LEVETIRACETAM (Page 3 of 9)

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. 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 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 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% 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% 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 ≥0.7X109 /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 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:

  • 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) ]
  • 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, 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, Add-On 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
Adverse Reaction Levetiracetam tablets (N=769) % Placebo (N=439) %
Somnolence 4 2
Dizziness 1 0

Pediatric Patients 4 Years to <16 Years

The adverse reaction data presented below was obtained from a pooled analysis of two controlled pediatric clinical studies in pediatric patients 4 to 16 years of age with partial onset seizures. The most common adverse reactions in pediatric patients receiving Levetiracetam tablets in combination with other AEDs, for events with rates greater than placebo, were fatigue, aggression, nasal congestion, decreased appetite, and irritability.

Table 5 lists adverse reactions from the pooled pediatric controlled studies (4 to 16 years of age) that

occurred in at least 2% of pediatric Levetiracetam tablets-treated patients and were numerically more common than in pediatric patients treated with placebo. In these studies, either Levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures
Levetiracetam tablets (N=165) % Placebo (N=131) %
Headache 19 15
Nasopharyngitis 15 12
Vomiting 15 12
Somnolence 13 9
Fatigue 11 5
Aggression 10 5
Cough 9 5
Nasal Congestion 9 2
Upper Abdominal Pain 9 8
Decreased Appetite 8 2
Abnormal Behavior 7 4
Dizziness 7 5
Irritability 7 1
Pharyngolaryngeal Pain 7 4
Diarrhea 6 2
Lethargy 6 5
Insomnia 5 3
Agitation 4 1
Anorexia 4 3
Head Injury 4 0
Altered Mood 3 1
Constipation 3 1
Contusion 3 1
Depression 3 1
Fall 3 2
Influenza 3 1
Affect Lability 2 1
Anxiety 2 1
Arthralgia 2 0
Confusional State 2 0
Conjunctivitis 2 0
Ear Pain 2 1
Gastroenteritis 2 0
Joint Sprain 2 1
Mood Swings 2 1
Neck Pain 2 1
Rhinitis 2 0
Sedation 2 1

In the controlled pooled pediatric clinical studies in patients 4-16 years of age, 7% of patients receiving Levetiracetam tablets and 9% receiving placebo discontinued as a result of an adverse reaction.

Pediatric Patients 1 Month to < 4 Years

In the 7-day, controlled pediatric clinical study in children 1 month to less than 4 years of age with partial onset seizures, the most common adverse reactions in patients receiving Levetiracetam tablets in combination with other AEDs, for events with rates greater than placebo, were somnolence and irritability. Because of the shorter exposure period, incidences of adverse reactions are expected to be lower than in other pediatric studies in older patients. Therefore, other controlled pediatric data, presented above, should also be considered to apply to this age group.

Table 6 lists adverse reactions that occurred in at least 5% of pediatric epilepsy patients (ages 1 month to < 4 years) treated with Levetiracetam tablets in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 6: Adverse Reactions in a Placebo-Controlled, Add-On Study in Pediatric Patients Ages 1 Month to < 4 Years Experiencing Partial Onset Seizures
Levetiracetam tablets (N=60) % Placebo (N=56) %
Somnolence 13 2
Irritability 12 0

In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving Levetiracetam tablets and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. There was no adverse reaction that resulted in discontinuation for more than one patient.

Myoclonic Seizures

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with JME is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical study in patients 12 years of age and older with myoclonic seizures, the most common adverse reactions in patients receiving Levetiracetam tablets in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

Table 7 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with Levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 7: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 12 Years of Age and Older with Myoclonic Seizures
Levetiracetam tablets (N=60) % Placebo (N=60) %
Somnolence 12 2
Neck pain 8 2
Pharyngitis 7 0
Depression 5 2
Influenza 5 2
Vertigo 5 3

In the placebo-controlled study, 8% of patients receiving Levetiracetam tablets and 2% receiving placebo either discontinued or had a dose reduction as a result of an adverse reaction. The adverse reactions that led to discontinuation or dose reduction and that occurred more frequently in Levetiracetam tablets-treated patients than in placebo-treated patients are presented in Table 8.

Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in a Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy
Adverse Reaction Levetiracetam tablets (N=60) % Placebo (N=60) %
Anxiety 3 2
Depressed mood 2 0
Depression 2 0
Diplopia 2 0
Hypersomnia 2 0
Insomnia 2 0
Irritability 2 0
Nervousness 2 0
Somnolence 2 0

Primary Generalized Tonic-Clonic Seizures

Although the pattern of adverse reactions in this study seems somewhat different from that seen in patients with partial seizures, this is likely due to the much smaller number of patients in this study compared to partial seizure studies. The adverse reaction pattern for patients with primary generalized tonic-clonic (PGTC) seizures is expected to be essentially the same as for patients with partial seizures.

In the controlled clinical study that included patients 4 years of age and older with PGTC seizures, the most common adverse reaction in patients receiving Levetiracetam tablets in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 9 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with Levetiracetam tablets and were numerically more common than in patients treated with placebo. In this study, either Levetiracetam tablets or placebo was added to concurrent AED therapy.

Table 9: Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older with PGTC Seizures
Levetiracetam tablets (N=79) % Placebo (N=84) %
Nasopharyngitis 14 5
Fatigue 10 8
Diarrhea 8 7
Irritability 6 2
Mood Swings 5 1

In the placebo-controlled study, 5% of patients receiving Levetiracetam tablets and 8% receiving placebo either discontinued or had a dose reduction during the treatment period as a result of an adverse reaction.

This study was too small to adequately characterize the adverse reactions that could be expected to result in discontinuation of treatment in this population. It is expected that the adverse reactions that would lead to discontinuation in this population would be similar to those resulting in discontinuation in other epilepsy trials (see tables 4 and 8).

In addition, the following adverse reactions were seen in other controlled adult studies of Levetiracetam tablets: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and blurred vision.
Comparison of Gender, Age and Race

The overall adverse reaction profile of Levetiracetam tablets was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race.

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