LEVETIRACETAM tablet, film coated, extended release

United States - English - NLM (National Library of Medicine)

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Active ingredient:
LEVETIRACETAM (UNII: 44YRR34555) (LEVETIRACETAM - UNII:44YRR34555)
Available from:
Sun Pharmaceutical Industries, Inc.
INN (International Name):
LEVETIRACETAM
Composition:
LEVETIRACETAM 500 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in patients 12 years of age and older. Levetiracetam extended-release tablets are contraindicated in patients with a hypersensitivity to levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions (5.4)]. Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, during pregnancy. Encourage women who are taking levetiracetam extended-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or visiting http://www.aedpregnancyregistry.org/. Risk Summary Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of major birth defects or miscarriage, based on published literature, which includes data from pregnancy regis
Product summary:
Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “573” with black ink on one side and plain on other side. They are supplied as follows: Bottles of 60’s with child-resistant cap…................... NDC 47335-573-86 Bottles of 100’s with child-resistant cap…................. NDC 47335-573-88 Bottles of 500.............................…................………. NDC 47335-573-13   Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored, biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted with “576” with black ink on one side and plain on other side. They are supplied as follows:   Bottles of 60’s with child-resistant cap…................... NDC 47335-576-86 Bottles of 100’s with child-resistant cap…................. NDC 47335-576-88 Bottles of 500...…...................…...................………. NDC 47335-576-13 Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see USP Controlled Room Temperature]. Dispense in tight, light-resistant container.
Authorization status:
Abbreviated New Drug Application
Authorization number:
47335-573-13, 47335-573-86, 47335-573-88, 47335-576-13, 47335-576-86, 47335-576-88

Sun Pharmaceutical Industries, Inc.

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MEDICATION GUIDE

Levetiracetam Extended-release Tablets

(LEE-ve-tye-RA-se-tam)

Read this Medication Guide before you start taking levetiracetam extended-release tablets and each time you

get a refill. There may be new information. This information does not take the place of talking to your

healthcare provider about your medical condition or treatment.

What is the most important information I should know about levetiracetam extended-release tablets?

Like other antiepileptic drugs, levetiracetam extended-release tablets may cause suicidal thoughts or actions

very

small

number

people,

about

people

taking

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse,

or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Do not stop levetiracetam extended-release tablets without first talking to a healthcare provider.

Stopping levetiracetam extended-release tablets suddenly can cause serious problems. Stopping a

seizure medicine suddenly can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

What

levetiracetam

extended-release

tablets?

Levetiracetam extended-release tablets are a prescription medicine taken by mouth that are used to treat

partial-onset

seizures

people

years

older.

It is not known if levetiracetam extended-release tablets are safe or effective in people under 12 years of age.

Before taking your medicine, make sure you have received the correct medicine. Compare the name above

with the name on your bottle and the appearance of your medicine with the description of levetiracetam

extended-release tablets provided below. Tell your pharmacist immediately if you think you have been given

the wrong medicine.

should

take

levetiracetam

extended-release

tablets?

Do not take levetiracetam extended-release tablets if you are allergic to levetiracetam.

What should I tell my healthcare provider before starting levetiracetam extended-release tablets?

Before taking levetiracetam extended-release tablets, tell your healthcare provider about all of your medical

conditions, including if you:

have or have had depression, mood problems or suicidal thoughts or behavior.

have kidney problems.

are pregnant or planning to become pregnant. It is not known if levetiracetam extended-release tablets

will harm your unborn baby. You and your healthcare provider will have to decide if you should take

levetiracetam extended-release tablets while you are pregnant. If you become pregnant while taking

levetiracetam extended-release tablets, talk to your healthcare provider about registering with the

North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-

888-233-2334 or go to http://www.aedpregnancyregistry.org. The purpose of this registry is to collect

information about the safety of levetiracetam extended-release tablets and other antiepileptic medicine

during pregnancy.

are breastfeeding or plan to breastfeed. Levetiracetam can pass into your breast milk. It is not known

if the levetiracetam that passes into your breast milk can harm your baby. Talk to your doctor about

the best way to feed your baby while you receive levetiracetam.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter

medicines, vitamins, and herbal supplements. Do not start a new medicine without first talking with your

healthcare

provider.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each time

you get a new medicine.

How should I take levetiracetam extended-release tablets?

Take levetiracetam extended-release tablets exactly as your healthcare provider tells you to take it.

Your healthcare provider will tell you how many levetiracetam extended-release tablets to take and

when to take it. Levetiracetam extended-release tablets are usually taken 1 time each day.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Take levetiracetam extended-release tablets with or without food.

Swallow the tablets whole. Do not chew, break, or crush tablets.

The inactive part of levetiracetam extended-release tablet may not dissolve after all the medicine has

been released in your body. You may sometimes notice something in your bowel movement that

looks like inert fragments of coating and/ or swollen pieces of the original tablet. This is normal.

If you take too many levetiracetam extended-release tablets, call your local Poison Control Center or

go to the nearest emergency room right away.

What

should

avoid

while

taking

levetiracetam

extended-release

tablets?

Do not drive, operate machinery or do other dangerous activities until you know how levetiracetam

extended-release tablets affect you. Levetiracetam extended-release tablets may make you dizzy or sleepy.

What

possible

side

effects

levetiracetam

extended-release

tablets?

Levetiracetam extended-release tablets can cause serious side effects.

See “What is the most important information I should know about levetiracetam extended-release

tablets?”

Call your healthcare provider right away if you have any of these symptoms:

mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings,

depression, hostility, and irritability. A few people may get psychotic symptoms such as

hallucinations (seeing or hearing things that are really not there), delusions (false or strange thoughts

or beliefs) and unusual behavior.

extreme sleepiness, tiredness, and weakness.

allergic reactions such as swelling of the face, lips, eyes, tongue, and throat, trouble swallowing or

breathing, and hives.

a skin rash. Serious skin rashes can happen after you start taking levetiracetam extended-release

tablets. There is no way to tell if a mild rash will become a serious reaction.

problems with muscle coordination (problems walking and moving)

The most common side effects seen in people who take levetiracetam extended-release tablets include:

sleepiness

irritability

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of levetiracetam extended-release tablets. For more information,

your

healthcare

provider

pharmacist.

Call your doctor for medical advice about side effects. You may also report side effects to FDA at 1-800--

FDA-1088.

How should I store levetiracetam extended-release tablets?

Store levetiracetam extended-release tablets at room temperature, between 15°C to 30°C (59°F to

86°F) away from heat and light.

Keep levetiracetam extended-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of levetiracetam extended-release tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use

levetiracetam extended-release tablets for a condition for which it was not prescribed. Do not give

levetiracetam extended-release tablets to other people, even if they have the same symptoms that you have. It

may harm them. You can ask your pharmacist or healthcare provider for information about levetiracetam

extended-release tablets that is written for health professionals.

What

ingredients

levetiracetam

extended-release

tablets?

Levetiracetam

extended-release

tablets

active

ingredient:

levetiracetam

Inactive ingredients: povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide,

magnesium stearate, talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, FD&C

Blue #1 aluminum lake, ethyl cellulose aqueous dispersion, dibutyl sebacate, triethyl citrate, polysorbate 20,

polyvinyl alcohol, polyethylene glycol, and polysorbate 80. The imprinting ink contains shellac glaze, iron

oxide

black,

N-butyl

alcohol,

propylene

glycol,

ammonium

hydroxide.

Levetiracetam

extended-release

tablets

contain

lactose

gluten.

Distributed

Pharmaceutical

Industries,

Inc.

Cranbury,

08512

Manufactured

Pharmaceutical

Industries

Ltd.

Halol-Baroda

Highway,

Halol-389

350,

Gujarat,

India.

PJPI0321H

This Medication Guide has been approved by the U.S. Food and Drug Administration.

ISS. 01/2020

Revised: 12/2019

Document Id: bb0f5c85-0acf-4c83-bad5-615931ad5728

34391-3

Set id: 5bb6ee93-27b0-46aa-ab78-445e076c47a3

Version: 15

Effective Time: 20191224

Sun Pharmaceutical Industries, Inc.

