Elepsia XR (Page 2 of 8)

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 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.

5.7 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.

5.8 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 x 106 /mm3), 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 x 109 /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 x 109 /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 × 109 /L and -0.3 × 109 /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 ≥0.7X109 /L).

5.9 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.

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