Levetiracetam: uses, appearance and warnings

Levetiracetam tablets are indicated for the treatment of partial-onset seizures in patients 1 month of age and older ( 1.1 ) Levetiracetam tablets 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 are 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 tablets 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 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, USP are available containing 250 mg, 500 mg, 750 mg or 1000 mg of levetiracetam, USP • 250 mg: blue oval shaped scored, film coated Tablets debossed with “LT250”on one side and score on other side. • 500 mg: yellow oval shaped scored, film coated Tablets debossed with “LT500”on one side and score on other side • 750 mg: peach-Orange, oval shaped scored, film coated Tablets debossed with “LT750”on one side and score on other side • 1000 mg: white, oval shaped scored, film coated Tablets debossed with “LT1g”on one side and score on other side • 250 mg, 500 mg, 750 mg, and 1000 mg film-coated, scored tablets ( 3 )

16.1 How Supplied • Levetiracetam tablets 250 mg, USP are blue oval shaped scored, film coated Tablets debossed with “LT250”on one side and score on other side. They supplied as: Bottles of 30 tablets (NDC 67877-768-30) Bottles of 120 tablets (NDC 67877-768-12) Bottles of 500 tablets (NDC 67877-768-05) Carton of 10 (1×10) Unit-dose Tablets (NDC 67877-768-33) • Levetiracetam tablets 500 mg, USP are yellow oval shaped scored, film coated Tablets debossed with “LT500”on one side and score on other side. They supplied as: Bottles of 30 tablets (NDC 67877-769-30) Bottles of 120 tablets (NDC 67877-769-12) Bottles of 500 tablets (NDC 67877-769-05) Carton of 10 (1×10) Unit-dose Tablets (NDC 67877-769-33) Carton of 100 (10 x 10) Unit-dose Tablets (NDC 67877-769-38) • Levetiracetam tablets 750 mg, USP are peach-orange, oval shaped scored, film coated Tablets debossed with “LT750”on one side and score on other side. They supplied as: Bottles of 30 tablets (NDC 67877-770-30) Bottles of 120 tablets (NDC 67877-770-12) Bottles of 500 tablets (NDC 67877-770-05) Carton of 10 (1×10) Unit-dose Tablets (NDC 67877-770-33) • Levetiracetam tablets 1000 mg, USP are white, oval shaped scored, film coated Tablets debossed with “LT1g”on one side and score on other side. They supplied as: Bottles of 30 tablets (NDC 67877-771-30) Bottles of 60 tablets (NDC 67877-771-60) Bottles of 500 tablets (NDC 67877-771-05) Carton of 10 (1×10) Unit-dose Tablets (NDC 67877-771-33) 16.2 Storage Store at 20°C to 25°C (68°F to 77°F); excursions permitted between 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature]

Levetiracetam tablets 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 )

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 levetiracetam tablets ( 5.3 ) Serious Dermatological Reactions: Discontinue levetiracetam tablets 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 levetiracetam tablets (5.7) Withdrawal Seizures: Levetiracetam tablets must be gradually withdrawn (5.8) 5.1 Behavioral Abnormalities and Psychotic Symptoms Levetiracetam tablets may cause behavioral abnormalities and psychotic symptoms. Patients treated with levetiracetam tablets should be monitored for psychiatric signs and symptoms. Behavioral abnormalities In clinical studies, 13% of adult levetiracetam tablets-treated patients and 38% of pediatric levetiracetam tablets-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 levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in levetiracetam tablets-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 to 18). In clinical studies in pediatric patients 1 month to < 4 years of age, irritability was reported in 12% of the levetiracetam tablets-treated patients compared to 0% of placebo-treated patients. In clinical studies, 1.7% of adult levetiracetam tablets-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 levetiracetam tablets-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of levetiracetam tablets-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 levetiracetam tablets-treated adult patients, 2% of levetiracetam tablets-treated pediatric patients 4 to 16 years of age, and 17% of levetiracetam tablets-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 levetiracetam tablets in pediatric patients 4 to 16 years of age, 1.6% of levetiracetam tablets-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of levetiracetam tablets-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%) levetiracetam tablets-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 levetiracetam tablets, 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 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, infecti …