Levetiracetam

KEPPRA is indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) KEPPRA 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 KEPPRA 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 KEPPRA 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 KEPPRA 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.

250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( 3 ) 100 mg/mL solution ( 3 ) KEPPRA Tablets 250 mg: blue, oblong-shaped, scored, film-coated, and debossed with "ucb 250" on one side 500 mg: yellow, oblong-shaped, scored, film-coated, and debossed with "ucb 500" on one side 750 mg: orange, oblong-shaped, scored, film-coated, and debossed with "ucb 750" on one side 1000 mg: white, oblong-shaped, scored, film-coated, and debossed with "ucb 1000" on one side KEPPRA Oral Solution 100 mg/mL: a clear, colorless, grape-flavored liquid

KEPPRA 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 )

Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed; monitor patients for psychiatric signs and symptoms ( 5.1 ) Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior ( 5.2 ) Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained sufficient experience on KEPPRA ( 5.3 ) Serious Dermatological Reactions: Discontinue KEPPRA at the first sign of rash unless clearly not drug related ( 5.5 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity: Discontinue if no alternative etiology ( 5.6 ) Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. Advise patients to not drive or operate machinery until they have gained experience on KEPPRA ( 5.7 ) Withdrawal Seizures: KEPPRA must be gradually withdrawn ( 5.8 )

5.1 Behavioral Abnormalities and Psychotic Symptoms KEPPRA may cause behavioral abnormalities and psychotic symptoms. Patients treated with KEPPRA should be monitored for psychiatric signs and symptoms. Behavioral abnormalities In clinical studies, 13% of adult KEPPRA-treated patients and 38% of pediatric KEPPRA-treated patients (4 to 16 years of age) compared to 6% and 19% of adult and pediatric placebo-treated patients, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder). A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of KEPPRA as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in KEPPRA-treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18). In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the KEPPRA-treated patients compared to 0% of placebo-treated patients. In clinical studies, 1.7% of adult KEPPRA-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult KEPPRA-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of KEPPRA-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients. Psychotic symptoms In clinical studies, 1% of KEPPRA-treated adult patients, 2% of KEPPRA-treated pediatric patients 4 to 16 years of age, and 17% of KEPPRA-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of KEPPRA in pediatric patients 4 to 16 years of age, 1.6% of KEPPRA-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of KEPPRA-treated patients experienced confusional state, compared to 0% of placebo-treated patients [see Use in Specific Populations (8.4) ] . In clinical studies, two (0.3%) KEPPRA-treated adult patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation. There was no difference between drug and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions.

5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including KEPPRA, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide. The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5

2.4 Psychiatric 5.7 8.5 1.5

2.9 Other 1.0 1.8 1.9

0.9 Total 2.4 4.3 1.8

1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing KEPPRA or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.3 Somnolence and Fatigue KEPPRA may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA to gauge whether it adversely affects their ability to drive or operate machinery. Somnolence In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of KEPPRA-treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study where there was no titration, about 45% of patients receiving 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of KEPPRA-treated patients, compared to 0% in the placebo group. […]

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 UCB, Inc. at 1-844-599-2273 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 KEPPRA 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 KEPPRA. Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving KEPPRA in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either KEPPRA or placebo was added to concurrent AED therapy. Table 3: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults Experiencing Partial-Onset Seizures KEPPRA (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 KEPPRA 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 KEPPRA-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 KEPPRA (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 KEPPRA 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 KEPPRA-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either KEPPRA 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 KEPPRA (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 4-16 years of age, 7% of patients receiving KEPPRA and 9% receiving placebo discontinued as a result of an adverse reaction. Pediatric Patients 1 Month to < 4 Years In the 7-day, controlled pediatric clinical study in children 1 month to less than 4 years of age with partial-onset seizures, the most common adverse reactions in patients receiving KEPPRA in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability. Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients. Therefore, other controlled pediatric data, presented above, should also be considered to apply to this age group. Table 6 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with KEPPRA in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either KEPPRA or placebo was added to concurrent AED therapy. Table 6: Adverse Reactions in a Placebo-Controlled, Adjunctive Study in Pediatric Patients Ages 1 Month to < 4 Years Experiencing Partial-Onset Seizures KEPPRA (N=60) % Placebo (N=56) % Somnolence 13 2 Irritability 12 0 In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving KEPPRA and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. There was no adverse reaction that resulted in discontinuation for more than one patient. 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 KEPPRA 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 KEPPRA and were numerically more common than in patients treated with placebo. In this study, either KEPPRA 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 KEPPRA (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 KEPPRA and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. […]

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 KEPPRA, during pregnancy. Encourage women who are taking KEPPRA 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 KEPPRA 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 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 KEPPRA 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 KEPPRA and any potential adverse effects on the breastfed infant from KEPPRA or from the underlying maternal condition.

8.4 Pediatric Use The safety and effectiveness of KEPPRA for the treatment of partial-onset seizures in patients 1 month to 16 years of age have been established [see Clinical Pharmacology (12.3) and Clinical Studies (14.1) ] . The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and Administration (2.2) ] . The safety and effectiveness of KEPPRA as adjunctive therapy for the treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established [see Clinical Studies (14.2) ] . The safety and effectiveness of KEPPRA as adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established [see Clinical Studies (14.3) ] . Safety and effectiveness for the treatment of partial-onset seizures in pediatric patients below the age of 1 month; adjunctive therapy for the treatment of myoclonic seizures in pediatric patients below the age of 12 years; and adjunctive therapy for the treatment of primary generalized tonic-clonic seizures in pediatric patients below the age of 6 years have not been established. A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of KEPPRA as adjunctive therapy in 98 (KEPPRA N=64, placebo N=34) pediatric patients, ages 4 to 16 years old, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated on average a worsening in KEPPRA-treated patients in aggressive behavior, one of the eight syndrome scores [see Warnings and Precautions (5.1) ] . Juvenile Animal Toxicity Data Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from postnatal weeks 3 through 7) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m 2 basis) did not demonstrate adverse effects on postnatal development.

8.5 Geriatric Use There were 347 subjects in clinical studies of KEPPRA that were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of KEPPRA in these patients. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function [see Clinical Pharmacology (12.3) ] .

8.6 Renal Impairment Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology (12.3) ] . […]

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.