N=60) % Placebo (N=60) % Anxiety 3 2 Depressed mood 2 0 Depression 2 0 Diplopia 2 0 Hypersomnia 2 0 Insomnia 2 0 Irritability 2 0 Nervousness 2 0 Somnolence 2 0 Primary Generalized Tonic-Clonic Seizures Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial-onset seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures. In the controlled clinical trial in patients with PGTC seizures [see Clinical Studies (14.3) ] , the most common adverse reaction in patients receiving levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis. Table 9 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Table 9: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Patients 4 Years of Age and Older with PGTC Seizures Adverse Reaction Levetiracetam (N=79) % Placebo (N=84) % Nasopharyngitis 14 5 Fatigue 10 8 Diarrhea 8 7 Irritability 6 2 Mood swings 5 1 In the placebo-controlled study, 5% of patients receiving levetiracetam and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction. This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see Table 5 and Table 8 ). In addition, the following adverse reactions were seen in other controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision. Comparison of Gender, Age, and Race The overall adverse reaction profile of levetiracetam was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race. 6.2 Postmarketing Experience The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The listing is alphabetized: abnormal liver function test, acute kidney injury, agranulocytosis, anaphylaxis, angioedema, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, obsessive-compulsive disorders (OCD), pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, weight loss, and worsening of seizures including in patients with SCN8A mutations. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.