Levetiracetam (Page 3 of 15)

5.3 Somnolence and Fatigue

Levetiracetam tablets 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 levetiracetam tablets 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 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 reported somnolence. The somnolence was considered serious in 0.3% of levetiracetam tablets-treated patients, compared to 0% in the placebo group. About 3% of levetiracetam tablets-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo-treated patients. In 1.4% of levetiracetam tablets-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the levetiracetam tablets-treated patients were hospitalized due to somnolence.

Asthenia

In controlled clinical studies of adult patients with epilepsy experiencing partial onset seizures, 15% of levetiracetam tablets-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of levetiracetam tablets-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of 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. In general, the incidences of somnolence and fatigue in the pediatric partial onset seizure studies, and in pediatric and adult myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult partial onset seizure studies.

5.4 Anaphylaxis and Angioedema

Levetiracetam tablets 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 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, levetiracetam tablets should be discontinued and the patient should seek immediate medical attention. Levetiracetam tablets 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 both pediatric and adult patients treated with levetiracetam tablets. 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 tablets has also been reported. Levetiracetam tablets 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

Levetiracetam tablets may cause coordination difficulties.

In controlled clinical studies in adult patients with partial onset seizure studies, 3.4% of adult 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 clinical studies discontinued levetiracetam tablets treatment due to ataxia, compared to 0% of placebo-treated patients. In 0.7% of levetiracetam tablets-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while one of the levetiracetam tablets-treated patients was hospitalized due to worsening of pre-existing 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 levetiracetam tablets to gauge whether it could adversely affect their ability to drive or operate machinery.

5.7 Withdrawal Seizures

Antiepileptic drugs, including levetiracetam tablets, should be withdrawn gradually to minimize the potential of increased seizure frequency.

5.8 Hematologic Abnormalities

Levetiracetam tablets can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (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 been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

Partial Onset Seizures

Adults

Minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 x 10 6 /mm 3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in levetiracetam tablets-treated patients in controlled trials.

A total of 3.2% of levetiracetam tablets-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤ 2.8 x 10 9 /L) decreased WBC, and 2.4% of levetiracetam tablets-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤ 1.0 x 10 9 /L) decreased neutrophil count. Of the 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.

Pediatric Patients 4 Years to < 16 Years

Statistically significant decreases in WBC and neutrophil counts were seen in levetiracetam tablets-treated patients as compared to placebo. The mean decreases from baseline in the levetiracetam tablets-treated group were -0.4 × 10 9 /L and -0.3 × 10 9 /L, respectively, whereas there were small increases in the placebo group. Mean relative lymphocyte counts increased by 1.7% in levetiracetam tablets-treated patients, compared to a decrease of 4% in placebo patients (statistically significant).

In the controlled trial, more levetiracetam tablets-treated patients had a possibly clinically significant abnormally low WBC value (3% of levetiracetam tablets-treated patients versus 0% of placebo-treated patients), however, there was no apparent difference between treatment groups with respect to neutrophil count (5% of levetiracetam tablets-treated patients versus 4.2% of placebo-treated patients). No patient was discontinued secondary to low WBC or neutrophil counts.

In the controlled cognitive and neuropsychological safety study, 5 patients (8.6%) in the levetiracetam tablets-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥ 10% or ≥ 0.7 X 10 9 /L).

5.9 Increase in Blood Pressure

In a randomized, placebo-controlled study in patients 1 month to < 4 years of age, a significantly higher risk of increased diastolic blood pressure was observed in the levetiracetam tablets-treated patients (17%), compared to the placebo-treated patients (2%). There was no overall difference in mean diastolic blood pressure between the treatment groups. This disparity between the levetiracetam tablets and placebo treatment groups was not observed in the studies of older children or in adults.

Monitor patients 1 month to < 4 years of age for increases in diastolic blood pressure.

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