Levetiracetam Injection: Indications, Dosage, Precautions, Adverse Effects
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Levetiracetam Injection - Product Information

Manufacture: Fresenius Kabi USA, LLC
Country: United States
Condition: Epilepsy, Seizures (Convulsions)
Class: Pyrrolidine anticonvulsants
Form: Liquid solution, Intravenous (IV)
Ingredients: Levetiracetam, Water for Injection, Sodium Chloride, Buffered at Approximately pH 5.5 with Glacial Acetic Acid and 8.2 mg Sodium Acetate Trihydrate

Indications and Usage

Partial Onset Seizures

Levetiracetam injection is indicated as adjunctive therapy in the treatment of partial onset seizures in adults and children 1 month of age and older with epilepsy. Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Levetiracetam injection 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 (JME). Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

1.3 Primary Generalized Tonic-Clonic Seizures

Levetiracetam injection 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. Levetiracetam injection is for intravenous use only as an alternative for patients when oral administration is temporarily not feasible.

Dosage and Administration

Dosing for Partial Onset Seizures

Adults 16 Years and Older

Initiate treatment with a daily dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Additional dosing increments may be given (1,000 mg/day additional every 2 weeks) to a maximum recommended daily dose of 3,000 mg. There is no evidence that doses greater than 3,000 mg/day confer additional benefit.

Pediatric Patients

1 Month to < 6 Months

Initiate treatment with a daily dose of 14 mg/kg in 2 divided doses (7 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 14 mg/kg to the recommended daily dose of 42 mg/kg (21 mg/kg twice daily). In the clinical trial, the mean daily dose was 35 mg/kg in this age group. The effectiveness of lower doses has not been studied.

6 Months to < 4 Years

Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose in 2 weeks by an increment of 20 mg/kg to the recommended daily dose of 50 mg/kg (25 mg/kg twice daily). If a patient cannot tolerate a daily dose of 50 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 47 mg/kg in this age group.

4 Years to < 16 Years

Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). If a patient cannot tolerate a daily dose of 60 mg/kg, the daily dose may be reduced. In the clinical trial, the mean daily dose was 44 mg/kg. The maximum daily dose was 3,000 mg/day.

Dosing for Myoclonic Seizures in Patients with Juvenile Myoclonic Epilepsy

Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase the dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been studied.

Dosing for Primary Generalized Tonic-Clonic Seizures

Adults 16 Years and Older

Initiate treatment with a dose of 1,000 mg/day, given as twice-daily dosing (500 mg twice daily). Increase dosage by 1,000 mg/day every 2 weeks to the recommended daily dose of 3,000 mg. The effectiveness of doses lower than 3,000 mg/day has not been adequately studied.

Pediatric Patients Ages 6 to < 16 Years

Initiate treatment with a daily dose of 20 mg/kg in 2 divided doses (10 mg/kg twice daily). Increase the daily dose every 2 weeks by increments of 20 mg/kg (10 mg/kg twice daily) to the recommended daily dose of 60 mg/kg (30 mg/kg twice daily). The effectiveness of doses lower than 60 mg/kg/day has not been adequately studied.

Switching from Oral Dosing

When switching from oral levetiracetam, the initial total daily intravenous dosage of levetiracetam injection should be equivalent to the total daily dosage and frequency of oral levetiracetam.

Switching to Oral Dosing

At the end of the intravenous treatment period, the patient may be switched to levetiracetam oral administration at the equivalent daily dosage and frequency of the intravenous administration.

Preparation and Administration Instructions

Levetiracetam injection is for intravenous use only and should be diluted in 100 mL of a compatible diluent prior to administration. If a smaller volume is required (e.g. pediatric patients), the amount of diluent should be calculated to not exceed a maximum levetiracetam concentration of 15 mg per mL of diluted solution. Consideration should also be given to the total daily fluid intake of the patient. Levetiracetam injection should be administered as a 15-minute IV infusion. One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg/5 mL).

Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Product with particulate matter or discoloration should not be used.

Any unused portion of the levetiracetam injection vial contents should be discarded.

