brand keppra 1,000 mg tablet

Uses

Seizure Disorders

Levetiracetam is used orally in combination with other anticonvulsants in the management of partial onset, myoclonic, and primary generalized tonic-clonic seizures. The drug also is commercially available as an IV formulation for the management of such seizure disorders when oral therapy is temporarily not feasible. Efficacy of IV levetiracetam is supported by studies using oral formulations of the drug since the oral and parenteral formulations are bioequivalent.

Partial Seizures

Levetiracetam conventional (immediate-release) tablets, oral solution, and injection are used in combination with other anticonvulsants in the management of partial onset seizures in adults and pediatric patients 1 month of age and older with epilepsy.

Efficacy of levetiracetam for this use was established in 3 double-blind, placebo-controlled trials in patients who had refractory partial onset seizures with or without secondary generalization while receiving a stable regimen of 1 or 2 anticonvulsants and had experienced at least 2 partial seizures during each 4-week interval of the baseline period (8-12 weeks). Patients received levetiracetam (1, 2, or 3 g daily as a conventional oral preparation) or placebo for 12 weeks after a 4- to 6-week titration period. The weekly frequency of partial seizures was reduced in patients receiving levetiracetam relative to placebo. More patients receiving levetiracetam experienced a reduction in seizure frequency of 50% or greater from baseline (i.e., responder rate) compared with placebo-treated patients. Clinical benefit was evident within 2 weeks in one study.

Data from open-label extension periods of phase 1, 2, and 3 studies with oral levetiracetam (as conventional preparations) in 1422 adult patients with epilepsy indicate that 39% of patients experienced a 50% or greater decrease in seizure frequency, while 13 and 8% of patients were seizure-free for at least 6 and 12 months, respectively, during therapy with the drug. Continuation rates for levetiracetam therapy in these patients were estimated to be 60, 37, and 32% after 1, 3, and 5 years, respectively.

Efficacy of levetiracetam as adjunctive therapy in pediatric patients with partial onset seizures was established in 2 randomized, double-blind, placebo-controlled studies. The first study was conducted in children 4-16 years of age who had refractory partial onset seizures with or without secondary generalization while receiving a stable regimen of 1 or 2 anticonvulsants and had experienced at least 4 partial seizures during the 4 weeks prior to screening as well as at least 4 partial seizures during each of the two 4-week baseline periods. Patients received levetiracetam (20-60 mg/kg daily as a conventional oral preparation) or placebo for 10 weeks after a 4-week titration period. Pediatric patients receiving levetiracetam experienced a reduction of 26.8% in mean weekly partial seizure frequency relative to placebo. The second study was conducted in infants and children 1 month to less than 4 years of age with refractory partial onset seizures (with or without secondary generalization). Seizures were assessed in this study using video electroencephalography (EEG). Patients who had experienced at least 2 partial seizures during a 48-hour baseline period while receiving a stable regimen of 1 or 2 anticonvulsants were randomized to receive levetiracetam oral solution (20-50 mg/kg daily based on age) or placebo; after an initial 1-day dose titration period, treatment was continued for an additional 4 days. The responder rate (i.e., proportion of patients experiencing a reduction in seizure frequency of 50% or greater from baseline) was substantially higher in pediatric patients receiving levetiracetam (43.1%) compared with those receiving placebo (19.6%), and these results were consistent across age groups in this study.

Levetiracetam also is commercially available as extended-release tablets for once-daily administration in the management of partial onset seizures in adults and pediatric patients 12 years of age and older. Efficacy of levetiracetam (as extended-release tablets) was established in a double-blind, placebo-controlled study in patients 12-70 years of age who had refractory partial onset seizures with or without secondary generalization. Patients who had experienced at least 8 partial seizures during an 8-week baseline period and at least 2 seizures during each 4-week interval of the baseline period while receiving a stable regimen of 1-3 anticonvulsants were randomized to receive levetiracetam 1 g daily (as extended-release tablets) or placebo for 12 weeks. The median percent reduction in weekly seizure frequency from baseline was 46.1% in patients receiving levetiracetam compared with 33.4% in those receiving placebo.

