2.1 Recommended Dosing

For adults and adolescent patients, the recommended dosing for monotherapy and adjunctive therapy is the same; as outlined below.

2.2 Dosage Adjustments in Adult Patients with Renal Impairment

KEPPRA XR dosing must be individualized according to the patient's renal function status. Recommended dosage adjustments for adults are shown in Table 1. In order to calculate the dose recommended for 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:

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

2.3 Discontinuation of KEPPRA XR

Avoid abrupt withdrawal from KEPPRA XR in order to reduce the risk of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

5.1 Behavioral Abnormalities and Psychotic Symptoms

KEPPRA XR may cause behavioral abnormalities and psychotic symptoms. Patients treated with KEPPRA XR should be monitored for psychiatric signs and symptoms.

5.2 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including KEPPRA XR, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24% among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week after starting drug treatment with AEDs and persisted for the duration of treatment assessed. Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed. The finding of increased risk with AEDs of varying mechanisms of action and across a range of indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary substantially by age (5-100 years) in the clinical trials analyzed. Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the epilepsy and psychiatric indications.

Anyone considering prescribing KEPPRA XR or any other AED must balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge during treatment, the prescriber needs to consider whether the emergence of these symptoms in any given patient may be related to the illness being treated.

5.3 Somnolence and Fatigue

KEPPRA XR may cause somnolence and fatigue. Patients should be monitored for these signs and symptoms and advised not to drive or operate machinery until they have gained sufficient experience on KEPPRA XR to gauge whether it adversely affects their ability to drive or operate machinery.

5.4 Anaphylaxis and Angioedema

KEPPRA XR 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 in patients treated with levetiracetam 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, KEPPRA XR should be discontinued and the patient should seek immediate medical attention. KEPPRA XR should be discontinued permanently if a clear alternative etiology for the reaction cannot be established [see Contraindications (4)].

5.5 Serious Dermatological Reactions

Serious dermatological reactions, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), have been reported in 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. KEPPRA XR should be discontinued at the first sign of a rash, unless the rash is clearly not drug-related. If signs or symptoms suggest SJS/TEN, use of this drug should not be resumed and alternative therapy should be considered.

5.6 Coordination Difficulties

Coordination difficulties were not observed in the KEPPRA XR controlled trial, however, the number of patients exposed to KEPPRA XR was considerably smaller than the number of patients exposed to immediate-release KEPPRA tablets in controlled trials. However, adverse reactions observed in the immediate-release KEPPRA controlled trials may also occur in patients receiving KEPPRA XR.

5.7 Withdrawal Seizures

As with most antiepileptic drugs, KEPPRA XR should generally be withdrawn gradually because of the risk of increased seizure frequency and status epilepticus. If withdrawal is needed because of a serious adverse reaction, rapid discontinuation can be considered.

5.8 Hematologic Abnormalities

KEPPRA XR can cause hematologic abnormalities. Hematologic abnormalities occurred in clinical trials and included decreases in white blood cell (WBC), neutrophil, and red blood cell (RBC) counts; decreases in hemoglobin and hematocrit; and increases in eosinophil counts. Cases of agranulocytosis, pancytopenia, and thrombocytopenia have also been reported in the postmarketing setting. A complete blood count is recommended in patients experiencing significant weakness, pyrexia, recurrent infections, or coagulation disorders.

In controlled trials of immediate-release KEPPRA tablets in patients experiencing partial-onset seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count (0.03 × 106/mm3), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-release KEPPRA-treated patients.

A total of 3.2% of KEPPRA-treated and 1.8% of placebo-treated patients had at least one possibly significant (≤2.8 × 109/L) decreased WBC, and 2.4% of KEPPRA-treated and 1.4% of placebo-treated patients had at least one possibly significant (≤1.0 × 109/L) decreased neutrophil count. Of the KEPPRA-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.

In pediatric patients (4 to <16 years of age), statistically significant decreases in WBC and neutrophil counts were seen in patients treated with immediate-release KEPPRA, as compared to placebo. The mean decreases from baseline in the immediate-release KEPPRA group were -0.4 × 109/L and -0.3 × 109/L, respectively, whereas there were small increases in the placebo group. A significant increase in mean relative lymphocyte counts was observed in 1.7% of patients treated with immediate-release KEPPRA compared to a decrease of 4% in patients on placebo.

In the controlled pediatric trial, a possibly clinically significant abnormal low WBC value was observed in 3% of patients treated with immediate-release KEPPRA, compared to no patients on placebo. However, there was no apparent difference between treatment groups with respect to neutrophil count. No patient was discontinued secondary to low WBC or neutrophil counts.

