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Lepixa 500/Lepixa 1000: In accordance with current clinical practice, if Levetiracetam has to be discontinued, it is recommended to withdraw it gradually (eg, in adults: 500 mg decreases twice-daily every 2-4 weeks, in children: dose decrease should not exceed 10 mg/kg twice daily every 2 weeks).
In a study reflecting clinical practice, the concomitant antiepileptic medication could be withdrawn in a limited number of patients who responded to Levetiracetam adjunctive therapy. Available data in children did not suggest impact on growth and puberty. However, long-term effects on learning, intelligence, growth, endocrine function, puberty and childbearing potential in children remain unknown.
An increase in seizure frequency of >25% has been reported in 14% of Levetiracetam-treated adult and pediatric patients with partial onset seizures, whereas it was reported in 26 and 21% of placebo-treated adult and pediatric patients, respectively.
The administration of Levetiracetam to patients with renal impairment may require dose adaptation. In patients with severely impaired hepatic function, assessment of renal function is recommended before dose selection.
Effects on the Ability to Drive or Operate Machinery: No studies on the effects on the ability to drive and use machines have been performed.
Due to possible different individual sensitivity, some patients might experience, especially at the beginning of treatment or following a dose increase, somnolence or other central nervous system related symptoms. Therefore, caution is recommended in those patients when performing skilled tasks eg, driving vehicles or operating machinery. Patients are advised not to drive or used machines until it is established that their ability to perform such activities is not affected.
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Lepixa: Oral Solution: 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 9 significant (≤2.8 x 10 /L) decreased WBC, and 2.4% of treated and 1.4% of placebo patients had at least one possibly significant (≤1.0 x 190 /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.
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.
Hepatic Abnormalities: There were no meaningful changes in mean liver function tests (LFT) in controlled trials in adult or pediatric patients; lesser LFT abnormalities were similar in drug and placebo treated patients in controlled trials (1.4%). No adult or pediatric patients were discontinued from controlled trials for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.
Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam, may increase the risk of suicidal thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of 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.
Patients should be advised that levetiracetam may cause changes in behavior (e.g. aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and in rare cases patients may experience psychotic symptoms.
Patients should be advised to notify their physician if they become pregnant or intend to become pregnant during therapy. Patients should be encouraged to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. UCB, Inc. has established the UCB AED Pregnancy Registry to advance scientific knowledge about safety and outcomes associated with pregnant women being treated with all UCB antiepileptic drugs, including levetiracetam.
Laboratory Tests: Although most laboratory tests are not systematically altered with levetiracetam treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and liver function tests.
Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenesis: Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300 and 1800 mg/kg/day. The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of 3000 mg on a mg/m2 basis and it also provided systemic exposure (AUC) approximately 6 times that achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960 mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m2 or exposure basis). Although no evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully evaluated in that species because adequate doses have not been studied.
Mutagenesis: Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or the in vitro mouse lymphoma assay.
Impairment of Fertility: No adverse effects on male or female fertility or reproductive performance were observed in rats at doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a mg/m2 or exposure basis).
Use In Patients With Impaired Renal Function: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance. Caution should be taken in dosing patients with moderate and severe renal impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with impaired renal function receiving levetiracetam and supplemental doses should be given to patients after dialysis.
Effects on the Ability to Drive or Operate Machinery: Patients should be advised that levetiracetam may cause dizziness and somnolence. Accordingly, patients should be advised not to drive or operate machinery or engage in other hazardous activities until they have gained sufficient experience on levetiracetam to gauge whether it adversely affects their performance of these activities.
Use in Children: Minor, but statistically significant, decreases in WBC and neutrophil count 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 well-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.
Safety and effectiveness in patients below 4 years of age have not been established.
Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric 2 dose of 60 mg/kg/day on a mg/m2 basis) did not indicate a potential for age specific toxicity.
Use in the Elderly: Of the total number of subjects in clinical studies of levetiracetam, 347 were 65 and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of levetiracetam in these patients. Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function.
Solution for injection: Behavioral Abnormalities and Psychotic Symptoms: Levetiracetam may cause behavioral abnormalities and psychotic symptoms. Patients treated with Levetiracetam should be monitored for psychiatric signs and symptoms.
Behavioral abnormalities: In clinical studies using an oral formulation of Levetiracetam, 13% of adult Levetiracetam-treated patients and 38% of pediatric Levetiracetam-treated patients (4 to 16 years of age), compared to 6% and 19% of adult and pediatric placebo-treated patients, 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 an oral formulation 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 clinical studies in pediatric patients 1 month to <4 years of age, irritability was reported in 12% of the Levetiracetam-treated patients compared to 0% of placebo-treated patients.
In clinical studies, 1.7% of adult Levetiracetam-treated patients discontinued treatment due to behavioral adverse reactions, compared to 0.2% of placebo-treated patients. The treatment dose was reduced in 0.8% of adult Levetiracetam-treated patients and in 0.5% of placebo-treated patients. Overall, 11% of Levetiracetam-treated pediatric patients experienced behavioral symptoms associated with discontinuation or dose reduction, compared to 6% of placebo-treated patients.
Psychotic symptoms: In clinical studies using an oral formulation of Levetiracetam, 1% of Levetiracetam-treated adult patients, 2% of Levetiracetam-treated pediatric patients 4 to 16 years of age, and 17% of Levetiracetam-treated pediatric patients 1 month to <4 years of age experienced psychotic symptoms, compared to 0.2%, 2%, and 5% in the corresponding age groups treated with placebo. In a controlled study that assessed the neurocognitive and behavioral effects of an oral formulation of Levetiracetam in pediatric patients 4 to 16 years of age, 1.6% of Levetiracetam-treated patients experienced paranoia, compared to 0% of placebo-treated patients. In the same study, 3.1% of Levetiracetam-treated patients experienced confusional state, compared to 0% of placebo treated patients (see Use in Children as follows).