Adults

See Table 1 for the recommended preparation and administration of levetiracetam injection for adults to achieve a dose of 500 mg, 1,000 mg, or 1,500 mg.

Table 1: Preparation and Administration of Levetiracetam Injection for Adults
Dose Withdraw Volume Volume of Diluent Infusion Time
500 mg 5 mL (5 mL vial) 100 mL 15 minutes
1,000 mg 10 mL (two 5 mL vials) 100 mL 15 minutes
1,500 mg 15 mL (three 5 mL vials) 100 mL 15 minutes

For example, to prepare a 1,000 mg dose, dilute 10 mL of levetiracetam injection in 100 mL of a compatible diluent and administer intravenously as a 15-minute infusion.

Pediatric Patients

When using levetiracetam injection for pediatric patients, dosing is weight-based (mg per kg).

The following calculation should be used to determine the appropriate daily dose of levetiracetam injection for pediatric patients:

Total daily dose (mL/day) = Daily dose (mg/kg/day) x patient weight (kg)
100 mg/mL

Dosage Adjustments in Adult Patients with Renal Impairment

Levetiracetam injection dosing must be individualized according to the patient’s renal function status. Recommended dosage adjustments for adults with renal impairment are shown in Table 2. Information is unavailable for dosage adjustments in pediatric patients with renal impairment. In order to calculate the dose recommended for adult patients with renal impairment, creatinine clearance adjusted for body surface area must be calculated. To do this an estimate of the patient’s creatinine clearance (CLcr) in mL/min must first be calculated using the following formula:

CLcr = [140-age (years)] x weight (kg) (x 0.85 for female patients)
72 x serum creatinine (mg/dL)

Then CLcr is adjusted for body surface area (BSA) as follows:

CLcr (mL/min/1.73 m2) = CLcr (mL/min) x 1.73
BSA subject (m2)
Table 2: Dosage Adjustment Regimen for Adult Patients with Renal Impairment
Group Creatinine Clearance (mL/min/1.73 m2) Dosage(mg) Frequency
Normal > 80 500 to 1,500 Every 12 hours
Mild 50 to 80 500 to 1,000 Every 12 hours
Moderate 30 to 50 250 to 750 Every 12 hours
Severe < 30 250 to 500 Every 12 hours
ESRD patients using dialysis —————­ 500 to 1,0001 Every 24 hours1

1 Following dialysis, a 250 to 500 mg supplemental dose is recommended.

Compatibility and Stability

Levetiracetam injection was found to be physically compatible and chemically stable when mixed with the following diluents and antiepileptic drugs for at least 24 hours and stored in polyvinyl chloride (PVC) bags at controlled room temperature 20° to 25°C (68° to 77°F) [see USP].

Diluents

Sodium chloride (0.9%) injection, USP

Lactated Ringer’s injection

Dextrose 5% injection, USP

Other Antiepileptic Drugs

Lorazepam

Diazepam

Valproate sodium

There is no data to support the physical compatibility of levetiracetam injection with antiepileptic drugs that are not listed above.

Dosage Forms and Strengths

One vial of levetiracetam injection contains 500 mg levetiracetam (500 mg per 5 mL).

Contraindications

None.

Warnings and Precautions

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 Specific Populations].

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 3,000 mg/day. In a study in which there was no titration, about 45% of patients receiving levetiracetam 4,000 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.

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 cell count (RBC), hemoglobin, and hematocrit, and increases in eosinophil counts. Decreased white blood cell count (WBC) and decreased 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 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).

More levetiracetam-treated patients had a possibly clinically significant abnormally low WBC value (3% of levetiracetam-treated patients versus 0% of placebo-treated patients); however, there was no apparent difference between treatment groups with respect to neutrophil count (5% on levetiracetam versus 4.2% on placebo). No patient was discontinued because of low WBC or neutrophil count.

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.

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.