LEVETIRACETAM - levetiracetam tablet, film coated, extended release

Sun Pharmaceutical Industries, Inc.

----------

HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use LEVETIRACETAM EXTENDED-RELEASE

TABLETS safely and effectively. See full prescribing information for LEVETIRACETAM EXTENDED-RELEASE

TABLETS.

LEVETIRACETAM extended-release tablets, for oral use

Initial U.S. Approval: 1999

RECENT MAJOR CHANGES

Indications and Usage (1) 10/2019

Dosage and Administration (2.1, 2.3) 10/2019

INDICATIONS AND USAGE

Levetiracetam is indicated for the treatment of partial-onset seizures in patients 12 years of age and older (1)

DOSAGE AND ADMINISTRATION

Initiate treatment with a dose of 1,000 mg once daily; increase by 1,000 mg every 2 weeks to a maximum recommended

dose of 3,000 mg once daily (2)

See full prescribing information for use in patients with impaired renal function (2.1)

DOSAGE FORMS AND STRENGTHS

500 mg blue and white to off-white colored biconvex, bilayer, film-coated extended-release tablet (3)

750 mg blue and white to off-white colored biconvex, bilayer, film-coated extended-release tablet (3)

CONTRAINDICATIONS

Known hypersensitivity to levetiracetam; angioedema and anaphylaxis have occurred (4, 5.4)

WARNINGS AND PRECAUTIONS

Behavioral abnormalities including psychotic symptoms, suicidal ideation, irritability, and aggressive behavior have

been observed; monitor patients for psychiatric signs and symptoms (5.1)

Suicidal Behavior and Ideation: Monitor patients for new or worsening depression, suicidal thoughts/behavior, and/or

unusual changes in mood or behavior (5.2)

Monitor for somnolence and fatigue and advise patients not to drive or operate machinery until they have gained

sufficient experience on levetiracetam extended-release tablets (5.3)

Serious Dermatological Reactions: Discontinue levetiracetam at the first sign of rash unless clearly not drug related.

(5.5)

Coordination Difficulties: Monitor for ataxia, abnormal gait, and incoordination. Advise patients to not drive or operate

machinery until they have gained experience on levetiracetam. (5.6)

Withdrawal Seizures: Levetiracetam extended-release tablets must be gradually withdrawn (5.7)

ADVERSE REACTIONS

Most common adverse reactions (incidence ≥5% more than placebo) include: somnolence and irritability (6.1)

To report SUSPECTED ADVERSE REACTIONS, contact Sun Pharmaceutical Industries, Inc. at 1-800-818-4555

or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

Pregnancy: Plasma levels of levetiracetam may be decreased and therefore need to be monitored closely during

pregnancy. Based on animal data, may cause fetal harm (5.9, 8.1)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 1/2020

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

2.2 Dosage Adjustments in Adult Patients with Renal Impairment

2.3 Discontinuation of Levetiracetam Extended-Release Tablets

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Behavioral Abnormalities and Psychotic Symptoms

5.2 Suicidal Behavior and Ideation

5.3 Somnolence and Fatigue

5.4 Anaphylaxis and Angioedema

5.5 Serious Dermatological Reactions

5.6 Coordination Difficulties

5.7 Withdrawal Seizures

5.8 Hematologic Abnormalities

5.9 Seizure Control During Pregnancy

6 ADVERSE REACTIONS

6.1 Clinical Trials Experience

6.2 Postmarketing Experience

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Renal Impairment

10 OVERDOSAGE

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

10.2 Management of Overdose

10.3 Hemodialysis

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

14 CLINICAL STUDIES

14.1 Levetiracetam Extended-Release Tablets in Adults

14.2 Immediate-Release Levetiracetam in Adults

14.3 Immediate-Release Levetiracetam in Pediatric Patients

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

Levetiracetam extended-release tablets are indicated for the treatment of partial-onset seizures in

patients 12 years of age and older.

2 DOSAGE AND ADMINISTRATION

2.1 Recommended Dosing

For adults and adolescent patients, the recommended dosing for monotherapy and adjunctive therapy is

the same; as outlined below.

Adults and Adolescents 12 Years of Age and Older Weighing 50 kg or More

Initiate treatment with a dose of 1,000 mg once daily. The once daily dosage may be adjusted in

increments of 1,000 mg every 2 weeks to a maximum recommended daily dose of 3,000 mg/day once

Sections or subsections omitted from the full prescribing information are not listed.

daily.

Administration

Levetiracetam extended-release tablets are administered once daily. Levetiracetam extended-release

tablets should be swallowed whole. The tablets should not be chewed, broken, or crushed.

2.2 Dosage Adjustments in Adult Patients with Renal Impairment

Levetiracetam extended-release tablets 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 CL is adjusted for body surface area (BSA) as follows:

Table 1: Dosage Adjustment Regimen for Adult Patients with Renal Impairment

Group

Creatinine Clearance

(mL/min/1.73m )

Dosage (mg)

Frequency

Normal

> 80

1,000 to 3,000

Every 24 hours

Mild

50 to 80

1,000 to 2,000

Every 24 hours

Moderate

30 to 50

500 to 1,500

Every 24 hours

Severe

< 30

500 to 1,000

Every 24 hours

2.3 Discontinuation of Levetiracetam Extended-Release Tablets

Avoid abrupt withdrawal from levetiracetam extended-release tablets in order to reduce the risk of

increased seizure frequency and status epilepticus [see Warnings and Precautions (5.7)].

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored,

biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted

with “573” with black ink on one side and plain on other side.

Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored,

biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted

with “576” with black ink on one side and plain on other side.

2

4 CONTRAINDICATIONS

Levetiracetam extended-release tablets are contraindicated in patients with a hypersensitivity to

levetiracetam. Reactions have included anaphylaxis and angioedema [see Warnings and Precautions

(5.4)].

5 WARNINGS AND PRECAUTIONS

5.1 Behavioral Abnormalities and Psychotic Symptoms

Levetiracetam extended-release tablets may cause behavioral abnormalities and psychotic symptoms.

Patients treated with levetiracetam extended-release tablets should be monitored for psychiatric signs

and symptoms.

Behavioral abnormalities

Levetiracetam Extended-Release Tablets

A total of 7% of levetiracetam extended-release tablets-treated patients experienced non-psychotic

behavioral disorders (reported as irritability and aggression) compared to 0% of placebo-treated

patients. Irritability was reported in 7% of levetiracetam extended-release tablets-treated patients.

Aggression was reported in 1% of levetiracetam extended-release tablets-treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than

the number of patients exposed to immediate-release levetiracetam tablets in controlled trials.

Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled

trials will likely occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

A total of 13% of adult patients and 38% of pediatric patients (4 to 16 years of age) treated with

immediate-release levetiracetam tablets experienced non-psychotic behavioral symptoms (reported as

aggression, agitation, anger, anxiety, apathy, depersonalization, depression, emotional lability, hostility,

hyperkinesias, irritability, nervousness, neurosis, and personality disorder), compared to 6% and 19%

of adult and pediatric patients on placebo. A randomized, double-blind, placebo-controlled study was

performed to assess the neurocognitive and behavioral effects of immediate-release levetiracetam

tablets as adjunctive therapy in pediatric patients (4 to 16 years of age). An exploratory analysis

suggested a worsening in aggressive behavior in patients treated with immediate-release levetiracetam

tablets in that study [see Use in Specific Populations (8.4)].

A total of 1.7% of adult patients treated with immediate-release levetiracetam tablets 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 patients treated with immediate-release levetiracetam

tablets, compared to 0.5% of placebo-treated patients. Overall, 11% of pediatric patients treated with

immediate-release levetiracetam tablets experienced behavioral symptoms associated with

discontinuation or dose reduction, compared to 6.2% of placebo-treated pediatric patients.

