Levetiracetam is an antiepileptic drug indicated for adjunctive therapy in the treatment of:
Partial onset seizures in patients four years of age and older with epilepsy ( 1.1 )
Myoclonic seizures in patients 12 years of age and older with juvenile myoclonic epilepsy ( 1.2 )
Primary generalized tonic-clonic seizures in patients 6 years of age and older with idiopathic generalized epilepsy ( 1.3 )
1.1Partial Onset Seizures
Levetiracetam is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children four years of age and older with epilepsy. Information describing the use of levetiracetam 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.
1.2Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy
Levetiracetam is indicated as adjunctive therapy in the treatment of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.
1.3Primary Generalized Tonic-Clonic Seizures
Levetiracetam is indicated as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.
Psychiatric Symptoms: Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have been observed. Monitor patients for psychiatric signs and symptoms ( 5.1 )
Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or unusual changes in mood or behavior ( 5.2 )
Somnolence and Fatigue: Monitor patients for these symptoms and advise patients not to drive or operate machinery until they have gained sufficient experience on Levetiracetam ( 5.3 )
Withdrawal Seizures: Levetiracetam must be gradually withdrawn ( 5.6 )
5.1Psychiatric Reactions
In some patients Levetiracetam causes behavioral abnormalities. The incidences of behavioral abnormalities in the myoclonic and primary generalized tonic-clonic seizure studies were comparable to those of the adult and pediatric partial onset seizure studies. A total of 13.3% of adult Levetiracetam-treated patients and 37.6% of pediatric Levetiracetam-Treated patients (4 to 16 years of age) compared to 6.2% and 18.6% of adult and pediatric placebo patients respectively, experienced non-psychotic behavioral symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, and personality disorder).
A randomized double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age). The results from an exploratory analysis indicated a worsening in Levetiracetam-Treated patients on aggressive behavior (one of eight behavior dimensions) as measured in a standardized and systematic way using a validated instrument, the Achenbach Child Behavior Checklist (CBCL/6-18).
In pediatric patients 1 month to < 4 years of age, irritability was reported in 11.7% of the Levetiracetam-Treated patients compared to 0% of placebo patients. A total of 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse events, compared to 0.2% of placebo patients. The treatment dose was reduced in 0.8% of adult Levetiracetam-Treated patients and in 0.5% of placebo patients.
Overall, 10.9% of Levetiracetam-Treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6.2% of placebo patients. One percent of adult Levetiracetam-Treated patients, 2% of children 4 to 16 years of age, and 17% of children 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% respectively, in the placebo patients. In the controlled study that assessed the neurocognitive and behavioral effects of Levetiracetam in pediatric patients 4 to 16 years of age, 1 (1.6%) Levetiracetam-Treated patient experienced paranoia compared to no placebo patients.
There were 2 (3.1%) Levetiracetam-Treated patients that experienced confusional state compared to no placebo patients [see Use in Specific Populations (8.4) ] . Two (0.3%) adult Levetiracetam-Treated patients were hospitalized and their treatment was discontinued due to psychosis. Both events, reported as psychosis, developed within the first week of treatment and resolved within 1 to 2 weeks following treatment discontinuation.
There was no difference between drug and placebo-treated patients in the incidence of the pediatric patients who discontinued treatment due to psychotic and non-psychotic adverse reactions. The above psychiatric signs and symptoms should be monitored.
5.2Suicidal Behavior and Ideation
Antiepileptic drugs (AEDs), including Levetiracetam, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior. Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo.
In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.
The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed. The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.
The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs. Tabel 2: Risk by indication for antiepileptic drugs in the pooled Analysis Indication Placebo Patients with Events Per 1000 Patients Drug Patients with Events Per 1000 Patients Relative Risk: Incidence of Events in Drug Patients/Incidence in Placebo Patients Risk Difference: Additional Drug Patients with Events Per 1000 Patients Epilepsy 1.0 3.4 3.5
2.4 Psychiatric 5.7 8.5 1.5
2.9 Other 1.0 1.8 1.9
0.9 Total 2.4 4.3 1.8
1.9 The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications. Anyone considering prescribing Levetiracetam or any other AED must balance the risk of suicidal thoughts or behaviors with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior.
Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated. Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Behaviors of concern should be reported immediately to healthcare providers.
5.3Somnolence 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 clea
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Interactions
No significant pharmacokinetic interactions were observed between levetiracetam or its major metabolite and concomitant medications via human liver cytochrome P450 isoforms, epoxide hydrolase, UDP-glucuronidation enzymes, P-glycoprotein, or renal tubular secretion [see Clinical Pharmacology (12.3) ].
Pregnancy and breastfeeding
8.1Pregnancy
Levetiracetam levels may decrease during pregnancy [see Warnings and Precautions (5.9) ]. Pregnancy Category C There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.
Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥350 mg/kg/day (equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m 2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis).
The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m 2 basis). There was no overt maternal toxicity at the doses used in this study. Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses ≥600 mg/kg/day (4 times MRHD on a mg/m 2 basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a mg/m 2 basis).
The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m 2 basis). Maternal toxicity was also observed at 1800 mg/kg/day. When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600 mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect dose.
There was no evidence of maternal toxicity in this study. Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1800 mg/kg/day (6 times the MRHD on a mg/m 2 basis). Pregnancy Registries To provide information regarding the effects of in utero exposure to Levetiracetam, physicians are advised to recommend that pregnant patients taking Levetiracetam enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry.
This can be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves. Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.
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) ] Most common adverse reactions (incidence in Levetiracetam-Treated patients is ≥ 5% more than in placebo-treated patients) include:
Adult patients: somnolence, asthenia, infection and dizziness ( 6.1 )
Pediatric patients: fatigue, aggression, nasal congestion, decreased appetite, and irritability ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Prinston Pharmaceuticals, Inc. at 866-257-2597 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.
6.1Clinical 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 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 4-16 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, for ev
Our copy of this section ends here. The full text is in the official label at the FDA. Open Drugs@FDA
Composition
Active ingredients
LEVETIRACETAM 750MG
Strengths and forms
The FDA lists each strength of a product separately; these pages share one label.
Prognia shows this product information for reference and learning. It is not treatment advice and can lag behind the official text. Always check the current product information and local protocols before prescribing.