Adverse Reactions

The following adverse reactions are discussed in more details in other sections of labeling:

  • Behavioral Abnormalities and Psychotic Symptoms [see Warnings and Precautions]
  • Somnolence and Fatigue [see Warnings and Precautions]
  • Serious Dermatological Reactions [see Warnings and Precautions]
  • Coordination Difficulties [see Warnings and Precautions]
  • Hematologic Abnormalities [see Warnings and Precautions]
  • Increase in Blood Pressure [see Warnings and Precautions]

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 adverse reactions that result from levetiracetam injection use include all of those reported for levetiracetam tablets and oral solution. Equivalent doses of intravenous (IV) levetiracetam and oral levetiracetam result in equivalent Cmax , Cmin , and total systemic exposure to levetiracetam when the IV levetiracetam is administered as a 15-minute infusion.

Partial Onset Seizures

Adults

In controlled clinical studies using levetiracetam tablets in adults with partial onset seizures, the most common adverse reactions in adult patients receiving levetiracetam 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.

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 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
(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

* Adverse reactions occurred in at least 1% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients.

In controlled adult clinical studies using levetiracetam tablets, 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 Resulted in Discontinuation or Dose Reduction inPooled Placebo-Controlled Studies in Adults Experiencing Partial Onset Seizures
Adverse Reaction Levetiracetam
(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 using an oral formulation in pediatric patients 4 to 16 years of age with partial onset seizures. The most common adverse reactions in pediatric patients receiving 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.

Table 5: Adverse Reactions* in Pooled Placebo-Controlled, Add-On Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial Onset Seizures
  Levetiracetam
(N=165) %
Placebo
(N=131) %
Headache 19 15
Nasopharyngitis 15 12
Vomiting 15 12
Somnolence 13 9
Fatigue 11 5
Aggression 10 5
Abdominal Pain Upper 9 8
Cough 9 5
Nasal Congestion 9 2
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
Constipation 3 1
Contusion 3 1
Depression 3 1
Fall 3 2
Influenza 3 1
Mood Altered 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

*Adverse reactions occurred in at least 2% of pediatric levetiracetam-treated patients and occurred more frequently than placebo-treated patients.

In the 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 reaction.

Pediatric Patients 1 Month to < 4 Years

In the 7-day controlled pediatric clinical study using an oral formulation of levetiracetam in children 1 month to less than 4 years of age with partial onset seizures, the most common adverse reactions in patients receiving levetiracetam 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 in the placebo-controlled study and were numerically more common than in patients treated with placebo. In this study, either levetiracetam 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
(N=60)
%
Placebo
(N=56)
%
Somnolence 13 2
Irritability 12 0

* Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients.

In the 7-day controlled pediatric clinical study in patients 1 month to < 4 years of age, 3% of patients receiving levetiracetam 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 using levetiracetam tablets in patients with myoclonic seizures, the most common adverse reactions in patients receiving levetiracetam 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 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
(N=60)
%
Placebo
(N=60)
%
Somnolence 12 2
Neck Pain 8 2
Pharyngitis 7 0
Depression 5 2
Influenza 5 2
Vertigo 5 3

* Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients.

In the placebo-controlled study using levetiracetam tablets in patients with JME, 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 8.

Table 8: Adverse Reactions that Resulted in Discontinuation or Dose Reduction in Patients with Juvenile MyoclonicEpilepsy
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 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 oral formulation 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 and were numerically more common than in patients treated with placebo. In this study, either levetiracetam 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
(N=79)
%
Placebo
(N=84)
%
Nasopharyngitis 14 5
Fatigue 10 8
Diarrhea 8 7
Irritability 6 2
Mood Swings 5 1

* Adverse reactions occurred in at least 5% of levetiracetam-treated patients and occurred more frequently than placebo-treated patients.

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 controlled adult studies of levetiracetam: 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 was similar between females and males. There are insufficient data to support a statement regarding the distribution of adverse reactions by age and race.

Postmarketing Experience

The following adverse reactions have been identified during postapproval use of levetiracetam. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

The following adverse reactions have been reported in patients receiving levetiracetam worldwide. The listing is alphabetized: abnormal liver function test, choreoathetosis, drug reaction with eosinophilia and systemic symptoms (DRESS), dyskinesia, erythema multiforme, hepatic failure, hepatitis, hyponatremia, muscular weakness, pancreatitis, pancytopenia (with bone marrow suppression identified in some of these cases), panic attack, thrombocytopenia, and weight loss. Alopecia has been reported with levetiracetam use; recovery was observed in majority of cases where levetiracetam was discontinued.