In the controlled pediatric cognitive and neuropsychological safety study, two subjects (6.1%) in the placebo group and 5 subjects (8.6%) in the immediate-release KEPPRA-treated group had high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7×109/L).

5.9 Seizure Control During Pregnancy

Physiological changes may gradually decrease plasma levels of levetiracetam throughout pregnancy. This decrease is more pronounced during the third trimester. It is recommended that patients be monitored carefully during pregnancy. Close monitoring should continue through the postpartum period especially if the dose was changed during pregnancy.

6.1 Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of immediate-release KEPPRA tablets. 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 listing is alphabetized: abnormal liver function test, acute kidney injury, anaphylaxis, angioedema, agranulocytosis, 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, weight loss, and worsening of seizures. Alopecia has been reported with immediate-release KEPPRA use; recovery was observed in majority of cases where immediate-release KEPPRA was discontinued.

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

Safety and effectiveness in patients 12 years of age and older have been established based on pharmacokinetic data in adults and adolescents using KEPPRA XR and efficacy and safety data in controlled pediatric studies using immediate-release KEPPRA [see Adverse Reactions (6.1), Clinical Pharmacology (12.3), and Clinical Studies (14.1)].

Safety and effectiveness in pediatric patients below the age of 12 have not been established.

A 3-month, randomized, double-blind, placebo-controlled study was performed to assess the neurocognitive and behavioral effects of immediate-release KEPPRA as adjunctive therapy in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (KEPPRA N=64; placebo N=34). The target dose of immediate-release KEPPRA was 60 mg/kg/day. Neurocognitive effects were measured by the Leiter-R Attention and Memory (AM) Battery, which assesses various aspects of a child's memory and attention. Although no substantive differences were observed between the placebo- and KEPPRA-treated groups in the median change from baseline in this battery, the study was not adequate to assess formal statistical non-inferiority between 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 a worsening in aggressive behavior, one of the eight syndrome scores, in patients treated with KEPPRA [see Warnings and Precautions (5.1)].

8.5 Geriatric Use

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately assess the effectiveness of KEPPRA XR in these patients. It is expected that the safety of KEPPRA XR in elderly patients 65 and over would be comparable to the safety observed in clinical studies of immediate-release KEPPRA tablets.

There were 347 subjects in clinical studies of immediate-release KEPPRA that 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 immediate-release KEPPRA 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 (12.3)].

8.6 Renal Impairment

The effect of KEPPRA XR on renally impaired patients was not assessed in the controlled study. However, it is expected that the effect on KEPPRA XR-treated patients would be similar to the effect seen in controlled studies of immediate-release KEPPRA tablets. Clearance of levetiracetam is decreased in patients with renal impairment and is correlated with creatinine clearance [see Clinical Pharmacology (12.3)]. Dose adjustment is recommended for patients with impaired renal function [see Dosage and Administration (2.2)].

10.1 Signs, Symptoms and Laboratory Findings of Acute Overdosage in Humans

The signs and symptoms for KEPPRA XR overdose are expected to be similar to those seen with immediate-release KEPPRA tablets.

The highest known dose of oral immediate-release KEPPRA received in the clinical development program was 6000 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 immediate-release KEPPRA overdoses in postmarketing use.

10.2 Management of Overdose

There is no specific antidote for overdose with KEPPRA XR. 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 KEPPRA XR.

10.3 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.

12.1 Mechanism of Action

The precise mechanism(s) by which levetiracetam exerts its antiepileptic effect is unknown.

A saturable and stereoselective neuronal binding site in rat brain tissue has been described for levetiracetam. Experimental data indicate that this binding site is the synaptic vesicle protein SV2A, thought to be involved in the regulation of vesicle exocytosis. Although the molecular significance of levetiracetam binding to synaptic vesicle protein SV2A is not understood, levetiracetam and related analogs showed a rank order of affinity for SV2A which correlated with the potency of their antiseizure activity in audiogenic seizure-prone mice. These findings suggest that the interaction of levetiracetam with the SV2A protein may contribute to the antiepileptic mechanism of action of the drug.

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14.1 KEPPRA XR in Adults

The effectiveness of KEPPRA XR for the treatment of partial-onset seizures in adults was established in one multicenter, randomized, double-blind, placebo-controlled clinical study across 7 countries in patients who had refractory partial-onset seizures with or without secondary generalization (Study 1).