One percent of adult patients and 2% of pediatric patients (4 to 16 years of age) treated with immediate-

release levetiracetam tablets experienced psychotic symptoms, compared to 0.2% and 2%, respectively,

in adult and placebo-treated pediatric patients. In the controlled study that assessed the neurocognitive

and behavioral effects of immediate-release levetiracetam tablets in pediatric patients 4 to 16 years of

age, 1.6% levetiracetam tablets-treated patients experienced paranoia, compared to no placebo-treated

patients. There were 3.1% patients treated with immediate-release levetiracetam tablets who

experienced confusional state, compared to no placebo-treated patients [see Use in Specific Populations

(8.4)].

Psychotic symptoms

Immediate-Release Levetiracetam Tablets

One percent of levetiracetam tablets-treated adult patients experienced psychotic symptoms compared to

0.2% of placebo-treated patients.

Two (0.3%) levetiracetam tablets-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 pediatric patients who discontinued

treatment due to psychotic and non-psychotic adverse reactions.

5.2 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, 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 to 100 years) in the clinical trials analyzed. Table 2 shows absolute and relative

risk by indication for all evaluated AEDs.

Table 2: Risk by Indication for Antiepileptic Drugs in the Pooled Analysis

Indication

Placebo Patients with

Events Per

1,000 Patients

Drug Patients

with Events

Per 1,000 Patients

Relative Risk: Incidence of

Events in Drug

Patients/Incidence in

Placebo Patients

Risk Difference:

Additional Drug Patients

with Events Per 1,000

Patients

Epilepsy

Psychiatric

Other

Total

The relative risk for suicidal thoughts or behavior was higher in clinical trials for epilepsy than in

clinical trials for psychiatric or other conditions, but the absolute risk differences were similar for the

epilepsy and psychiatric indications.

Anyone considering prescribing levetiracetam extended-release tablets 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

Levetiracetam extended-release tablets 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 levetiracetam extended-release tablets to gauge whether it adversely affects

their ability to drive or operate machinery.

Somnolence

Levetiracetam Extended-Release Tablets

In the levetiracetam extended-release tablets double-blind, controlled trial in patients experiencing

partial-onset seizures, 8% of levetiracetam extended-release tablets-treated patients experienced

somnolence compared to 3% of placebo-treated patients.

No patient discontinued treatment or had a dose reduction as a result of these adverse reactions.

The number of patients exposed to levetiracetam extended-release tablets was considerably smaller than

the number of patients exposed to immediate-release levetiracetam tablets in controlled trials.

Therefore, certain adverse reactions observed in the immediate-release levetiracetam tablets controlled

trials will likely occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of

levetiracetam tablets-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 where there was no titration, about

45% of patients receiving 4,000 mg/day reported somnolence. The somnolence was considered serious

in 0.3% of the levetiracetam tablets-treated patients, compared to 0% in the placebo group. About 3% of

levetiracetam tablets-treated patients discontinued treatment due to somnolence, compared to 0.7% of

placebo-treated patients. In 1.4% of levetiracetam tablets-treated patients and in 0.9% of placebo-treated

patients the dose was reduced, while 0.3% of the treated patients were hospitalized due to somnolence.

Asthenia

Immediate-Release Levetiracetam Tablets

In controlled trials of adult patients with epilepsy experiencing partial-onset seizures, 15% of

levetiracetam tablets-treated patients reported asthenia, compared to 9% of placebo-treated patients.

Treatment was discontinued due to asthenia in 0.8% of levetiracetam tablets-treated patients as

compared to 0.5% of placebo-treated patients. In 0.5% of levetiracetam tablets-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.

5.4 Anaphylaxis and Angioedema

Levetiracetam extended-release tablets 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, levetiracetam extended-release tablets should be discontinued and the patient should seek

immediate medical attention. Levetiracetam extended-release tablets 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. Levetiracetam extended-release tablets 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 levetiracetam extended-release tablets controlled

trial, however, the number of patients exposed to levetiracetam extended-release tablets was

considerably smaller than the number of patients exposed to immediate-release levetiracetam tablets in

controlled trials. However, adverse reactions observed in the immediate-release levetiracetam tablets

controlled trials may also occur in patients receiving levetiracetam extended-release tablets.

Immediate-Release Levetiracetam Tablets

A total of 3.4% of adult levetiracetam tablets-treated patients experienced coordination difficulties,

(reported as either ataxia, abnormal gait, or incoordination) compared to 1.6% of placebo-treated

patients. A total of 0.4% of patients in controlled trials discontinued levetiracetam tablets treatment due

to ataxia, compared to 0% of placebo-treated patients. In 0.7% of levetiracetam tablets-treated patients

and in 0.2% of placebo-treated patients, the dose was reduced due to coordination difficulties, while

one of the levetiracetam tablets-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 these signs and symptoms and advised not to drive or operate

machinery until they have gained sufficient experience on levetiracetam tablets to gauge whether it

could adversely affect their ability to drive or operate machinery.

5.7 Withdrawal Seizures

As with most antiepileptic drugs, levetiracetam extended-release tablets 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

Levetiracetam extended-release tablets 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 levetiracetam tablets in patients experiencing partial-onset

seizures, minor, but statistically significant, decreases compared to placebo in total mean RBC count

(0.03 x 10 /mm ), mean hemoglobin (0.09 g/dL), and mean hematocrit (0.38%), were seen in immediate-

release levetiracetam tablets-treated patients.

A total of 3.2% of levetiracetam tablets-treated and 1.8% of placebo-treated patients had at least one

possibly significant (≤2.8 x 10 /L) decreased WBC, and 2.4% of levetiracetam tablets-treated and 1.4%

of placebo-treated patients had at least one possibly significant (≤1 x 10 /L) decreased neutrophil count.

Of the levetiracetam tablets-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 levetiracetam tablets, as compared to

placebo. The mean decreases from baseline in the immediate-release levetiracetam tablets group were -

0.4 × 10 /L and -0.3 × 10 /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 levetiracetam tablets 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 levetiracetam tablets, 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 levetiracetam tablets-treated group had

high eosinophil count values that were possibly clinically significant (≥10% or ≥0.7X10 /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 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 (5.1)]

Suicidal Behavior and Ideation [see Warnings and Precautions (5.2)]

Somnolence and Fatigue [see Warnings and Precautions (5.3)]

Anaphylaxis and Angioedema [see Warnings and Precautions (5.4)]

Serious Dermatological Reactions [see Warnings and Precautions (5.5)]

Coordination Difficulties [see Warnings and Precautions (5.6)]

Hematologic Abnormalities [see Warnings and Precautions (5.8)]

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.

Levetiracetam Extended-Release Tablets

In the controlled clinical study in patients with partial-onset seizures [see Clinical Studies (14.1)], the

most common adverse reactions in patients receiving levetiracetam extended-release tablets in

combination with other AEDs, for events with rates greater than placebo, were irritability and

somnolence.

Table 3 lists adverse reactions that occurred in at least 5% of epilepsy patients receiving levetiracetam

extended-release tablets in the placebo-controlled study and were numerically more common than in

patients treated with placebo. In this study, either levetiracetam extended-release tablets or placebo was

added to concurrent AED therapy.

Table 3: Adverse Reactions in the Placebo-Controlled,

Adjunctive Study in Patients Experiencing Partial-Onset

Seizures

Levetiracetam

Extended-Release Tablets

(N=77)

%

Placebo

(N=79)

%

Influenza

Somnolence

Irritability

Nasopharyngitis

Dizziness

Nausea

Discontinuation or Dose Reduction in the Levetiracetam Extended-Release Tablets Controlled Clinical Study

In the controlled clinical study, 5% of patients receiving levetiracetam extended-release tablets and 3%

receiving placebo discontinued as a result of an adverse reaction. The adverse reactions that resulted in

discontinuation and that occurred more frequently in levetiracetam extended-release tablets-treated

patients than in placebo-treated patients were asthenia, epilepsy, mouth ulceration, rash, and respiratory

failure. Each of these adverse reactions led to discontinuation in a levetiracetam extended-release

tablets-treated patient and no placebo-treated patients.