Myoclonic Seizures

Levetiracetam conventional (immediate-release) tablets, oral solution, and injection are used in combination with other anticonvulsants in the management of myoclonic seizures in adults and adolescents 12 years of age and older with juvenile myoclonic epilepsy.

Efficacy of levetiracetam for this use was established in a randomized, double-blind, placebo-controlled study in patients who had myoclonic seizures while receiving a stable regimen of 1 anticonvulsant and had experienced at least one myoclonic seizure daily for at least 8 days during the 8-week baseline period. Patients received levetiracetam 3 g daily (as a conventional oral preparation) or placebo for 12 weeks after a 4-week titration period. More patients receiving levetiracetam (60.4%) experienced a reduction in seizure frequency of 50% or greater from baseline (i.e., responder rate) compared with placebo-treated patients (23.7%).

Primary Generalized Tonic-Clonic Seizures

Levetiracetam conventional (immediate-release) tablets, oral solution, and injection are used in combination with other anticonvulsants in the management of primary generalized tonic-clonic seizures in adults and children 6 years of age and older with idiopathic generalized epilepsy.

Efficacy of levetiracetam for this use was established in a randomized, double-blind, placebo-controlled study in patients who had primary generalized tonic-clonic seizures while receiving a stable regimen of 1 or 2 anticonvulsants and had experienced at least 3 primary generalized tonic-clonic seizures during the 8-week combined baseline period (4-week pre-prospective baseline period and 4-week prospective baseline period). Patients received levetiracetam 3 g daily (adult dosage) or 60 mg/kg daily (pediatric dosage) as a conventional oral preparation or placebo for 20 weeks after a 4-week titration period. The median percent reduction in weekly seizure frequency from baseline was 77.6% in patients receiving levetiracetam compared with 44.6% in those receiving placebo. In addition, more patients receiving levetiracetam (72.2%) experienced a reduction in seizure frequency of 50% or greater from baseline (i.e., responder rate) compared with placebo-treated patients (45.2%).

Dosage and Administration

Administration

Levetiracetam is administered orally (as immediate-release tablets, extended-release tablets, or oral solution). The drug also may be administered by IV infusion in patients in whom oral therapy is temporarily not feasible.

Commercially available levetiracetam conventional (immediate-release) tablets, extended-release tablets, oral solution, and IV formulations have been shown to be bioequivalent.

Patients currently receiving or beginning therapy with levetiracetam and/or any other anticonvulsant for any indication should be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or any unusual changes in mood or behavior.(See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Oral Administration

Levetiracetam immediate-release tablets and oral solution are administered orally twice daily without regard to meals. The immediate-release tablets should be swallowed whole and not chewed or crushed. A calibrated dosing device (e.g., medicine dropper, medicine cup) should be used to measure and administer doses of the oral solution; a household teaspoon or tablespoon is not an adequate measuring device.

Levetiracetam extended-release tablets are administered once daily; the tablets must be swallowed intact and not chewed, broken, or crushed.

IV Administration

For IV administration, levetiracetam is commercially available as an injection concentrate that must be diluted prior to use and as a premixed solution in sodium chloride injection that is administered without further dilution; the premixed injection is indicated for use only in adults 16 years of age or older.

When using the injection concentrate, the appropriate dose should be diluted in 100 mL of a compatible IV solution (e.g., 0.9% sodium chloride injection, lactated Ringer's, 5% dextrose injection) and administered by IV infusion over 15 minutes. A smaller volume of diluent may be used (e.g., in pediatric patients or patients who may be susceptible to fluid volume overload), but the final concentration of the diluted solution should not exceed 15 mg/mL. Following dilution, the infusion solution may be stored in polyvinyl chloride (PVC) bags for up to 4 hours at controlled room temperature (15-30°C). Unused contents of the levetiracetam injection vial should be discarded after use.