14.2 Immediate-Release KEPPRA in Adults

The effectiveness of immediate-release KEPPRA for the treatment of partial-onset seizures in adults was established in three multicenter, randomized, double-blind, placebo-controlled clinical studies in patients who had refractory partial-onset seizures with or without secondary generalization (Studies 2, 3, and 4). The tablet formulation was used in all three studies. In these studies, 904 patients were randomized to placebo, KEPPRA 1000 mg, KEPPRA 2000 mg, or KEPPRA 3000 mg/day. Patients enrolled in Study 2 or Study 3 had refractory partial-onset seizures for at least two years and had taken two or more AEDs. Patients enrolled in Study 4 had refractory partial-onset seizures for at least 1 year and had taken one AED. At the time of the study, patients were taking a stable dose regimen of at least one AED and could take a maximum of two AEDs. During the baseline period, patients had to have experienced at least two partial-onset seizures during each 4-week period.

Study 2

Study 2 was a double-blind, placebo-controlled, parallel-group study conducted at 41 sites in the United States, comparing immediate-release KEPPRA 1000 mg/day (N=97), immediate-release KEPPRA 3000 mg/day (N=101), and placebo (N=95), given in equally divided doses twice daily. After a prospective baseline period of 12 weeks, patients in Study 2 were randomized to one of the three treatment groups described above. The 18-week treatment period consisted of a 6-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 2 was a between-group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial-onset seizure frequency). The results of Study 2 are displayed in Table 6.

Table 6: Reduction In Mean Over Placebo In Weekly Frequency Of Partial-Onset Seizures In Study 2

	Placebo (N=95)	Immediate-release KEPPRA 1000 mg/day (N=97)	Immediate-release KEPPRA 3000 mg/day (N=101)
* statistically significant versus placebo
Percent reduction in partial seizure frequency over placebo	–	26.1%*	30.1%*

The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial-onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 2 is presented in Figure 1.

Figure 1: Responder Rate (≥50% Reduction From Baseline) In Study 2

	* statistically significant versus placebo

Study 3

Study 3 was a double-blind, placebo-controlled, crossover study conducted at 62 centers in Europe, comparing immediate-release KEPPRA 1000 mg/day (N=106), immediate-release KEPPRA 2000 mg/day (N=105), and placebo (N=111), given in equally divided doses twice daily.

The first period of the study (Period A) was designed to be analyzed as a parallel-group study. After a prospective baseline period of up to 12 weeks, patients in Study 3 were randomized to one of the three treatment groups described above. The 16-week treatment period consisted of the 4-week titration period followed by a 12-week fixed dose evaluation period, during which concomitant AED regimens were held constant. The primary measure of effectiveness in Study 3 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial-onset seizure frequency). The results of the analysis of Period A are displayed in Table 7.

Table 7: Reduction In Mean Over Placebo In Weekly Frequency Of Partial-Onset Seizures In Study 3: Period A

	Placebo (N=111)	Immediate-release KEPPRA 1000 mg/day (N=106)	Immediate-release KEPPRA 2000 mg/day (N=105)
* statistically significant versus placebo
Percent reduction in partial seizure frequency over placebo	–	17.1%*	21.4%*

The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial-onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the three treatment groups (x-axis) in Study 3 is presented in Figure 2.

      Figure 2: Responder Rate (≥50% Reduction From Baseline) In Study 3: Period A

	* statistically significant versus placebo

The comparison of immediate-release KEPPRA 2000 mg/day to immediate-release KEPPRA 1000 mg/day for responder rate in Study 3 was statistically significant (P=0.02). Analysis of the trial as a cross-over study yielded similar results.

Study 4

Study 4 was a double-blind, placebo-controlled, parallel-group study conducted at 47 centers in Europe comparing immediate-release KEPPRA 3000 mg/day (N=180) and placebo (N=104) in patients with refractory partial-onset seizures, with or without secondary generalization, receiving only one concomitant AED. Study drug was given in two divided doses. After a prospective baseline period of 12 weeks, patients in Study 4 were randomized to one of two treatment groups described above. The 16-week treatment period consisted of a 4-week titration period, followed by a 12-week fixed dose evaluation period, during which concomitant AED doses were held constant. The primary measure of effectiveness in Study 4 was a between group comparison of the percent reduction in weekly seizure frequency relative to placebo over the entire randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥50% reduction from baseline in partial-onset seizure frequency). Table 8 displays the results of Study 4.

Table 8: Reduction In Mean Over Placebo In Weekly Frequency Of Partial-Onset Seizures In Study 4

	Placebo (N=104)	Immediate-release KEPPRA 3000 mg/day (N=180)
* statistically significant versus placebo
Percent reduction in partial seizure frequency over placebo	–	23.0%*

The percentage of patients (y-axis) who achieved ≥50% reduction from baseline in weekly partial-onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) in Study 4 is presented in Figure 3.