Immediate-Release Levetiracetam Tablets

Table 4 lists the adverse reactions in the controlled studies of immediate-release levetiracetam tablets

in adult patients experiencing partial-onset seizures [see Clinical Studies (14.2)]. Although the pattern of

adverse reactions in the levetiracetam extended-release tablets study seems somewhat different from

that seen in partial-onset seizure controlled studies for immediate-release levetiracetam tablets, this is

possibly due to the much smaller number of patients in this study compared to the immediate-release

tablet studies. The adverse reactions for levetiracetam extended-release tablets are expected to be

similar to those seen with immediate-release levetiracetam tablets.

Adults

In controlled clinical studies of immediate-release levetiracetam tablets as adjunctive therapy to other

AEDs in adults with partial-onset seizures, the most common adverse reactions, for events with rates

greater than placebo, were somnolence, asthenia, infection, and dizziness.

Table 4 lists adverse reactions that occurred in at least 1% of adult epilepsy patients receiving

immediate-release levetiracetam tablets in placebo-controlled studies and were numerically more

common than in patients treated with placebo. In these studies, either immediate-release levetiracetam

tablets or placebo was added to concurrent AED therapy.

Table 4: Adverse Reactions in Pooled Placebo-Controlled,

Adjunctive Studies in Adults Experiencing Partial-Onset Seizures

Immediate-Releas e

Levetiracetam Tablets

(N=769)

%

Placebo

(N=439)

%

Asthenia

Somnolence

Headache

Infection

Dizziness

Pain

Pharyngitis

Depression

Nervousness

Rhinitis

Anorexia

Ataxia

Vertigo

Amnesia

Anxiety

Cough Increased

Diplopia

Emotional Lability

Hostility

Paresthesia

Sinusitis

Pediatric Patients 4 Years to <16 Years

In a pooled analysis of two controlled pediatric clinical studies in children 4 to 16 years of age with

partial-onset seizures [see Clinical Studies (14.3)], the adverse reactions most frequently reported with

the use of immediate-release levetiracetam tablets in combination with other AEDs, and with greater

frequency than in patients on placebo, were fatigue, aggression, nasal congestion, decreased appetite,

and irritability.

Table 5 lists adverse reactions that occurred in at least 2% of pediatric patients treated with immediate-

release levetiracetam tablets and were more common than in pediatric patients on placebo. In these

studies, either immediate-release levetiracetam tablets or placebo was added to concurrent AED

therapy. Adverse reactions were usually mild to moderate in intensity.

Table 5: Adverse Reactions in Pooled Placebo-Controlled, Adjunctive

Studies in Pediatric Patients Ages 4 to 16 Years Experiencing Partial-

Onset Seizures

Immediate-Releas e

Levetiracetam Tablets

(N=165)

%

Placebo

(N=131)

%

Headache

Nasopharyngitis

Vomiting

Somnolence

Fatigue

Aggression

Upper Abdominal Pain

Cough

Nasal Congestion

Decreased Appetite

Abnormal Behavior

Dizziness

Irritability

Pharyngolaryngeal Pain

Diarrhea

Lethargy

Insomnia

Agitation

Anorexia

Head Injury

Constipation

Contusion

Depression

Fall

Influenza

Mood Altered

Affect Lability

Anxiety

Arthralgia

Confusional State

Conjunctivitis

Ear Pain

Gastroenteritis

Joint Sprain

Mood Swings

Neck Pain

Rhinitis

Sedation

In controlled pediatric clinical studies in patients 4 to 16 years of age, 7% of patients treated with

immediate-release levetiracetam tablets and 9% of patients on placebo discontinued as a result of an

adverse event.

In addition, the following adverse reactions were seen in other controlled studies of immediate-release

levetiracetam tablets: balance disorder, disturbance in attention, eczema, hyperkinesia, memory

impairment, myalgia, personality disorders, pruritus, and blurred vision.

Comparison of Gender, Age and Race

There are insufficient data for levetiracetam extended-release tablets to support a statement regarding

the distribution of adverse reactions by gender, age, and race.

6.2 Postmarketing Experience

The following adverse reactions have been identified during postapproval use of immediate-release

levetiracetam 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, and weight loss. Alopecia has been reported with immediate-release

levetiracetam tablets use; recovery was observed in majority of cases where immediate-release

levetiracetam tablets were discontinued.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to

antiepileptic drugs (AEDs), including levetiracetam extended-release tablets, during pregnancy.

Encourage women who are taking levetiracetam extended-release tablets during pregnancy to enroll in

the North American Antiepileptic Drug (NAAED) pregnancy registry by calling 1-888-233-2334 or

visiting http://www.aedpregnancyregistry.org/.

Risk Summary

Prolonged experience with levetiracetam in pregnant women has not identified a drug-associated risk of

major birth defects or miscarriage, based on published literature, which includes data from pregnancy

registries and reflects experience over two decades [see Human Data]. In animal studies, levetiracetam

produced developmental toxicity (increased embryofetal and offspring mortality, increased incidences

of fetal structural abnormalities, decreased embryofetal and offspring growth, neurobehavioral

alterations in offspring) at doses similar to human therapeutic doses [see Animal Data].

In the U.S. general population, the estimated background risk of major birth defects and miscarriage in

clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. The background risk of

major birth defects and miscarriage for the indicated population is unknown.

Clinical Considerations

Levetiracetam extended-release tablets levels may decrease during pregnancy [see Warnings and

Precautions (5.9)].

Physiological changes during pregnancy may affect levetiracetam concentration. Decrease in

levetiracetam plasma concentrations has been observed during pregnancy. This decrease is more

pronounced during the third trimester. Dose adjustments may be necessary to maintain clinical response.

Data

Human Data

While available studies cannot definitively establish the absence of risk, data from the published

literature and pregnancy registries have not established an association with levetiracetam use during

pregnancy and major birth defects or miscarriage.

Animal Data

When levetiracetam (0 mg/kg/day, 400 mg/kg/day, 1,200 mg/kg/day, or 3,600 mg/kg/day) was

administered orally to pregnant rats during the period of organogenesis, reduced fetal weights and

increased incidence of fetal skeletal variations were observed at the highest dose tested. There was no

evidence of maternal toxicity. The no-effect dose for adverse effects on embryofetal developmental in

rats (1,200 mg/kg/day) is approximately 4 times the maximum recommended human dose (MRHD) of

3,000 mg on a body surface area (mg/m ) basis.

Oral administration of levetiracetam (0 mg/kg/day, 200 mg/kg/day, 600 mg/kg/day, or 1,800 mg/kg/day)

to pregnant rabbits during the period of organogenesis resulted in increased embryofetal mortality and

incidence of fetal skeletal variations at the mid and high dose and decreased fetal weights and increased

incidence of fetal malformations at the high dose, which was associated with maternal toxicity. The no-

effect dose for adverse effects on embryofetal development in rabbits (200 mg/kg/day) is approximately

equivalent to the MRHD on a mg/m basis.

Oral administration of levetiracetam (0 mg/kg/day, 70 mg/kg/day, 350 mg/kg/day, or 1,800 mg/kg/day) to

female rats throughout pregnancy and lactation led to an increased incidence of fetal skeletal variations,

reduced fetal body weight, and decreased growth in offspring at the mid and high doses and increased

pup mortality and neurobehavioral alterations in offspring at the highest dose tested. There was no

evidence of maternal toxicity. The no-effect dose for adverse effects on pre- and postnatal development

in rats (70 mg/kg/day) is less than the MRHD on a mg/m basis.

Oral administration of levetiracetam to rats during the latter part 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/m basis).

8.2 Lactation

Risk Summary

Levetiracetam is excreted in human milk. There are no data on the effects of levetiracetam on the

breastfed infant, or the effects on milk production.

The developmental and health benefits of breastfeeding should be considered along with the mother’s

clinical need for levetiracetam and any potential adverse effects on the breastfed infant from

levetiracetam or from the underlying maternal condition.

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 levetiracetam extended-release tablets and efficacy

and safety data in controlled pediatric studies using immediate-release levetiracetam tablets [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 levetiracetam tablets as adjunctive therapy

in 98 pediatric patients with inadequately controlled partial seizures, ages 4 to 16 years (levetiracetam

tablets N=64; placebo N=34). The target dose of immediate-release levetiracetam tablets 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 levetiracetam tablets-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 levetiracetam tablets [see Warnings and Precautions

(5.1)].

