Levetiracetam

RECENT MAJOR CHANGES SECTION Indications and Usage, Partial Onset Seizures (1.1) [12/2011] Dosage and Administration, Partial Onset Seizures ( 2.1, 2.2 , 2.5 ) [12/2011] Warnings and Precautions ( 5.1 , 5.3 , 5.4 , 5.7 , 5.8 , 5.9 ) [12/2011]

1 INDICATIONS AND USAGE Levetiracetam tablets, USP are antiepileptic drug indicated for adjunctive therapy in the treatment of: Partial onset seizures in patients 4 years of age and older with epilepsy ( 1.1 ) 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, USP are indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 4 years of age and older with epilepsy. Information describing the use of levetiracetam in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.’s levetiracetam tablets and oral solution. However, due to UCB Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information. 1.2 Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy Levetiracetam tablets, USP are indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy. 1.3 Primary Generalized Tonic-Clonic Seizures Levetiracetam tablets, USP are indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

2.1 Important Administration Instructions Levetiracetam tablets are given orally with or without food. The levetiracetam 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). Levetiracetam tablets should be swallowed whole. Levetiracetam tablets should not be chewed or crushed. 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 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 1Following dialysis, a 250 to 500 mg supplemental dose is recommended. 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 250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( 3 ) Levetiracetam 250 mg tablets, USP are blue colored, oval shaped, film-coated tablets debossed with breakline separating '250' and 'MG' on one side and '1014' on other side. Levetiracetam 500 mg tablets, USP are yellow colored, oval shaped, film-coated tablets debossed with breakline separating '500' and 'MG' on one side and '1015' on other side. Levetiracetam 750 mg tablets, USP are orange colored, oval shaped, film-coated tablets debossed with breakline separating '750' and 'MG' on one side and '1016' on other side. Levetiracetam 1000 mg tablets, USP are white to off white, oval shaped, film-coated tablets debossed with breakline separating '1000' and 'MG' on one side and '1017' on other side.

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

The following adverse reactions are discussed in more details in other sections of labeling: Behavior Abnormalities and Psychotic Symptoms [seeWarnings and Precautions (5.1)] Suicidal Behavior and Ideation [seeWarnings and Precautions (5.2)] Somnolence and Fatigue [seeWarnings and Precautions (5.3)] Anaphylaxis and Angioedema [seeWarnings and Precautions (5.4)] Serious Dermatological Reactions [seeWarnings and Precautions (5.5)] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity [see Warnings and Precautions (5.6)] Coordination Difficulties [seeWarnings and Precautions (5.7)] Hematologic Abnormalities [seeWarnings and Precautions (5.9)] Increase in Blood Pressure [seeWarnings and Precautions (5.10)] 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 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 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial-Onset Seizures Levetiracetam (N=165) % Placebo (N=131) % Heada …

7 DRUG INTERACTIONS No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications via human liver cytochrome P450 isoforms, epoxide hydrolase, UDP-glucuronidation enzymes, P-glycoprotein, or renal tubular secretion [see Clinical Pharmacology (12.3) ].

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, 400, 1,200, 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, 200, 600, 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, 70, 350, 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 adverse developmental or maternal effects at doses of up to 1,800 mg/kg/day (6 times the MRHD …

12.1 Mechanism of Action The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown. The antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures. Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold tests. Protection was observed, however, against secondarily generalized activity from focal seizures induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some features of human complex partial seizures with secondary generalization. Levetiracetam also displayed inhibitory properties in the kindling model in rats, another model of human complex partial seizures, both during kindling development and in the fully kindled state. The predictive value of these animal models for specific types of human epilepsy is uncertain. In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation of seizure activity. Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid), glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore, in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-type calcium currents and levetiracetam does not appear to directly facilitate GABAergic neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium currents in neuronal cells. 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, USP is an antiepileptic drug available as 250 mg (blue), 500 mg (yellow) and 750 mg (pink) 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 contain the labeled amount of levetiracetam. Inactive ingredients: Corn starch, povidone, colloidal silicon dioxide, talc, magnesium stearate, and additional agents listed below: 250 mg tablets Opadry Blue (hydroxypropyl methylcellulose, polyethylene glycol 4000, titanium dioxide FD&C Blue #2 Indigo and Carmine Aluminum Lake) 500 mg tablets Opadry Yellow (hydroxypropyl methylcellulose polyethylene glycol 4000 titanium dioxide and Iron oxide Yellow) 750 mg tablets Opadry Pink (hydroxypropyl methylcellulose, polyethylene glycol 4000, titanium dioxide Iron oxide Red and Iron oxide Yellow Meets USP Dissolution Test 3 str

10 OVERDOSAGE 10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans The highest known dose of levetiracetam tablets received in the clinical development program was 6000 mg/day. Other than drowsiness, there were no adverse events 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 tablets overdoses in postmarketing use. 10.2 Management of Overdose There is no specific antidote for overdose with levetiracetam 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 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 Tablets, USP 250 mg are blue, modified oval, scored, film-coated tablets debossed with “JX ǀ 011” on one side. Bottles of 30 tablets (NDC 87063-190-30 repackaged from NDC 27808-263-XX) Bottles of 60 tablets (NDC 87063-190-60 repackaged from NDC 27808-263-XX) Bottles of 90 tablets (NDC 87063-190-90 repackaged from NDC 27808-263-XX) Bottles of 120 tablets (NDC 87063-190-12 relabeled from NDC 27808-263-01) Levetiracetam Tablets, USP 500 mg are green, modified oval, scored, film-coated tablets debossed with “JX ǀ 012” on one side. Bottles of 30 tablets (NDC 87063-191-30 repackaged from NDC 27808-264-XX) Bottles of 60 tablets (NDC 87063-191-60 repackaged from NDC 27808-264-XX) Bottles of 90 tablets (NDC 87063-191-90 repackaged from NDC 27808-264-XX) Bottles of 120 tablets (NDC 87063-191-12 relabeled from NDC 27808-264-01) Levetiracetam Tablets, USP 750 mg are pink, modified oval, scored, film-coated tablets debossed with “JX ǀ 015” on one side. Bottles of 30 tablets (NDC 87063-192-30 repackaged from NDC 27808-265-XX) Bottles of 60 tablets (NDC 87063-192-60 repackaged from NDC 27808-265-XX) Bottles of 90 tablets (NDC 87063-192-90 repackaged from NDC 27808-265-XX) Bottles of 120 tablets (NDC 87063-192-12 relabeled from NDC 27808-265-01) Levetiracetam Tablets, USP 1000 mg are white, modified oval, scored, film-coated tablets debossed with “JX ǀ 017” on one side. Bottles of 30 tablets (NDC 87063-193-30 repackaged from NDC 27808-266-XX) Bottles of 60 tablets (NDC 87063-193-60 relabeled from NDC 27808-266-01) Bottles of 90 tablets (NDC 87063-193-90 repackaged from NDC 27808-266-XX) 16.2 Storage Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].