When using the premixed solution, a single 100-mL bag containing 500 mg, 1 g, or 1.5 g of levetiracetam in sodium chloride 0.82, 0.75, or 0.54%, respectively, should be administered by IV infusion over 15 minutes without further dilution. Doses that are not commercially available as a premixed solution (e.g., 250 or 750 mg) should be prepared by transferring the appropriate volume of solution from an intact commercial infusion bag into a separate sterile, empty infusion bag; any unused contents of the original infusion bag should be discarded and should not be reused or stored. Levetiracetam in sodium chloride injection should not be used in series connections.

Levetiracetam injection and diluted solutions of the drug should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Levetiracetam injection solutions may be mixed with diazepam, lorazepam, or valproate sodium.

Dispensing and Administration Precautions

Because of similarity in spelling between Keppra (a trade name for levetiracetam) and Kaletra (the trade name for the fixed combination of lopinavir and ritonavir, both antiretroviral agents), the potential exists for dispensing errors involving these drugs. Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for Keppra and Kaletra. The manufacturer of Keppra recommends that clinicians consider including the intended use of the particular drug on the prescription, in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist. Some experts also recommend that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these drugs by spelling both the trade and generic names to prescribers, using computerized name alerts, attaching reminders to drug containers and pharmacy shelves, separating the drugs on pharmacy shelves, employing independent checks in the dispensing process, counseling patients).(See Dispensing and Administration Precautions under Warnings/Precautions: General Precautions, in Cautions.)

Dosage

Levetiracetam therapy should not be discontinued abruptly. The manufacturer recommends that oral levetiracetam be withdrawn gradually (e.g., by reducing the dosage by 1 g daily at 2-week intervals).

When switching from oral to IV levetiracetam therapy, the initial total daily dosage of IV levetiracetam should be equivalent to the daily dose and frequency of oral levetiracetam. At the completion of the IV treatment period, the patient may be switched back to oral levetiracetam at the equivalent daily dose and frequency that was administered IV.

Partial Seizures

Adult Dosage

In adults 16 years of age and older, the recommended initial oral dosage of levetiracetam for adjunctive therapy of partial seizures is 1 g daily (administered as 500 mg twice daily as conventional tablets or oral solution, or 1 g once daily as extended-release tablets). Dosage may be increased in increments of 1 g daily at 2-week intervals up to the maximum recommended dosage of 3 g daily. However, some clinicians reportedly have initiated therapy with oral dosages of 2-4 g daily. Dosages exceeding 3 g daily have been used in open-label studies for periods of 6 months or longer; however, the manufacturers state that there is no evidence that these higher dosages provide additional therapeutic benefit.

When oral therapy is temporarily not feasible, levetiracetam may be administered by IV infusion at the same dosages recommended for conventional oral preparations.

Pediatric Dosage

When conventional oral preparations of levetiracetam are used in pediatric patients, the manufacturer recommends that children weighing 20 kg or less receive the oral solution; children weighing more than 20 kg may receive either the immediate-release tablets or oral solution. Extended-release levetiracetam tablets are indicated for use only in pediatric patients 12 years of age and older.

In pediatric patients 1 to younger than 6 months of age, the recommended initial oral dosage of levetiracetam for adjunctive therapy of partial seizures is 14 mg/kg daily, administered as 7 mg/kg twice daily (as immediate-release preparations). Dosage should be increased in increments of 14 mg/kg daily at 2-week intervals up to the recommended dosage of 42 mg/kg daily, given as 21 mg/kg twice daily. In the clinical trial, the mean daily dosage was 35 mg/kg in this age group; efficacy of lower dosages has not been established.

In pediatric patients 6 months to younger than 4 years of age, the recommended initial oral dosage of levetiracetam is 20 mg/kg daily, administered as 10 mg/kg twice daily (as immediate-release preparations). Dosage should be increased in increments of 20 mg/kg daily at 2-week intervals up to the recommended dosage of 50 mg/kg daily, given as 25 mg/kg twice daily. Dosage may be reduced if the patient is unable to tolerate a dosage of 50 mg/kg daily. In the clinical trial, the mean daily dosage was 47 mg/kg in this age group.