Juvenile Animal Toxicity Data

Studies of levetiracetam in juvenile rats (dosed on postnatal days 4 through 52) and dogs (dosed from

postnatal weeks 3 through 7) 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/m basis) did not

demonstrate adverse effects on postnatal development.

8.5 Geriatric Use

There were insufficient numbers of elderly subjects in controlled trials of epilepsy to adequately

assess the effectiveness of levetiracetam extended-release tablets in these patients. It is expected that

the safety of levetiracetam extended-release tablets in elderly patients 65 and over would be

comparable to the safety observed in clinical studies of immediate-release levetiracetam tablets.

There were 347 subjects in clinical studies of immediate-release levetiracetam tablets 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 levetiracetam tablets 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 levetiracetam extended-release tablets on renally impaired patients was not assessed in the

controlled study. However, it is expected that the effect on levetiracetam extended-release tablets-

treated patients would be similar to the effect seen in controlled studies of immediate-release

levetiracetam 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 OVERDOSAGE

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

The signs and symptoms for levetiracetam extended-release tablets overdose are expected to be similar

to those seen with immediate-release levetiracetam tablets.

The highest known dose of oral immediate-release levetiracetam tablets 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 immediate-release

levetiracetam tablets overdoses in postmarketing use.

10.2 Management of Overdose

There is no specific antidote for overdose with levetiracetam extended-release tablets. 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 extended-release tablets.

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.

11 DESCRIPTION

Levetiracetam is an antiepileptic drug available as 500 mg and 750 mg (blue and white to off-white)

extended-release tablets for oral administration.

The chemical name of levetiracetam, a single enantiomer, is (-)-(S)-α-ethyl-2-oxo-1-pyrrolidine

acetamide, its molecular formula is C H N O and its molecular weight is 170.21. Levetiracetam is

chemically unrelated to existing antiepileptic drugs (AEDs). It has the following structural formula:

Levetiracetam, USP is a white to off-white crystalline powder with a faint odor and a bitter taste. It is

very soluble in water (104 g/100 mL). It is freely soluble in chloroform (65.3 g/100 mL) and in

methanol (53.6 g/100 mL), soluble in ethanol (16.5 g/100 mL), sparingly soluble in acetonitrile (5.7

g/100 mL) and practically insoluble in n-hexane. (Solubility limits are expressed as g/100 mL solvent.)

Levetiracetam extended-release tablets contain the labeled amount of levetiracetam. Inactive ingredients:

povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide, magnesium stearate,

talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate, FD&C Blue #1

aluminum lake, ethyl cellulose aqueous dispersion, dibutyl sebacate, triethyl citrate, polysorbate 20,

polyvinyl alcohol, polyethylene glycol, and polysorbate 80. The imprinting ink contains shellac glaze,

iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

Levetiracetam extended-release tablet is a bilayer coated tablet. The medication is present in core of

tablet and release controlling polymers are present in core and coating of tablet. The biologically inert

components of core tablet and/or coating may occasionally remain intact during GI transit and may

be eliminated in feces as inert fragments of coating and/ or soft, hydrated mass.

12 CLINICAL PHARMACOLOGY

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

Effects on QTc Interval

The effects of levetiracetam extended-release tablets on QTc prolongation is expected to be the same

as that of immediate-release levetiracetam tablets. The effect of immediate-release levetiracetam tablets

on QTc prolongation was evaluated in a randomized, double-blind, positive-controlled (moxifloxacin

400 mg) and placebo-controlled crossover study of levetiracetam tablets (1,000 mg or 5,000 mg) in 52

healthy subjects. The upper bound of the 90% confidence interval for the largest placebo-adjusted,

baseline-corrected QTc was below 10 milliseconds. Therefore, there was no evidence of significant

QTc prolongation in this study.

12.3 Pharmacokinetics

Overview

Bioavailability of levetiracetam extended-release tablets is similar to that of the immediate-release

levetiracetam tablets. The pharmacokinetics (AUC and C

) were shown to be dose proportional after

single dose administration of 1,000 mg, 2,000 mg, and 3,000 mg extended-release levetiracetam.

Plasma half-life of extended-release levetiracetam is approximately 7 hours.

Levetiracetam is almost completely absorbed after oral administration. The pharmacokinetics of

levetiracetam are linear and time-invariant, with low intra- and inter-subject variability. Levetiracetam is

not significantly protein-bound (<10% bound) and its volume of distribution is close to the volume of

intracellular and extracellular water. Sixty-six percent (66%) of the dose is renally excreted unchanged.

The major metabolic pathway of levetiracetam (24% of dose) is an enzymatic hydrolysis of the

acetamide group. It is not liver cytochrome P450 dependent. The metabolites have no known

pharmacological activity and are renally excreted. Plasma half-life of levetiracetam across studies is

approximately 6 to 8 hours. The half-life is increased in the elderly (primarily due to impaired renal

clearance) and in subjects with renal impairment.

The pharmacokinetics of levetiracetam are similar when used as monotherapy or as adjunctive therapy

for the treatment of partial-onset seizures.

Absorption and Distribution

Extended-release levetiracetam peak plasma concentrations occur in about 4 hours. The time to peak

plasma concentrations is about 3 hours longer with extended-release levetiracetam than with immediate-

release tablets.

Single administration of two 500 mg extended-release levetiracetam tablets once daily produced

comparable maximal plasma concentrations and area under the plasma concentration versus time as did

the administration of one 500 mg immediate-release tablet twice daily in fasting conditions. After

multiple dose extended-release levetiracetam tablets intake, extent of exposure (AUC0-24) was similar

to extent of exposure after multiple dose immediate-release tablets intake. Cmax and Cmin were lower

by 17% and 26% after multiple dose extended-release levetiracetam tablets intake in comparison to

multiple dose immediate-release tablets intake. Intake of a high fat, high calorie breakfast before the

administration of extended-release levetiracetam tablets resulted in a higher peak concentration, and

longer median time to peak. The median time to peak (Tmax) was 2 hours longer in the fed state.

Two 750 mg extended-release levetiracetam tablets were bioequivalent to a single administration of

three 500 mg extended-release levetiracetam tablets.

Metabolism

Levetiracetam is not extensively metabolized in humans. The major metabolic pathway is the enzymatic

hydrolysis of the acetamide group, which produces the carboxylic acid metabolite, ucb L057 (24% of

dose) and is not dependent on any liver cytochrome P450 isoenzymes. The major metabolite is inactive

in animal seizure models. Two minor metabolites were identified as the product of hydroxylation of the

2-oxo-pyrrolidine ring (2% of dose) and opening of the 2-oxo-pyrrolidine ring in position 5 (1% of

dose). There is no enantiomeric interconversion of levetiracetam or its major metabolite.

Elimination

Levetiracetam plasma half-life in adults is 7 ± 1 hour and is unaffected by either dose or repeated

administration. Levetiracetam is eliminated from the systemic circulation by renal excretion as

unchanged drug which represents 66% of administered dose. The total body clearance is 0.96

mL/min/kg and the renal clearance is 0.6 mL/min/kg. The mechanism of excretion is glomerular filtration

with subsequent partial tubular reabsorption. The metabolite ucb L057 is excreted by glomerular

filtration and active tubular secretion with a renal clearance of 4 mL/min/kg. Levetiracetam elimination

is correlated to creatinine clearance. Levetiracetam clearance is reduced in patients with impaired renal

function [see Dosage and Administration (2.2) and Use in Specific Populations (8.6)].

Specific Populations

Elderly

There are insufficient pharmacokinetic data to specifically address the use of extended-release

levetiracetam in the elderly population.

Pharmacokinetics of immediate-release levetiracetam were evaluated in 16 elderly subjects (age 61 to

88 years) with creatinine clearance ranging from 30 to 74 mL/min. Following oral administration of

twice-daily dosing for 10 days, total body clearance decreased by 38% and the half-life was 2.5 hours

longer in the elderly compared to healthy adults. This is most likely due to the decrease in renal

function in these subjects.