      Figure 3: Responder Rate (≥50% Reduction From Baseline) In Study 4

	* statistically significant versus placebo

14.3 Immediate-Release KEPPRA in Pediatric Patients 4 Years to 16 Years

The use of KEPPRA XR in pediatric patients 12 years of age and older is supported by Study 5, which was conducted using immediate-release KEPPRA. KEPPRA XR is not indicated in children below 12 years of age.

Study 5

The effectiveness of immediate-release KEPPRA for the treatment of partial-onset seizures in pediatric patients was established in a multicenter, randomized double-blind, placebo-controlled study, conducted at 60 sites in North America, in children 4 to 16 years of age with partial seizures uncontrolled by standard antiepileptic drugs (Study 5). Eligible patients on a stable dose of 1-2 AEDs, who still experienced at least 4 partial-onset seizures during the 4 weeks prior to screening, as well as at least 4 partial-onset seizures in each of the two 4-week baseline periods, were randomized to receive either immediate-release KEPPRA or placebo. The enrolled population included 198 patients (KEPPRA N=101; placebo N=97) with refractory partial-onset seizures, with or without secondarily generalization. Study 5 consisted of an 8-week baseline period and 4-week titration period followed by a 10-week evaluation period. Dosing was initiated at a dose of 20 mg/kg/day in two divided doses. During the treatment period, the immediate-release KEPPRA doses were adjusted in 20 mg/kg/day increments, at 2-week intervals to the target dose of 60 mg/kg/day. The primary measure of effectiveness in Study 5 was a between group comparison of the percent reduction in weekly partial seizure frequency relative to placebo over the entire 14-week randomized treatment period (titration + evaluation period). Secondary outcome variables included the responder rate (incidence of patients with ≥ 50% reduction from baseline in partial-onset seizure frequency per week). Table 9 displays the results of this study.

Table 9: Reduction In Mean Over Placebo In Weekly Frequency Of Partial-Onset Seizures in Study 5

	Placebo (N=97)	Immediate-release KEPPRA (N=101)
* statistically significant versus placebo
Percent reduction in partial seizure frequency over placebo	-	26.8%*

The percentage of patients (y-axis) who achieved ≥ 50% reduction in weekly partial-onset seizure frequency over the entire randomized treatment period (titration + evaluation period) within the two treatment groups (x-axis) in Study 5 is presented in Figure 4.

      Figure 4: Responder Rate (≥ 50% Reduction From Baseline) in Study 5

	* statistically significant versus placebo

16.1 How Supplied

KEPPRA XR 500 mg tablets are white, oblong-shaped, film-coated tablets imprinted with "UCB 500XR" in red on one side. They are supplied in white HDPE bottles containing 60 tablets (NDC 50474-598-66).

KEPPRA XR 750 mg tablets are white, oblong-shaped, film-coated tablets imprinted with "UCB 750XR" in red on one side. They are supplied in white HDPE bottles containing 60 tablets (NDC 50474-599-66).

16.2 Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP Controlled Room Temperature].

Psychiatric Reactions and Changes in Behavior

Advise patients that KEPPRA XR may cause changes in behavior (e.g. irritability and aggression). In addition, patients should be advised that they may experience changes in behavior that have been seen with other formulations of KEPPRA, which include agitation, anger, anxiety, apathy, depression, hostility, and psychotic symptoms [see Warnings and Precautions (5.1)].

Suicidal Behavior and Ideation

Counsel patients, their caregivers, and/or families that antiepileptic drugs (AEDs), including KEPPRA XR, 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 [see Warnings and Precautions (5.2)].

Effects on Driving or Operating Machinery

Inform patients that KEPPRA XR may cause dizziness and somnolence. Inform patients not to drive or operate machinery until they have gained sufficient experience on KEPPRA XR to gauge whether it adversely affects their ability to drive or operate machinery [see Warnings and Precautions (5.3)].

Anaphylaxis and Angioedema

Advise patients to discontinue KEPPRA XR and seek medical care if they develop signs and symptoms of anaphylaxis or angioedema [see Warnings and Precautions (5.4)].

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 [see Warnings and Precautions (5.5)].

Dosing and Administration

Patients should be instructed to only take KEPPRA XR once daily and to swallow the tablets whole. They should not be chewed, broken, or crushed.

Inform patients that they should not be concerned if they occasionally notice something that looks like swollen pieces of the original tablet in their stool.

Withdrawal of KEPPRA

Advise patients and caregivers not to discontinue use of KEPPRA XR without consulting with their healthcare provider. KEPPRA XR should normally be gradually withdrawn to reduce the potential of increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

Pregnancy

Advise patients to notify their healthcare provider if they become pregnant or intend to become pregnant during KEPPRA therapy. Encourage patients to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry if they become pregnant [see Use in Specific Populations (8.1)].