Levetiracetam (Page 3 of 11)

5.4 Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in both children and adults 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. Levetiracetam 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.

5.5 Coordination Difficulties

Coordination difficulties were only observed in the adult partial onset seizure studies. A total of 3.4% of adult Levetiracetam-Treated patients experienced coordination difficulties, (reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo patients. A total of 0.4% of patients in controlled trials discontinued Levetiracetam treatment due to ataxia, compared to 0% of placebo patients. In 0.7% of treated patients and in 0.2% of placebo patients the dose was reduced due to coordination difficulties, while one of the 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 to gauge whether it could adversely affect their ability to drive or operate machinery.

5.6 Withdrawal Seizures

Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.

5.7 Hematologic Abnormalities

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-Treated patients in controlled trials.

A total of 3.2% of treated and 1.8% of placebo patients had at least one possibly significant (≤2.8 x 109 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 109 /L) decreased neutrophil count. Of the 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-Treated patients as compared to placebo. The mean decreases from baseline in the Levetiracetam-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-Treated patients, compared to a decrease of 4% in placebo patients (statistically significant).

In the controlled trial, more Levetiracetam-Treated patients had a possibly clinically significant abnormally low WBC value (3.0% Levetiracetam-Treated versus 0% placebo), however, there was no apparent difference between treatment groups with respect to neutrophil count (5.0% Levetiracetam-Treated versus 4.2% placebo). No patient was discontinued secondary to low WBC or neutrophil counts.

In the controlled cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the Levetiracetam-Treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥ 0.7 X 109 /L).

Juvenile Myoclonic Epilepsy

Although there were no obvious hematologic abnormalities observed in patients with JME, the limited number of patients makes any conclusion tentative. The data from the partial seizure patients should be considered to be relevant for JME patients.

5.8 Blood Pressure Increases

In a randomized, placebo-controlled study in patients aged 1 month to <4 years of age, a significantly higher risk of at least one measured increase in diastolic blood pressure was observed in the Levetiracetam-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 and placebo treatment groups was not observed in the studies of older children or in adults.

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.

6 ADVERSE REACTIONS

The following adverse reactions are discussed in more details in other sections of labeling:

Psychiatric 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)]
Serious Dermatological Reactions [see Warnings and Precautions (5.4)]
Coordination Difficulties [see Warnings and Precautions (5.5)]
Withdrawal Seizures [see Warnings and Precautions (5.6)]
Hematologic Abnormalities [see Warnings and Precautions (5.7)]
Blood Pressure Increases [see Warnings and Precautions (5.8)]
Seizure Control During Pregnancy [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.

The prescriber should be aware that the adverse reaction incidence figures in the following tables, obtained when Levetiracetam was added to concurrent AED therapy, cannot be used to predict the frequency of adverse reactions in the course of usual medical practice where patient characteristics and other factors may differ from those prevailing during clinical trials. Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical investigations involving different treatments, uses, or investigators. An inspection of these frequencies, however, does provide the prescriber with one basis to estimate the relative contribution of drug and non-drug factors to the adverse reaction incidences in the population studied.

Partial Onset Seizures

Adults

In controlled clinical studies in adults with partial onset seizures, the most frequently reported adverse reactions in patients receiving Levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, asthenia, infection and dizziness. Of the most frequently reported adverse reactions in adults experiencing partial onset seizures, asthenia, somnolence and dizziness appeared to occur predominantly during the first 4 weeks of treatment with Levetiracetam.

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

Table 3: Incidence (%) Of Adverse Reactions In Placebo-Controlled, Add-On Studies In Adults Experiencing Partial Onset Seizures By Body System (Adverse Reactions Occurred In At Least 1% Of Levetiracetam-Treated Patients And Occurred More Frequently Than Placebo-Treated Patients)

Body System/

Adverse Reaction

Levetiracetam (N=769) %

Placebo (N=439) %

Body as a Whole

Asthenia

15

9

Headache

14

13

Infection

13

8

Pain

7

6

Digestive System

Anorexia

3

2

Nervous System

Somnolence

15

8

Dizziness

9

4

Depression

4

2

Nervousness

4

2

Ataxia

3

1

Vertigo

3

1

Amnesia

2

1

Anxiety

2

1

Hostility

2

1

Paresthesia

2

1

Emotional Lability

2

0

Respiratory System

Pharyngitis

6

4

Rhinitis

4

3

Cough Increased

2

1

Sinusitis

2

1

Special Senses

Diplopia

2

1

In controlled adult clinical studies, 15% of patients receiving Levetiracetam 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-Treated patients than in placebo-treated patients.

Table 4: Adverse Reactions That Most Commonly Resulted In Discontinuation Or Dose Reduction That Occurred More Frequently In Levetiracetam-Treated Patients In Placebo-Controlled Studies In Adult Patients Experiencing Partial Onset Seizures

Adverse Reaction

Levetiracetam (N=769) %

Placebo (N=439) %

Dizziness

1

0

Somnolence

4

2

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