ELEPSIA XR 1000 MG

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 ELEPSIA XR ( 5.3 ) Serious Dermatological Reactions: Discontinue ELEPSIA XR at the first sign of rash unless clearly not drug related ( 5.5 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multi-Organ 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machinery until they have gained experience on ELEPSIA XR ( 5.7 ) Withdrawal Seizures: ELEPSIA XR must be gradually withdrawn ( 5.8 ) 5.1 Behavioral Abnormalities and Psychotic Symptoms ELEPSIA XR may cause behavioral abnormalities and psychotic symptoms. Patients treated with ELEPSIA XR should be monitored for psychiatric signs and symptoms. Behavioral Abnormalities Levetiracetam Extended-Release Tablets A total of 7% of levetiracetam extended-release tablets-treated patients experienced non-psychotic behavioral disorders (reported as irritability and aggression), compared to 0% of placebo-treated patients. Irritability was reported in 7% of levetiracetam extended-release tablet-treated patients. Aggression was reported in 1% of levetiracetam extended-release tablet-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam controlled trials will likely to occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam tablets experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19% of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis suggested a worsening in aggressive behavior in patients treated with immediate-release levetiracetam tablets in that study [see Use in Specific Populations (8.4) ] . A total of 1.7% of adult patients treated with immediate-release levetiracetam tablets 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 patients treated with immediate-release levetiracetam tablets, compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with immediate-release levetiracetam tablets experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients. One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-release levetiracetam tablets experienced psychotic symptoms, compared to 0.2% and 2%, respectively, in adult and pediatric placebo-treated patients. In the controlled study that assessed the neurocognitive and behavioral effects of immediate- release levetiracetam tablets in pediatric patients 4 to 16 years of age, 1.6% levetiracetam -treated patients experienced paranoia, compared to no placebo-treated patients. There were 3.1% patients treated with immediate-release levetiracetam tablets who experienced confusional state, compared to no placebo-treated patients [see Use in Specific Populations (8.4) ] . Psychotic Symptoms Immediate-Release Levetiracetam Tablets One percent of immediate-release levetiracetam tablets-treated adult patients experienced psychotic symptoms, compared to 0.2% of placebo-treated patients. Two (0.3%) immediate-release 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 pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. 5.2 Suicidal Behavior and Ideation Antiepileptic drugs (AEDs), including ELEPSIA XR, 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 to 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 3.4 3.5 2.4 Psychiatric 5.7 8.5 1.5 2.9 Other 1 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 ELEPSIA XR or any other AED must balance the risk of suicidal thoughts or behavior 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 ELEPSIA XR 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 ELEPSIA XR to gauge whether it adversely affects their ability to drive or operate machinery. Somnolence Levetiracetam Extended-Release Tablets In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing partial-onset seizures, 8% of levetiracetam extended-release tablets-treated patients experienced somnolence, compared to 3% of placebo-treated patients. No patient discontinued treatment or had a dose reduction as a result of these adverse reactions. The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled trials will likely occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of immediate-release levetiracetam tablets-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 (1.33 times the maximum recommended dosage) reported somnolence. The somnolence was considered serious in 0.3% of the immediate-release levetiracetam tablets-treated patients, compared to 0% in the placebo group. About 3% of immediate-release levetiracetam tablets-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of immediate-release levetiracetam tablets-treated patients and in 0.9% of placebo-treated patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence. Asthenia Immediate-Release Levetiracetam Tablets In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of immediate-release levetiracetam tablets-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of immediate-release levetiracetam tablets-treated patients, as compared to 0.5% of placebo treated patients. In 0.5% of immediate-release levetiracetam tablets-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia. Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. 5.4 Anaphylaxis and Angioedema ELEPSIA XR can cause anaphylaxis or angioedema after the first dose or at any time during treatment. Signs and symptoms in cases reported in the postmarketing setting in patients treated with levetiracetam have included hypotension, hives, rash, respiratory distress, and swelling of the face, lip, mouth, eye, tongue, throat, and feet. In some reported cases, reactions were life-threatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, ELEPSIA XR should be discontinued and the patient should seek immediate medical attention. ELEPSIA XR should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4) ] . 5.5 Serious Dermatological Reactions Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in patients treated with levetiracetam. The median time of onset is reported to be 14 to 17 days, but cases have been reported at least four months after initiation of treatment. Recurrence of the serious skin reactions following rechallenge with levetiracetam has also been reported. ELEPSIA XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered. 5.6 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as multiorgan hypersensitivity, has been reported in patients taking antiepileptic drugs, including levetiracetam. These events can be fatal or life-threatening, particularly if diagnosis and treatment do not occur as early as possible. DRESS typically, although not exclusively, presents with fever, rash, lymphadenopathy, and/or facial swelling, in association with other organ system involvement, such as hepatitis, nephritis, hematological abnormalities, myocarditis, or myositis, sometimes resembling an acute viral infection. Eosinophilia is often present. Because this disorder is variable in its expression, other organ systems not noted here may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present, the patient should be evaluated immediately. ELEPSIA XR should be discontinued if an alternative etiology for the signs or symptoms cannot be established [see Contraindications (4) ] . 5.7 Coordination Difficulties Coordination difficulties were not observed in the extended-release levetiracetam controlled trials, however, the number of patients exposed to levetiracetam extended-release tablets was considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in controlled trials. However, adverse reactions observed in the immediate-release levetiracetam controlled trials may also occur in patients receiving ELEPSIA XR. Immediate-Release Levetiracetam Tablets A total of 3.4% of adult immediate-release levetiracetam tablets-treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination), compared to 1.6% of placebo-treated patients. A total of 0.4% of patients in controlled trials discontinued immediate-release levetiracetam tablets treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of immediate-release levetiracetam tablets-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the immediate-release levetiracetam tablets-treated patients was hospitalized due to worsening of preexisting ataxia. These events occurred most frequently within the first 4 weeks of treatment. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on ELEPSIA XR to gauge whether it could adversely affect their ability to drive or operate machinery. 5.8 Withdrawal Seizures As with most antiepileptic drugs, ELEPSIA XR should be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus [see Dosage and Administration (2.3) ] . But if withdrawal is needed because of an adverse event, rapid discontinuation can be considered. 5.9 Hematologic Abnormalities ELEPSIA XR can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials of immediate- release levetiracetam and included decreases in white blood cells (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have also been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders. Immediate-Release Levetiracetam Tablets In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial-onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 × 10 6 /mm 3 ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release levetiracetam tablets-treated patients. A total of 3.2% of immediate-release levetiracetam tablets-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 × 10 9 /L) decreased WBC, and 2.4% of immediate-release levetiracetam tablets-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 × 10 9 /L) decreased neutrophil count. Of the immediate-release levetiracetam tablets-treated patients with a low neutrophil count, all but one rose towards or to baseline with continued treatment. No patient was discontinued secondary to low neutrophil counts. In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release levetiracetam tablets, as compared to placebo. The mean decreases from baseline in the immediate-release levetiracetam tablets group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release levetiracetam tablets compared to a decrease of 4% in patients on placebo. In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release levetiracetam tablets, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts. In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release levetiracetam tablets-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7×10 9 /L). 5.10 Seizure Control During Pregnancy Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.