In clinical studies, two (0.3%) Levetiracetam-treated adult 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.
Somnolence and Fatigue: Levetiracetam may cause somnolence and fatigue. Patients should be monitored for somnolence and fatigue, and be 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.
Somnolence: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported somnolence, compared to 8% of placebo-treated patients. There was no clear dose response up to 3000 mg/day. In a study in which there was no titration, about 45% of patients receiving Levetiracetam 4000 mg/day reported somnolence. The somnolence was considered serious in 0.3% of Levetiracetam-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 treated patients. In 1.4% of Levetiracetam-treated patients and 0.9% of placebo-treated patients, the dose was reduced, while 0.3% of the Levetiracetam-treated patients were hospitalized due to somnolence.
Asthenia: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 15% of Levetiracetam-treated patients reported asthenia, compared to 9% of placebo-treated patients. Treatment was discontinued due to asthenia in 0.8% of Levetiracetam-treated patients as compared to 0.5% of placebo-treated patients. In 0.5% of Levetiracetam-treated patients and in 0.2% of placebo-treated patients, the dose was reduced due to asthenia.
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. 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 studies were comparable to those of the adult partial onset seizure studies.
Anaphylaxis and Angioedema: Levetiracetam 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 should be discontinued and the patient should seek immediate medical attention.
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 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.
Coordination Difficulties: Levetiracetam may cause coordination difficulties.
In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, 3.4% of Levetiracetam-treated patients experienced coordination difficulties, (reported as 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 treatment due to ataxia, compared to 0% of placebo treated patients. In 0.7% of Levetiracetam-treated patients and in 0.2% of placebo-treated 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 signs and symptoms of coordination difficulties 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.
Withdrawal Seizures: Antiepileptic drugs, including Levetiracetam, should be withdrawn gradually to minimize the potential of increased seizure frequency.
Hematologic Abnormalities: Levetiracetam can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in red blood cells count (RBC), hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cells count (WBC) and neutrophil counts also occurred in clinical trials. Cases of agranulocytosis have been reported in the postmarketing setting.
Partial Onset Seizures: Adults: In controlled clinical studies using an oral formulation of Levetiracetam in adult patients with partial onset seizures, minor but statistically significant decreases compared to placebo in total mean RBC (0.03 x 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in Levetiracetam-treated patients.
A total of 3.2% of Levetiracetam-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-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-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: In a controlled study in pediatric patients age 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-treated patients (statistically significant).
Somnolence and asthenia occurred most frequently within the first 4 weeks of treatment. 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 studies were comparable to those of the adult partial onset seizure studies.
In a randomized, double-blind, placebo-controlled study to assess the neurocognitive and behavioral effects of an oral formulation of Levetiracetam as adjunctive therapy in pediatric patients (4 to 16 years of age), 5 patients (8.6%) in the Levetiracetam-treated group and two patients (6.1%) in the placebo-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7 x 109/L).
Increase in Blood Pressure: In a randomized, placebo-controlled study in patients 1 month to <4 years of age using an oral formulation of Levetiracetam, a significantly higher risk of increased diastolic blood pressure was observed in the Levetiracetam-treated patients (17%), compared to 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.
Renal Impairment: Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance (see Pharmacology: Pharmacokinetics under Actions). Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis (see Dosage Adjustments in Adult Renal Impairment under Dosage & Administration).
Use in Pregnancy: See Use in Pregnancy & Lactation section for further information.
Use in Children: The safety and effectiveness of Levetiracetam in the adjunctive treatment of partial onset seizures in pediatric patients age 1 month to 16 years with epilepsy have been established (see Pharmacology: Clinical Studies: Partial Onset Seizures under Actions). The dosing recommendation in these pediatric patients varies according to age group and is weight-based (see Preparation and Administration Instructions under Dosage & Administration).
The safety and effectiveness of Levetiracetam as adjunctive treatment of myoclonic seizures in adolescents 12 years of age and older with juvenile myoclonic epilepsy have been established (see Pharmacology: Clinical Studies: Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy under Actions).
The safety and effectiveness of Levetiracetam as adjunctive therapy in the treatment of primary generalized tonic-clonic seizures in pediatric patients 6 years of age and older with idiopathic generalized epilepsy have been established (see Pharmacology: Clinical Studies: Primary Generalized Tonic-Clonic Seizures under Actions).
A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of Levetiracetam as adjunctive therapy in 98 (Levetiracetam N=64, placebo N=34) pediatric patients, ages 4 years to 16 years, with partial seizures that were inadequately controlled. The target dose was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which measures various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo and drug treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority of the drug and placebo. The Achenbach Child Behavior Checklist (CBCL/6-18), a standardized validated tool used to assess a child's competencies and behavioral/emotional problems, was also assessed in this study. An analysis of the CBCL/6-18 indicated, on average, a worsening in Levetiracetam-treated patients in aggressive behavior, one of the eight syndrome scores [see Behavioral Abnormalities and Psychotic Symptoms under Precautions].
Studies of levetiracetam in juvenile rats (dosing from day 4 through day 52 of age) and dogs (dosing from week 3 through week 7 of age) at doses of up to 1800 mg/kg/day (approximately 7 and 24 times, respectively, the maximum recommended pediatric dose of 60 mg/kg/day on a mg/m2 basis) did not indicate a potential for age-specific toxicity.
Use in the Elderly: There were 347 subjects in clinical studies of levetiracetam that were 65 years old and over. No overall differences in safety were observed between these subjects and younger subjects. There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of Levetiracetam in these patients.
Levetiracetam is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection, and it may be useful to monitor renal function (see Pharmacology: Pharmacokinetics under Actions).
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