In pediatric patients 4 years to younger than 16 years of age, the recommended initial oral dosage of levetiracetam is 20 mg/kg daily, administered as 10 mg/kg twice daily (as immediate-release preparations). Dosage should be increased in increments of 20 mg/kg daily at 2-week intervals up to the recommended dosage of 60 mg/kg daily, given as 30 mg/kg twice daily. Dosage may be reduced if the patient is unable to tolerate a dosage of 60 mg/kg daily. In the clinical trial, the mean daily dosage was 44 mg/kg and the maximum daily dosage was 3 g daily. If levetiracetam immediate-release tablets are used in pediatric patients weighing 20-40 kg, the recommended initial dosage is 500 mg daily, given as 250 mg twice daily; dosage may be increased in increments of 500 mg daily every 2 weeks up to a maximum of 1.5 g daily, given as 750 mg twice daily. If levetiracetam immediate-release tablets are used in pediatric patients weighing more than 40 kg, the recommended initial dosage is 1 g daily, given as 500 mg twice daily; dosage may be increased in increments of 1 g daily every 2 weeks up to a maximum of 3 g daily, given as 1.5 g twice daily.

In pediatric patients 12 years of age and older, the recommended initial dosage of levetiracetam (as extended-release tablets) is 1 g once daily. Dosage may be increased in increments of 1 g daily at 2-week intervals up to the maximum recommended dosage of 3 g daily.

When oral therapy is temporarily not feasible, levetiracetam may be administered by IV infusion at the same dosages recommended for conventional oral preparations.

Myoclonic Seizures

The recommended initial dosage of oral levetiracetam as adjunctive therapy for myoclonic seizures in patients 12 years of age and older is 1 g daily, given as 500 mg twice daily (as immediate-release preparations). Dosage should be increased in increments of 1 g daily at 2-week intervals up to the recommended dosage of 3 g daily, given as 1.5 g twice daily. Efficacy of dosages lower than 3 g daily has not been established.

When oral therapy is temporarily not feasible, levetiracetam may be administered by IV infusion at the same dosages recommended above.

Primary Generalized Tonic-Clonic Seizures

Adult Dosage

The recommended initial dosage of oral levetiracetam as adjunctive therapy for primary generalized tonic-clonic seizures in adults 16 years of age and older is 1 g daily, given as 500 mg twice daily (as immediate-release preparations). Dosage should be increased in increments of 1 g daily at 2-week intervals up to the recommended dosage of 3 g daily, given as 1.5 g twice daily. Efficacy of dosages lower than 3 g daily has not been established.

When oral therapy is temporarily not feasible, levetiracetam may be administered by IV infusion at the same dosages recommended above.

Pediatric Dosage

The recommended initial dosage of oral levetiracetam as adjunctive therapy for primary generalized tonic-clonic seizures in pediatric patients 6 to younger than 16 years of age is 20 mg/kg daily, given as 10 mg/kg twice daily (as immediate-release preparations). Children weighing 20 kg or less should receive the oral solution; children weighing more than 20 kg may receive either the tablets (administered whole) or the oral solution. Dosage should be increased in increments of 20 mg/kg daily at 2-week intervals up to the recommended dosage of 60 mg/kg daily, given as 30 mg/kg twice daily. Efficacy of dosages lower than 60 mg/kg daily has not been established.

When oral therapy is temporarily not feasible, levetiracetam may be administered by IV infusion at the same dosages recommended above.

Special Populations

In adults with impaired renal function, dosage of levetiracetam must be modified according to the degree of impairment. Dosage should be based on the patient's creatinine clearance adjusted for body surface area. (See Tables 1and 2.)