Pediatric Patients

An open label, multicenter, parallel-group, two-arm study was conducted to evaluate the

pharmacokinetics of levetiracetam extended-release tablets in pediatric patients (13 to 16 years old) and

in adults (18 to 55 years old) with epilepsy. Levetiracetam extended-release tablets (1,000 mg to 3,000

mg) were administered once daily with a minimum of 4 days and a maximum of 7 days of treatment to 12

pediatric patients and 13 adults in the study. Dose-normalized steady-state exposure parameters, C

and AUC, were comparable between pediatric and adult patients.

Pregnancy

Levetiracetam extended-release tablets levels may decrease during pregnancy [see Warnings and

Precautions (5.9) and Use in Specific Populations (8.1)].

Gender

Extended-release levetiracetam C

was 21 to 30% higher and AUC was 8 to 18% higher in women

(N=12) compared to men (N=12). However, clearances adjusted for body weight were comparable.

Race

Formal pharmacokinetic studies of the effects of race have not been conducted with extended-release

or immediate-release levetiracetam. Cross study comparisons involving Caucasians (N=12) and Asians

(N=12), however, show that pharmacokinetics of immediate-release levetiracetam were comparable

between the two races. Because levetiracetam is primarily renally excreted and there are no important

racial differences in creatinine clearance, pharmacokinetic differences due to race are not expected.

Renal Impairment

The effect of levetiracetam extended-release tablets on renally impaired patients was not assessed in the

controlled study. However, it is expected that the effect on levetiracetam extended-release tablets-

treated patients would be similar to that seen in controlled studies of immediate-release levetiracetam

tablets. In patients with end stage renal disease on dialysis, it is recommended that immediate-release

levetiracetam tablets be used instead of levetiracetam extended-release tablets.

The disposition of immediate-release levetiracetam was studied in adult subjects with varying degrees

of renal function. Total body clearance of levetiracetam is reduced in patients with impaired renal

function by 40% in the mild group (CL = 50 to 80 mL/min), 50% in the moderate group (CL = 30 to

50 mL/min) and 60% in the severe renal impairment group (CL <30 mL/min). Clearance of

levetiracetam is correlated with creatinine clearance.

In anuric (end stage renal disease) patients, the total body clearance decreased 70% compared to normal

subjects (CL >80 mL/min). Approximately 50% of the pool of levetiracetam in the body is removed

during a standard 4- hour hemodialysis procedure [see Dosage and Administration (2.2)].

Hepatic Impairment

In subjects with mild (Child-Pugh A) to moderate (Child-Pugh B) hepatic impairment, the

pharmacokinetics of levetiracetam were unchanged. In patients with severe hepatic impairment (Child-

Pugh C), total body clearance was 50% that of normal subjects, but decreased renal clearance accounted

for most of the decrease. No dose adjustment is needed for patients with hepatic impairment.

Drug Interactions

In vitro data on metabolic interactions indicate that levetiracetam is unlikely to produce, or be subject to,

pharmacokinetic interactions. Levetiracetam and its major metabolite, at concentrations well above C

levels achieved within the therapeutic dose range, are neither inhibitors of, nor high affinity substrates

for, human liver cytochrome P450 isoforms, epoxide hydrolase or UDP-glucuronidation enzymes. In

addition, levetiracetam does not affect the in vitro glucuronidation of valproic acid.

Potential pharmacokinetic interactions of or with levetiracetam were assessed in clinical

pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive, probenecid) and

through pharmacokinetic screening with immediate-release levetiracetam tablets in the placebo-

controlled clinical studies in epilepsy patients. The potential for drug interactions for levetiracetam

extended-release tablets is expected to be essentially the same as that with immediate-release

levetiracetam tablets.

Phenytoin

Immediate-release levetiracetam tablets (3,000 mg daily) had no effect on the pharmacokinetic

disposition of phenytoin in patients with refractory epilepsy. Pharmacokinetics of levetiracetam were

also not affected by phenytoin.

Valproate

Immediate-release levetiracetam tablets (1,500 mg twice daily) did not alter the pharmacokinetics of

valproate in healthy volunteers. Valproate 500 mg twice daily did not modify the rate or extent of

levetiracetam absorption or its plasma clearance or urinary excretion. There also was no effect on

exposure to and the excretion of the primary metabolite, ucb L057.

Other Antiepileptic Drugs

Potential drug interactions between immediate-release levetiracetam tablets and other AEDs

(carbamazepine, gabapentin, lamotrigine, phenobarbital, phenytoin, primidone and valproate) were also

assessed by evaluating the serum concentrations of levetiracetam and these AEDs during placebo-

controlled clinical studies. These data indicate that levetiracetam does not influence the plasma

concentration of other AEDs and that these AEDs do not influence the pharmacokinetics of

levetiracetam.

Oral Contraceptives

Immediate-release levetiracetam tablets (500 mg twice daily) did not influence the pharmacokinetics of

an oral contraceptive containing 0.03 mg ethinyl estradiol and 0.15 mg levonorgestrel, or of the

luteinizing hormone and progesterone levels, indicating that impairment of contraceptive efficacy is

unlikely. Coadministration of this oral contraceptive did not influence the pharmacokinetics of

levetiracetam.

Digoxin

Immediate-release levetiracetam tablets (1,000 mg twice daily) did not influence the pharmacokinetics

and pharmacodynamics (ECG) of digoxin given as a 0.25 mg dose every day. Coadministration of

digoxin did not influence the pharmacokinetics of levetiracetam.

Warfarin

Immediate-release levetiracetam tablets (1,000 mg twice daily) did not influence the pharmacokinetics

of R and S warfarin. Prothrombin time was not affected by levetiracetam. Coadministration of warfarin

did not affect the pharmacokinetics of levetiracetam.

Probenecid

Probenecid, a renal tubular secretion blocking agent, administered at a dose of 500 mg four times a day,

did not change the pharmacokinetics of levetiracetam 1,000 mg twice daily. C

of the metabolite,

ucb L057, was approximately doubled in the presence of probenecid while the fraction of drug

excreted unchanged in the urine remained the same. Renal clearance of ucb L057 in the presence of

probenecid decreased 60%, probably related to competitive inhibition of tubular secretion of ucb L057.

The effect of immediate-release levetiracetam tablets on probenecid was not studied.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis

Rats were dosed with levetiracetam in the diet for 104 weeks at doses of 50, 300, and 1,800 mg/kg/day.

Plasma exposure (AUC) at the highest dose was approximately 6 times that in humans at the maximum

recommended daily human dose (MRHD) of 3,000 mg. There was no evidence of carcinogenicity. In

mice, oral administration of levetiracetam for 80 weeks (doses up to 960 mg/kg/day) or 2 years (doses

up to 4,000 mg/kg/day, lowered to 3,000 mg/kg/day after 45 weeks due to intolerability) was not

associated with an increase in tumors. The highest dose tested in mice for 2 years (3,000 mg/kg/day) is

approximately 5 times the MRHD on a body surface area (mg/m ) basis.

Mutagenesis

Levetiracetam was negative in in vitro (Ames, chromosomal aberration in mammalian cells) and in vivo

(mouse micronucleus) assays. The major human metabolite of levetiracetam (ucb L057) was negative in

in vitro (Ames, mouse lymphoma) assays.

Impairment of Fertility

No adverse effects on male or female fertility or reproductive performance were observed in rats at

oral doses up to 1,800 mg/kg/day, which were associated with plasma exposures (AUC) up to

approximately 6 times that in humans at the MRHD.

14 CLINICAL STUDIES

The effectiveness of levetiracetam extended-release tablets for the treatment of partial-onset seizures

in adults was established in one multicenter, randomized, double-blind, placebo-controlled clinical

study in patients who had refractory partial-onset seizures with or without secondary generalization.

This was supported by the demonstration of efficacy of immediate-release levetiracetam tablets (see

below) in partial seizures in three multicenter, randomized, double-blind, placebo-controlled clinical

studies in adults, as well as a demonstration of comparable bioavailability between the extended-release

and immediate-release formulations [see Clinical Pharmacology (12.3)] in adults. The effectiveness for

levetiracetam extended-release tablets for the treatment of partial-onset seizures in pediatric patients, 12

years of age and older, was based upon a single pharmacokinetic study showing comparable

pharmacokinetics of levetiracetam extended-release tablets in adults and adolescents [see Clinical

Pharmacology (12.3)]. All studies are described below.

