Levetiracetam (Page 3 of 10)

5.3 Somnolence and Fatigue

In some patients, levetiracetam causes somnolence and fatigue. The incidences of somnolence and fatigue provided below are from controlled adult partial onset seizure studies. 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.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of levetiracetam-treated patients reported somnolence, compared to 8.4% of placebo 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 the treated patients, compared to 0% in the placebo group. About 3% of levetiracetam-treated patients discontinued treatment due to somnolence, compared to 0.7% of placebo patients. In 1.4% of treated patients and in 0.9% of placebo patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of levetiracetam-treated patients reported asthenia, compared to 9.1% of placebo patients. Treatment was discontinued due to asthenia in 0.8% of treated patients as compared to 0.5% of placebo patients. In 0.5% of treated patients and in 0.2% of placebo patients the dose was reduced due to asthenia.

Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment.

Patients should be monitored for these signs symptoms and advised not to drive or operate machinery until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their ability to drive or operate machinery.

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 x 109 /L and — 0.3 x 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≥0.7X109 /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 figure 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 then 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

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 children 4 to 16 years of age with partial onset seizures. The adverse reactions most frequently reported with the use of levetiracetam 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-treated patients and were numerically more common than in pediatric 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 5: Incidence (%) of Adverse Reactions in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures by Body System (Adverse Reactions Occurred in At Least 2% of Levetiracetam-Treated Patients and Occurred More Frequently Than Placebo-Treated Patients)
Body System / Adverse Reaction Levetiracetam ( N = 165 ) % Placebo ( N = 131 ) %
Ear and Labyrinth Disorders
Ear Pain 2 1
Eye Disorders
Conjunctivitis 2 0
Gastrointestinal Disorders
Vomiting 15 12
Abdominal Pain Upper 9 8
Diarrhea 6 5
Constipation 3 1
General Disorders and Administration Site Conditions
Fatigue 11 5
Infections and Infestations
Nasopharyngitis 15 12
Influenza 3 1
Gastroenteritis 2 0
Rhinitis 2 0
Injury , Poisoning and Procedural Complications
Head Injury 4 0
Contusion 3 1
Fall 3 2
Joint Sprain 2 1
Metabolism and Nutrition Disorders
Decreased Appetite 8 2
Anorexia 4 3
Musculoskeletal and Connective Tissue Disorders
Arthralgia 2 0
Neck Pain 2 1
Nervous System
Headache 19 15
Somnolence 13 9
Dizziness 7 5
Lethargy 6 2
Sedation 2 1
Psychiatric Disorders
Aggression 10 5
Abnormal Behavior 7 4
Irritability 7 1
Insomnia 5 3
Agitation 4 1
Depression 3 1
Mood Altered 3 1
Affect Lability 2 1
Anxiety 2 1
Confusional State 2 0
Mood Swings 2 1
Respiratory , Thoracic and Mediastinal Disorders
Cough 9 5
Nasal Congestion 9 2
Pharyngolaryngeal Pain 7 4

In the well controlled pooled pediatric clinical studies in patients 4 to 16 years of age, 7% of patients receiving levetiracetam and 9% receiving placebo discontinued as a result of an adverse event.

Adverse reaction information in pediatric patients less than 4 years of age as adjunctive therapy in the treatment of partial onset seizures is approved for UCB, Inc.’s levetiracetam tablets. However, due to UCB, Inc.’s marketing exclusivity rights, this drug product is not labeled with that pediatric information.

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 well-controlled clinical study that included both adolescent (12 to 16 years of age) and adult patients with myoclonic seizures, the most frequently reported adverse reactions in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, were somnolence, neck pain, and pharyngitis.

Table 6 lists adverse reactions that occurred in at least 5% of juvenile myoclonic epilepsy patients experiencing myoclonic seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 6: Incidence (%) of Adverse Reactions in A Placebo-Controlled, Add-On Study in Patients 12 Years of Age and Older With Myoclonic Seizures by Body System (Adverse Reactions Occurred in At Least 5% of Levetiracetam -Treated Patients and Occurred More Frequently than Placebo-Treated Patients)
Body System / Adverse Reaction Levetiracetam ( N = 60 ) % Placebo ( N = 60 ) %
Ear and labyrinth disorders
Vertigo 5 3
Infections and infestations
Pharyngitis 7 0
Influenza 5 2
Musculoskeletal and connective tissue disorders
Neck Pain 8 2
Nervous system disorders
Somnolence 12 2
Psychiatric disorders
Depression 5 2

In the placebo-controlled study, 8% of patients receiving levetiracetam 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-treated patients than in placebo-treated patients are presented in Table 7.

Table 7: Adverse Reactions that Resulted in Discontinuation or Dose Reduction that Occurred More Frequently in Levetiracetam-Treated Patients in the Placebo-Controlled Study in Patients with Juvenile Myoclonic Epilepsy
Adverse Reaction Levetiracetam ( 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 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 primary generalized tonic-clonic (PGTC) seizures, the most frequently reported adverse reaction in patients using levetiracetam in combination with other AEDs, for events with rates greater than placebo, was nasopharyngitis.

Table 8 lists adverse reactions that occurred in at least 5% of idiopathic generalized epilepsy patients experiencing PGTC seizures treated with levetiracetam and were numerically more common than in patients treated with placebo. In this study, either levetiracetam or placebo was added to concurrent AED therapy. Adverse reactions were usually mild to moderate in intensity.

Table 8: Incidence (%) of Adverse Reactions in a Placebo-Controlled, Add-On Study in Patients 4 Years of Age and Older With PGTC Seizures By MedDRA System Organ Class (Adverse Reactions Occurred in At Least 5% of Levetiracetam -Treated Patients and Occurred More Frequently than Placebo-Treated Patients)
Body System / Adverse Reaction Levetiracetam ( N = 79 ) % Placebo ( N = 84 ) %
Gastrointestinal disorders
Diarrhea 8 7
General disorders and administration site conditions
Fatigue 10 8
Infections and infestations
Nasopharyngitis 14 5
Psychiatric disorders
Irritability 6 2
Mood Swings 5 1

In the placebo-controlled study, 5% of patients receiving levetiracetam 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 7).

In addition, the following adverse reactions were seen in other well-controlled adult studies of levetiracetam: balance disorder, disturbance in attention, eczema, memory impairment, myalgia, and vision blurred.

Comparison of Gender, Age and Race

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

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