Table 1. Immediate-release Levetiracetam Dosage Adjustment in Adults with Impaired Renal Function

Renal Function	Creatinine Clearance (mL/minute per 1.73 m2)	Dosage (mg)	Interval (hours)
Normal	>80	500-1500	12
Mild	50-80	500-1000	12
Moderate	30-50	250-750	12
Severe	<30	250-500	12
Patients with end-stage renal disease undergoing dialysis	-	500-1000	24

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

Table 2. Extended-release Levetiracetam Dosage Adjustment in Adults with Impaired Renal Function

Renal Function	Creatinine Clearance (mL/minute per 1.73 m2)	Dosage (mg)	Interval (hours)
Normal	>80	1000-3000	24
Mild	50-80	1000-2000	24
Moderate	30-50	500-1500	24
Severe	<30	500-1000	24

Dosage should be selected carefully and renal function monitoring should be considered in geriatric patients 65 years of age and older because of the greater frequency of decreased renal function observed in this age group. Total body clearance was reduced by 38% and half-life was increased by 2.5 hours in geriatric patients with creatinine clearances of 30-74 mL/minute.

No dosage adjustment is necessary in patients with hepatic impairment. Levetiracetam pharmacokinetics were unchanged in patients with mild (Child-Pugh class A) to moderate (Child-Pugh class B) hepatic impairment. Total body clearance was reduced by 50% in patients with severe hepatic impairment (Child-Pugh class C), principally because of decreased renal clearance.

Cautions

Contraindications

Levetiracetam is contraindicated in patients with known hypersensitivity to the drug.

Warnings/Precautions

Warnings

Nervous System Effects

Adverse neuropsychiatric effects reported during levetiracetam therapy are classified into 3 categories: somnolence and fatigue, coordination difficulties, and behavioral/psychiatric abnormalities. Patients should be monitored for these adverse effects during therapy. In addition, patients should be advised not to drive or operate machinery until the effects of levetiracetam are known.

In controlled studies in adults, approximately 15% of patients with partial onset seizures who received levetiracetam (as an oral conventional preparation) experienced somnolence compared with 8% of placebo-treated patients, and about 3% of levetiracetam-treated patients discontinued treatment because of somnolence. Pediatric patients and adults with other seizure types who receive levetiracetam appear to experience similar rates of somnolence and fatigue. In controlled studies in adults, asthenia was reported in about 15% of patients who received levetiracetam (as conventional preparations) compared with 9% of placebo-treated patients, and 0.8% of levetiracetam-treated patients discontinued treatment because of asthenia. Coordination difficulties (e.g., ataxia, abnormal gait, incoordination) were experienced by 3.4% of patients receiving levetiracetam (as conventional preparations) compared with 1.6% of placebo-treated patients. Somnolence, asthenia, and coordination difficulties occurred most frequently within the first 4 weeks of treatment. In studies with extended-release levetiracetam, somnolence was reported in 8% of patients receiving the drug compared with 3% of patients receiving placebo; however, the number of patients exposed to the extended-release preparation is considerably less than that of the immediate-release preparation.

In clinical studies, psychotic symptoms were reported in 1% of adults, 2% of children 4-16 years of age, and 17% of children younger than 4 years of age receiving conventional levetiracetam preparations compared with 0.2, 2, and 5% of the corresponding age groups receiving placebo, respectively. At least 2 adults who received levetiracetam in these studies were hospitalized as a result of psychosis. Nonpsychotic behavioral symptoms (e.g., aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility, hyperkinesias, irritability, nervousness, neurosis, personality disorder) were reported in 13% of adults and 38% of children 4-16 years of age receiving conventional levetiracetam preparations in clinical studies compared with 6 and 19% of placebo-treated patients, respectively. Exploratory analysis of a placebo-controlled study that evaluated neurocognitive and behavioral effects of conventional levetiracetam in children 4-16 years of age indicated possible worsening of aggression in pediatric patients receiving the drug. Increased irritability was reported in clinical studies of younger children (1 month to younger than 4 years of age). In studies with extended-release levetiracetam, behavioral abnormalities (irritability and aggression) were reported in 7% of patients receiving the drug compared with none of the patients receiving placebo; however, the number of patients exposed to the extended-release preparation is considerably less than that of the immediate-release preparation.(See Suicidality Risk under Warnings/Precautions: Warnings, in Cautions.)