14.1 Levetiracetam Extended-Release Tablets in Adults

The effectiveness of levetiracetam extended-release tablets 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).

Study 1

Patients enrolled in Study 1 had at least eight partial seizures with or without secondary generalization

during the 8-week baseline period and at least two partial seizures in each 4-week interval of the

baseline period. Patients were taking a stable dose regimen of at least one AED and could take a

maximum of three AEDs. After a prospective baseline period of 8 weeks, 158 patients were randomized

to placebo (N=79) or 1,000 mg (two 500 mg tablets) of levetiracetam extended-release tablets (N=79),

given once daily over a 12-week treatment period.

The primary efficacy endpoint in Study 1 was the percent reduction over placebo in mean weekly

frequency of partial-onset seizures. The median percent reduction in weekly partial-onset seizure

frequency from baseline over the treatment period was 46.1% in the levetiracetam extended-release

tablets 1,000 mg treatment group (N=74) and 33.4% in the placebo group (N=78). The estimated percent

reduction over placebo in weekly partial-onset seizure frequency over the treatment period was 14.4%

(statistically significant).

The relationship between the effectiveness of the same daily dose of levetiracetam extended-release

tablets and immediate-release levetiracetam tablets has not been studied and is unknown.

14.2 Immediate-Release Levetiracetam in Adults

The effectiveness of immediate-release levetiracetam 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, levetiracetam 1,000 mg, levetiracetam 2,000 mg, or levetiracetam 3,000

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 levetiracetam 1,000 mg/day (N=97), immediate-release

levetiracetam 3,000 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

Levetiracetam

1,000 mg/day

(N=97)

Immediate-release

Levetiracetam 3,000

mg/day (N=101)

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.

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 levetiracetam 1,000 mg/day (N=106), immediate-release levetiracetam

2,000 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

Levetiracetam

1,000 mg/day

(N=106)

Immediate-release

Levetiracetam 2,000

mg/day (N=105)

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.

The comparison of immediate-release levetiracetam 2,000 mg/day to immediate-release levetiracetam

1,000 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 levetiracetam 3,000 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

Immediate-release

statistically significant versus placebo

(N=104)

Levetiracetam

3,000 mg/day

(N=180)

Percent reduction in partial

seizure frequency over

placebo

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.

14.3 Immediate-Release Levetiracetam in Pediatric Patients

The use of levetiracetam extended-release tablets in pediatric patients 12 years of age and older is

supported by Study 5, which was conducted using immediate-release levetiracetam. Levetiracetam

extended-release tablets are not indicated in children below 12 years of age.

Study 5

The effectiveness of immediate-release levetiracetam 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 to 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 levetiracetam or placebo. The enrolled population included 198 patients

(levetiracetam N=101; placebo N=97) with refractory partial-onset seizures, with or without

statistically significant versus placebo

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 levetiracetam 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

Levetiracetam

(N=101)

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.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Levetiracetam extended-release tablets, 500 mg are oval, blue and white to off-white colored,

biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted

with “573” with black ink on one side and plain on other side. They are supplied as follows:

statistically significant versus placebo

Bottles of 60’s with child-resistant cap…................... NDC 47335-573-86

Bottles of 100’s with child-resistant cap…................. NDC 47335-573-88

Bottles of 500.............................…................………. NDC 47335-573-13

Levetiracetam extended-release tablets, 750 mg are oval, blue and white to off-white colored,

biconvex, bilayer, film-coated, extended-release tablets having laser drill on blue layer and imprinted

with “576” with black ink on one side and plain on other side. They are supplied as follows:

Bottles of 60’s with child-resistant cap…................... NDC 47335-576-86

Bottles of 100’s with child-resistant cap…................. NDC 47335-576-88

Bottles of 500...…...................…...................………. NDC 47335-576-13

16.2 Storage

Store at 20° to 25°C (68° to 77°F); excursions permitted between 15° and 30°C (59° and 86°F) [see

USP Controlled Room Temperature]. Dispense in tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Psychiatric Reactions and Changes in Behavior

Advise patients that levetiracetam extended-release tablets 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 levetiracetam, 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

levetiracetam extended-release tablets, 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 levetiracetam extended-release tablets may cause dizziness and somnolence. Inform

patients not to drive or operate machinery until they have gained sufficient experience on levetiracetam

extended-release tablets 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 levetiracetam extended-release tablets 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 levetiracetam extended-release tablets 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 inert fragments of coating

and/ or swollen pieces of the original tablet in their stool.

Withdrawal of Levetiracetam

Advise patients and caregivers not to discontinue use of levetiracetam extended-release tablets without

consulting with their healthcare provider. Levetiracetam extended-release tablets 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 levetiracetam extended-release tablets 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)].

MEDICATION GUIDE

Levetiracetam Extended-release Tablets

(LEE-ve-tye-RA-se-tam)

Read this Medication Guide before you start taking levetiracetam extended-release tablets and each time

you get a refill. There may be new information. This information does not take the place of talking to

your healthcare provider about your medical condition or treatment.

What is the most important information I should know about levetiracetam extended-release

tablets?

Like

other

antiepileptic

drugs,

levetiracetam

extended-release

tablets

may

cause

s uicidal

thoughts or actions in a very small number of people, about 1 in 500 people taking it.

Call a healthcare provider right away if you have any of these symptoms, especially if they are

new, worse, or worry you:

thoughts about suicide or dying

attempts to commit suicide

new or worse depression

new or worse anxiety

feeling agitated or restless

panic attacks

trouble sleeping (insomnia)

new or worse irritability

acting aggressive, being angry, or violent

acting on dangerous impulses

an extreme increase in activity and talking (mania)

other unusual changes in behavior or mood

Do not stop levetiracetam extended-release tablets without first talking to a healthcare provider.

Stopping levetiracetam extended-release tablets suddenly can cause serious problems. Stopping a

seizure medicine suddenly can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal

thoughts or actions, your healthcare provider may check for other causes.

How can I watch for early symptoms of suicidal thoughts and actions?

Pay attention to any changes, especially sudden changes, in mood, behaviors, thoughts, or feelings.

Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about

s ymptoms .

What are levetiracetam extended-release tablets?

Levetiracetam extended-release tablets are a prescription medicine taken by mouth that are used to treat

partial-onset seizures in people 12 years of age and older.

It is not known if levetiracetam extended-release tablets are safe or effective in people under 12 years

of age.

Before taking your medicine, make sure you have received the correct medicine. Compare the name

above with the name on your bottle and the appearance of your medicine with the description of

levetiracetam extended-release tablets provided below. Tell your pharmacist immediately if you think

you have been given the wrong medicine.

Who should not take levetiracetam extended-release tablets?

Do not take levetiracetam extended-release tablets if you are allergic to levetiracetam.

What should I tell my healthcare provider before starting levetiracetam extended-release tablets?

Before taking levetiracetam extended-release tablets, tell your healthcare provider about all of your

medical conditions, including if you:

have or have had depression, mood problems or suicidal thoughts or behavior.

have kidney problems.

are pregnant or planning to become pregnant. It is not known if levetiracetam extended-release

tablets will harm your unborn baby. You and your healthcare provider will have to decide if you

should take levetiracetam extended-release tablets while you are pregnant. If you become pregnant

while

taking

levetiracetam

extended-release

tablets,

talk

your

healthcare

provider

about

registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this

registry by calling 1-888-233-2334 or go to http://www.aedpregnancyregistry.org. The purpose of

this registry is to collect information about the safety of levetiracetam extended-release tablets and

other antiepileptic medicine during pregnancy.

are breastfeeding or plan to breastfeed. Levetiracetam can pass into your breast milk. It is not known

if the levetiracetam that passes into your breast milk can harm your baby. Talk to your doctor about

the best way to feed your baby while you receive levetiracetam.