Use in Specific Populations

Pregnancy

Levetiracetam blood levels may decrease during pregnancy [see Warnings and Precautions].

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 3,000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1,800 mg/kg/day (6 times the MRHD on a mg/m2 basis). The developmental no effect dose was 70 mg/kg/day (0.2 times the MRHD on a mg/m2 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/m2basis) and in decreased fetal weights and increased incidences of fetal malformations at a dose of 1,800 mg/kg/day (12 times the MRHD on a mg/m2 basis). The developmental no effect dose was 200 mg/kg/day (equivalent to the MRHD on a mg/m2 basis). Maternal toxicity was also observed at 1,800 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 3,600 mg/kg/day (12 times the MRHD). 1,200 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 during the last third of gestation and throughout lactation produced no adverse developmental or maternal effects at doses of up to 1,800 mg/kg/day (6 times the MRHD on a mg/m2 basis).

Pregnancy Registry

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/.

Labor and Delivery

The effect of levetiracetam on labor and delivery in humans is unknown.

Nursing Mothers

Levetiracetam is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from levetiracetam, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother.

Pediatric Use

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 Clinical Studies]. The dosing recommendation in these pediatric patients varies according to age group and is weight-based [see Dosage and 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 Clinical Studies].

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 Clinical Studies].

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 Warnings and 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 1,800 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.

Geriatric Use

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 Clinical Pharmacology ].

Renal Impairment

Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology]. Dosage adjustment is recommended for patients with impaired renal function and supplemental doses should be given to patients after dialysis [see Dosage and Administration].

Overdosage

Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

The highest known dose of oral levetiracetam received in the clinical development program was 6,000 mg/day. Other than drowsiness, there were no adverse reactions in the few known cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of consciousness, respiratory depression, and coma were observed with levetiracetam overdoses in postmarketing use.

Management of Overdose

There is no specific antidote for overdose with levetiracetam. If indicated, elimination of unabsorbed drug should be attempted by emesis or gastric lavage; usual precautions should be observed to maintain airway. General supportive care of the patient is indicated including monitoring of vital signs and observation of the patient’s clinical status. A Certified Poison Control Center should be contacted for up to date information on the management of overdose with levetiracetam.

Hemodialysis

Standard hemodialysis procedures result in significant clearance of levetiracetam (approximately 50% in 4 hours) and should be considered in cases of overdose. Although hemodialysis has not been performed in the few known cases of overdose, it may be indicated by the patient’s clinical state or in patients with significant renal impairment.

How Supplied/Storage and Handling

How Supplied

Levetiracetam injection is a clear, colorless, sterile solution. It is supplied as:

Product No. NDC No. Strength Vial Size
401005 63323-400-05 500 mg per 5 mL(100 mg per mL) 5 mL single-use vials supplied in packages of ten.

The container closure is not made with natural rubber latex.

Storage

Store at 20° to 25°C (68° to 77°F) [see USP Controlled Room Temperature].

Patient Counseling Information

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including levetiracetam, may increase the risk of suicidal thoughts and behavior and advise patients to be alert for the emergence or worsening of symptoms of depression; unusual changes in mood or behavior; or suicidal thoughts, behavior, or thoughts about self-harm. Advise patients, their caregivers, and/or families to immediately report behaviors of concern to a healthcare provider.

Psychiatric Reactions and Changes in Behavior

Advise patients and their caregivers that levetiracetam may cause changes in behavior (e.g., aggression, agitation, anger, anxiety, apathy, depression, hostility, and irritability) and psychotic symptoms.

Effects on Driving or Operating Machinery

Inform patients that levetiracetam may cause dizziness and somnolence. Inform patients 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.

Dermatological Adverse Reactions

Advise patients that serious dermatological adverse reactions have occurred in patients treated with levetiracetam and instruct them to call their physician immediately if a rash develops.

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during levetiracetam therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific Populations].

Fresenius Kabi USA, LLC
Lake Zurich, IL 60047

www.fresenius-kabi.us