Suicidality Risk

The FDA has alerted healthcare professionals about an increased risk of suicidality (suicidal behavior or ideation) observed in an analysis of studies using various anticonvulsants, including levetiracetam, compared with placebo. The analysis of suicidality reports from placebo-controlled studies involving 11 anticonvulsants (i.e., carbamazepine, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, valproate, zonisamide) in patients with epilepsy, psychiatric disorders (e.g., bipolar disorder, depression, anxiety), and other conditions (e.g., migraine, neuropathic pain) found that patients receiving anticonvulsants had approximately twice the risk of suicidal behavior or ideation (0.43%) compared with patients receiving placebo (0.24%). This increased suicidality risk was observed as early as one week after beginning therapy and continued through 24 weeks. Although patients treated with an anticonvulsant for epilepsy, psychiatric disorders, and other conditions were all found to have an increased suicidality risk compared with those receiving placebo, the relative suicidality risk was higher for patients with epilepsy compared with those receiving anticonvulsants for other conditions.

Based on the current analysis of the available data, FDA recommends that clinicians inform patients, their families, and caregivers about the potential for an increase in the risk of suicidality with anticonvulsant therapy and that all patients currently receiving or beginning therapy with any anticonvulsant for any indication be closely monitored for the emergence or worsening of depression, suicidal thoughts or behavior (suicidality), and/or unusual changes in mood or behavior. Symptoms such as anxiety, agitation, hostility, hypomania, and mania may be precursors to emerging suicidality.

Clinicians who prescribe levetiracetam or any other anticonvulsant should balance the risk of suicidality with the risk of untreated illness. Epilepsy and many other illnesses for which anticonvulsants are prescribed are themselves associated with an increased risk of morbidity and mortality and an increased risk of suicidal thoughts and behavior. If suicidal thoughts and behavior emerge during anticonvulsant therapy, the clinician should consider whether these symptoms may be related to the illness being treated.(See Nervous System Effects under Warnings/Precautions: Warnings, in Cautions, and also see Advice to Patients.)

Dermatologic Reactions

Serious dermatologic reactions, including Stevens-Johnson syndrome and toxic epidermal necrolysis, have been reported in both adults and pediatric patients receiving levetiracetam. The median time of onset is reported to be between 14 and 17 days, although cases have occurred at least 4 months after initiation of therapy.

Levetiracetam should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If manifestations suggestive of Stevens-Johnson syndrome or toxic epidermal necrolysis occur, levetiracetam therapy should be permanently discontinued and alternative therapy considered.

Discontinuance of Therapy

Because of the possibility of increased seizure frequency, anticonvulsant drugs, including levetiracetam, should not be discontinued suddenly. The manufacturer recommends that oral levetiracetam be withdrawn gradually by reducing the dosage by 1 g daily at 2-week intervals.

Hematologic Effects

Hematologic abnormalities (e.g., decreased red blood cell, white blood cell, and neutrophil counts) were reported in patients receiving levetiracetam in clinical studies. Agranulocytosis, leukopenia, neutropenia, pancytopenia, and thrombocytopenia also have occurred during postmarketing experience.

A complete blood count (CBC) is recommended in patients who experience any signs or symptoms of hematologic abnormalities (e.g., severe weakness, pyrexia, recurrent infections, coagulation disorders) during levetiracetam therapy.

Increased Blood Pressure

In a study of pediatric patients 1 month to younger than 4 years of age, increased diastolic blood pressure was observed in levetiracetam-treated patients (17%) compared with those receiving placebo (2%). However, there was no overall difference in mean diastolic blood pressure between the treatment groups. These findings were not observed in older children or adults receiving the drug.

Pediatric patients younger than 4 years of age should be monitored for increased diastolic blood pressure during levetiracetam therapy.

