LEVETIRACETAM (Page 3 of 9)
5.4 Anaphylaxis and Angioedema
Le veti racet am 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 lifethreatening and required emergency treatment. If a patient develops signs or symptoms of anaphylaxis or angioedema, le veti racetam should be discontinued and the patient should seek immediate medical attention. le veti racetam 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 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.
5.6 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.
5.7 Withdrawal Seizures
Antiepileptic drugs, including levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
5.8 Hematologic Abnormalities
Levetriacetam 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 × 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 × 109 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤ 1.0 × 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 ≥0.7×109 /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.
5.9 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.
5.10 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)]
- 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 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.
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 event. 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.
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, not seen at an equivalent frequency among placebo-treated patients, 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.
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 and oral solution. 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, not seen at an equivalent frequency among placebo-treated patients, 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 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.
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 in the well-controlled study and occurred more frequently in levetiracetam-treated patients than in placebo-treated patients are presented in Table 8.
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 well-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, not seen at an equivalent frequency among placebo-treated patients, was nasopharyngitis.
Table 9 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.
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 8).
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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