Tell your healthcare provider about all the medicines you take, including prescription and over-the-

counter medicines, vitamins, and herbal supplements. Do not start a new medicine without first talking

with your healthcare provider.

Know the medicines you take. Keep a list of them to show your healthcare provider and pharmacist each

time you get a new medicine.

How should I take levetiracetam extended-release tablets?

Take levetiracetam extended-release tablets exactly as your healthcare provider tells you to take it.

Your healthcare provider will tell you how many levetiracetam extended-release tablets to take and

when to take it. Levetiracetam extended-release tablets are usually taken 1 time each day.

Your healthcare provider may change your dose. Do not change your dose without talking to your

healthcare provider.

Take levetiracetam extended-release tablets with or without food.

Swallow the tablets whole. Do not chew, break, or crush tablets.

The inactive part of levetiracetam extended-release tablet may not dissolve after all the medicine has

been released in your body. You may sometimes notice something in your bowel movement that

looks like inert fragments of coating and/ or swollen pieces of the original tablet. This is normal.

If you take too many levetiracetam extended-release tablets, call your local Poison Control Center

or go to the nearest emergency room right away.

What should I avoid while taking levetiracetam extended-release tablets?

Do not drive, operate machinery or do other dangerous activities until you know how levetiracetam

extended-release tablets affect you. Levetiracetam extended-release tablets may make you dizzy or

sleepy.

What are the possible side effects of levetiracetam extended-release tablets?

Levetiracetam extended-release tablets can cause serious side effects.

See “What is the most important information I should know about levetiracetam extended-

release tablets?”

Call your healthcare provider right away if you have any of these symptoms:

mood and behavior changes such as aggression, agitation, anger, anxiety, apathy, mood swings,

depression,

hostility,

irritability.

people

psychotic

symptoms

such

hallucinations (seeing or hearing things that are really not there), delusions (false or strange

thoughts or beliefs) and unusual behavior.

extreme sleepiness, tiredness, and weakness.

allergic reactions such as swelling of the face, lips, eyes, tongue, and throat, trouble swallowing or

breathing, and hives.

a skin rash. Serious skin rashes can happen after you start taking levetiracetam extended-release

tablets. There is no way to tell if a mild rash will become a serious reaction.

problems with muscle coordination (problems walking and moving)

The most common side effects seen in people who take levetiracetam extended-release tablets

include:

sleepiness

irritability

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

These are not all the possible side effects of levetiracetam extended-release tablets. For more

information, ask your healthcare provider or pharmacist.

Call your doctor for medical advice about side effects. You may also report side effects to FDA at

1-800-FDA-1088.

How should I store levetiracetam extended-release tablets?

Store levetiracetam extended-release tablets at room temperature, between 15°C to 30°C (59°F to

86°F) away from heat and light.

Keep levetiracetam extended-release tablets and all medicines out of the reach of children.

General information about the safe and effective use of levetiracetam extended-release tablets.

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not

use levetiracetam extended-release tablets for a condition for which it was not prescribed. Do not give

levetiracetam extended-release tablets to other people, even if they have the same symptoms that you

have. It may harm them. You can ask your pharmacist or healthcare provider for information about

levetiracetam extended-release tablets that is written for health professionals.

What are the ingredients of levetiracetam extended-release tablets?

Levetiracetam extended-release tablets active ingredient: levetiracetam

Inactive ingredients: povidone, hypromellose, amino methacrylate copolymer, colloidal silicon dioxide,

magnesium stearate, talc, silicified microcrystalline cellulose, crospovidone, sodium lauryl sulfate,

FD&C Blue #1 aluminum lake, ethyl cellulose aqueous dispersion, dibutyl sebacate, triethyl citrate,

polysorbate

polyvinyl

alcohol,

polyethylene

glycol,

polysorbate

imprinting

contains shellac glaze, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide.

Levetiracetam extended-release tablets do not contain lactose or gluten.

Distributed by:

Sun Pharmaceutical Industries, Inc.

Cranbury, NJ 08512

Manufactured by:

Sun Pharmaceutical Industries Ltd.

Halol-Baroda Highway,

Halol-389 350, Gujarat, India.

PJPI0321H

This Medication Guide has been approved by the U.S. Food and Drug Administration.

ISS. 01/2020

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 500MG

NDC 47335-573-86

Once Daily Dosing

Levetiracetam Extended-release Tablets

500 mg

PHARMACIST: Please dispense with medication guide provided separately to each patient.

Rx only

60 TABLETS

SUN PHARMA

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL - LABEL - 750MG

NDC 47335-576-86

Once Daily Dosing

Levetiracetam Extended-Release Tablets

750 mg

PHARMACIST: Please dispense with medication guide provided separately to each patient.

Rx only

60 TABLETS

SUN PHARMA

LEVETIRACETAM

levetiracetam tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:47335-573

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LEVETIRACETAM (UNII: 44YRR34555) (LEVETIRACETAM - UNII:44YRR34555)

LEVETIRACETAM

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO VIDO NE K9 0 (UNII: RDH8 6 HJV5Z)

HYPRO MELLO SE 2 2 0 8 ( 150 0 0 MPA.S) (UNII: Z78 RG6 M2N2)

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

TALC (UNII: 7SEV7J4R1U)

CRO SPO VIDO NE ( 12 0 .MU.M) (UNII: 6 8 40 19 6 0 MK)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

ETHYLCELLULO SE, UNSPECIFIED (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

PO LYSO RBATE 2 0 (UNII: 7T1F30 V5YH)

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

Product Characteristics

Color

BLUE, WHITE (white to o ff-white)

S core

no sco re

S hap e

OVAL

S iz e

16 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:47335-573-8 6

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

2

NDC:47335-573-8 8

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

3

NDC:47335-573-13

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 30 59

0 9 /0 9 /20 13

LEVETIRACETAM

levetiracetam tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:47335-576

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

LEVETIRACETAM (UNII: 44YRR34555) (LEVETIRACETAM - UNII:44YRR34555)

LEVETIRACETAM

750 mg

Inactive Ingredients

Ingredient Name

Stre ng th

PO VIDO NE K9 0 (UNII: RDH8 6 HJV5Z)

HYPRO MELLO SE 2 2 0 8 ( 150 0 0 MPA.S) (UNII: Z78 RG6 M2N2)

DIMETHYLAMINO ETHYL METHACRYLATE - BUTYL METHACRYLATE - METHYL METHACRYLATE

CO PO LYMER (UNII: 9 0 5HNO1SIH)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

MAGNESIUM STEARATE (UNII: 70 0 9 7M6 I30 )

TALC (UNII: 7SEV7J4R1U)

CRO SPO VIDO NE ( 12 0 .MU.M) (UNII: 6 8 40 19 6 0 MK)

SO DIUM LAURYL SULFATE (UNII: 36 8 GB5141J)

FD&C BLUE NO . 1 (UNII: H3R47K3TBD)

ETHYLCELLULO SE, UNSPECIFIED (UNII: 7Z8 S9 VYZ4B)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

TRIETHYL CITRATE (UNII: 8 Z9 6 QXD6 UM)

PO LYSO RBATE 2 0 (UNII: 7T1F30 V5YH)

PO LYVINYL ALCO HO L, UNSPECIFIED (UNII: 532B59 J9 9 0 )

PO LYETHYLENE GLYCO L 3 3 50 (UNII: G2M7P15E5P)

PO LYSO RBATE 8 0 (UNII: 6 OZP39 ZG8 H)

Product Characteristics

Color

BLUE, WHITE (white to o ff-white)

S core

no sco re

S hap e

OVAL

S iz e

19 mm

Flavor

Imprint Code

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:47335-576 -8 6

6 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

2

NDC:47335-576 -8 8

10 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

3

NDC:47335-576 -13

50 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 9 /0 9 /20 13

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 30 59

0 9 /0 9 /20 13

Sun Pharmaceutical Industries, Inc.

Labeler -

Sun Pharmaceutical Industries, Inc. (146974886)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Sun Pharmaceutical Industries

Limite d

7259 59 238

ANALYSIS(47335-573, 47335-576 ) , MANUFACTURE(47335-573, 47335-

576 )

Revised: 12/2019

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