Seizure Control During Pregnancy

Physiologic changes that occur during pregnancy may gradually decrease plasma levels of levetiracetam in pregnant women. This effect is most notable during the third trimester.

Patients should be closely monitored during pregnancy and throughout the postpartum period, especially if levetiracetam dosage is adjusted during pregnancy.

Sensitivity Reactions

Anaphylaxis and Angioedema

Anaphylaxis and angioedema, in some cases life-threatening and/or requiring emergency treatment, have been reported during postmarketing experience in patients receiving levetiracetam. (See Cautions: Contraindications.) Manifestations have included hypotension, hives, rash, respiratory distress, facial swelling, and swelling of the tongue, throat, and feet. Such reactions can occur at any time during therapy.

If any signs or symptoms of anaphylaxis or angioedema occur, patients should discontinue levetiracetam immediately and seek medical attention. Levetiracetam therapy should be permanently discontinued if an alternative etiology cannot be identified.

General Precautions

Dispensing and Administration Precautions

Because of similarity in spelling between Keppra (a trade name for levetiracetam) and Kaletra (the trade name for the fixed combination of lopinavir and ritonavir, both antiretroviral agents), the potential exists for dispensing errors involving these drugs. These medication errors may be associated with serious adverse events (e.g., status epilepticus) due to lack of appropriate therapy for seizures or with the risk of developing adverse effects associated with the use of levetiracetam or lopinavir and ritonavir in patients for whom the drug was not prescribed. Therefore, extra care should be exercised in ensuring the accuracy of both oral and written prescriptions for these drugs. The manufacturer of Keppra recommends that clinicians consider including the intended use of the particular drug on the prescription in addition to alerting patients to carefully check the drug they receive and promptly bring any question or concern to the attention of the dispensing pharmacist. Some experts also recommend that pharmacists assess various measures of avoiding dispensing errors and implement them as appropriate (e.g., by verifying all orders for these drugs by spelling both the trade and generic names to prescribers, using computerized name alerts, attaching reminders to drug containers and pharmacy shelves, separating the drugs on pharmacy shelves, employing independent checks in the dispensing process, counseling patients).

Dispensing errors involving Keppra and Kaletra should be reported to the manufacturers, the USP Medication Errors Reporting Program by phone (800-233-7767), or directly to the FDA MedWatch program by phone (800-FDA-1088), fax (800-FDA-0178), internet (http://www.fda.gov/Safety/MedWatch/default.htm), or mail.

Specific Populations

Pregnancy

Category C.

Seizure control during pregnancy should be carefully monitored.(See Seizure Control During Pregnancy under Warnings/Precautions: Warnings, in Cautions.)

North American Antiepileptic Drug (NAAED) Pregnancy Registry at 888-233-2334 (for patients); NAAED registry information also available at http://www.aedpregnancyregistry.org.

The effect of levetiracetam on labor and delivery is unknown.

Lactation

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

Pediatric Use

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of partial onset seizures have not been established in pediatric patients younger than 1 month of age. Behavioral abnormalities (e.g., paranoia, confusional state, increased aggression) have been observed in pediatric patients 4-16 years of age with partial onset seizures receiving the drug. (See Nervous System Effects under Warnings/Precautions: Warnings, in Cautions.)

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of myoclonic seizures have not been established in pediatric patients younger than 12 years of age.

Safety and efficacy of levetiracetam immediate-release tablets, oral solution, and injection for the management of primary generalized tonic-clonic seizures have not been established in pediatric patients younger than 6 years of age.

Safety and efficacy of extended-release levetiracetam tablets have not been established in pediatric patients younger than 12 years of age. Use of the extended-release tablets in children 12 years of age and older is supported by a placebo-controlled study using the immediate-release preparation in patients 4-16 years of age.

Safety and efficacy of levetiracetam in sodium chloride injection have not been established in pediatric patients younger than 16 years of age.

