Prescription Drug Information: Levetiracetam (Page 3 of 11)

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

As with most antiepileptic drugs, levetiracetam tablets should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

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 106 /mm3), 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 109 /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 109 /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 × 109 /L and -0.3 × 109 /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 109/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.

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.

6 ADVERSE REACTIONS

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)]
Coordination Difficulties [see Warnings and Precautions (5.6)]
Hematologic Abnormalities [see Warnings and Precautions (5.8)]
Increase in Blood Pressure [see Warnings and Precautions (5.9)]

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 levetiracetam tablets 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 levetiracetam tablets.

Table 3 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving levetiracetam tablets in placebo-controlled studies and were numerically more common than in patients treated with placebo. In these studies, either levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 3: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive Studies in Adults Experiencing Partial-Onset Seizures

Levetiracetam Tablets(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 levetiracetam tablets 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 levetiracetam tablets-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

AdverseReaction

Levetiracetam Tablets(N = 769)%

Placebo(N = 439)%

Somnolence

4

2

Dizziness

1

0

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