Geriatric Use

Controlled clinical studies evaluating levetiracetam have not included sufficient numbers of patients 65 years of age and older to determine whether geriatric patients respond differently than younger adults. No substantial differences in safety have been observed in geriatric patients relative to younger adults.(See Dosage and Administration: Special Populations.)

Renal Impairment

Dosage adjustment is recommended for patients with decreased creatinine clearance.(See Dosage and Administration: Special Populations.)

Hepatic Impairment

Safety and efficacy of levetiracetam have been demonstrated in a limited number of epileptic patients with chronic liver disease. No dosage adjustment is necessary in patients with hepatic impairment.(See Dosage and Administration: Special Populations.)

Common Adverse Effects

Adverse effects occurring in 1% or more of adults receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include somnolence, asthenia, headache, infection, dizziness, pain, pharyngitis, depression, nervousness, rhinitis, anorexia, ataxia, vertigo, amnesia, anxiety, emotional lability, hostility, paresthesia, increased cough, sinusitis, and diplopia.

Adverse effects occurring in 2% or more of pediatric patients older than 4 years of age receiving oral levetiracetam (as conventional preparations) for adjunctive management of partial seizures include headache, vomiting, nasopharyngitis, somnolence, fatigue, aggression, upper abdominal pain, cough, nasal congestion, decreased appetite, dizziness, pharyngolaryngeal pain, abnormal behavior, dizziness, irritability, diarrhea, lethargy, insomnia, head injury, anorexia, agitation, constipation, influenza, contusion, fall, depression, altered mood, ear pain, conjunctivitis, gastroenteritis, rhinitis, joint sprain, arthralgia, neck pain, sedation, labile affect, anxiety, confusional state, and mood swing. The most common adverse effects in patients younger than 4 years of age were somnolence and irritability.

The adverse effect profile of levetiracetam (as conventional preparations) in patients with myoclonic seizures or primary generalized tonic-clonic seizures is generally similar to that of patients with partial seizures.

Adverse effects occurring in 5% or more of patients receiving extended-release levetiracetam tablets for adjunctive management of partial seizures include influenza, somnolence, irritability, nasopharyngitis, dizziness, and nausea.

Adverse effects associated with IV levetiracetam generally appear to be consistent with those associated with oral administration of the drug.

Drug Interactions

Drugs Affecting or Metabolized by Hepatic Microsomal Enzymes

Because levetiracetam is neither a substrate nor inhibitor of cytochrome P-450 (CYP), pharmacokinetic interactions are unlikely with drugs affecting or metabolized by CYP isoenzymes.

Anticonvulsants

Clinically important pharmacokinetic interactions are unlikely when levetiracetam is administered concomitantly with other anticonvulsants (e.g., carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone, valproic acid).

In pediatric patients, an approximate 22% increase in levetiracetam clearance was observed when the drug was administered concurrently with hepatic enzyme-inducing anticonvulsants (e.g., carbamazepine); however, dosage adjustment is not recommended by the manufacturer. Levetiracetam did not alter plasma concentrations of carbamazepine, lamotrigine, topiramate, or valproic acid in pediatric patients with epilepsy.

Digoxin

Levetiracetam does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., cardiac rhythm effects) of digoxin; digoxin also does not affect the pharmacokinetics of levetiracetam.

Oral Contraceptives

Pharmacokinetic interactions are unlikely when levetiracetam is coadministered with oral contraceptives.

Probenecid

When levetiracetam was administered concomitantly with probenecid, no effect on levetiracetam pharmacokinetics was observed, but steady-state plasma concentrations of the principal inactive metabolite were approximately doubled due to a 60% reduction in renal clearance. The manufacturer states, however, that this effect is not clinically important.

Protein-bound Drugs

Pharmacokinetic interactions are unlikely with protein-bound drugs.

Warfarin

Levetiracetam does not appear to affect the pharmacokinetics or pharmacodynamics (e.g., prothrombin time) of warfarin; warfarin also does not affect the pharmacokinetics of levetiracetam.