LEVETIRACETAM - 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:
Physicians Total Care, Inc.
INN (International Name):
LEVETIRACETAM
Composition:
LEVETIRACETAM 500 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Levetiracetam extended-release tablets are indicated as adjunctive therapy in the treatment of partial onset seizures in patients ≥ 16 years of age with epilepsy. None Teratogenic Effects Pregnancy category C There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or greater than human therapeutic doses. Levetiracetam extended-release tablets should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at doses ≥ 350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000 mg [MRHD] on a mg/m2 basis) and with increased pup mortality and offspring behavioral alterations at a dose of 1800 mg/kg/day (
Product summary:
Levetiracetam extended-release tablets are available as follows: 500 mg – white, oval-shaped, film-coated tablets imprinted with “TV/7795” with black ink on one side and plain on the other, in bottles of 90.....NDC 54868-6316-0. Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as required).
Authorization status:
Abbreviated New Drug Application
Authorization number:
54868-6316-0

LEVETIRACETAM - levetiracetam tablet, film coated, extended release

Physicians Total Care, Inc.

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MEDICATION GUIDE

Levetiracetam Extended-Release Tablets

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 in a very small number of people, about 1 in 500 people taking them.

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 are levetiracetam extended-release tablets?

Levetiracetam extended-release tablets are a prescription medicine taken by mouth that is used with other

medicines to treat partial onset seizures in people 16 years of age and older with epilepsy.

It is not known if levetiracetam extended-release tablets are safe or effective in people under 16 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.

500 mg levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release

tablets imprinted with “TV/7795” with black ink on one side and plain on the other.

750 mg levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release

tablets imprinted with “TV/7796” with black ink on one side and plain on the other.

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. The purpose of this registry is to collect information

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

pregnancy.

are breast feeding. Levetiracetam can pass into your milk and may harm your baby. You and your

healthcare provider should discuss whether you should take levetiracetam extended-release tablets

or breast feed; you should not do both.

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

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 prescribed.

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

and when to take them. Levetiracetam extended-release tablets are usually taken once a day. Take

levetiracetam extended-release tablets at the same 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.

If you miss a dose of levetiracetam extended-release tablets, take it as soon as you remember. If it

is almost time for your next dose, just skip the missed dose. Take the next dose at your regular

time. Do not take two doses at the same time.

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?

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

tablets?”

Levetiracetam extended-release tablets can cause serious side effects.

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

problems with muscle coordination (problems walking and moving)

Common side effects seen in people who take levetiracetam extended-release tablets and other

formulations of levetiracetam include:

sleepiness

weakness

dizziness

infection

These side effects can happen at any time but happen more often within the first 4 weeks of treatment.

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, 20° to 25°C (68° to 77°F) away

from heat and light.

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

General information about 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 they were not prescribed. Do not give

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

have. They may harm them.

This Medication Guide summarizes the most important information about levetiracetam extended-release

tablets. If you would like more information, talk with your healthcare provider. You can ask your

pharmacist or healthcare provider for information about levetiracetam extended-release tablets that is

written for health professionals. You can also get information about levetiracetam extended-release

tablets by calling 1-888-838-2872, MEDICAL AFFAIRS.

What are the ingredients of levetiracetam extended-release tablets?

Levetiracetam extended-release tablet active ingredient: levetiracetam

Inactive ingredients: dibutyl sebacate, ethylcellulose, hydrogenated castor oil powder, hypromellose,

magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide. The

imprinting ink contains iron oxide black and shellac glaze.

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

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

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. A 1/2011

Revised: 12/2011

Document Id: 011fff61-3327-45a3-ba99-86c12b9c28f3

Set id: 6ecf5268-7ed3-458e-b281-aec3c51656d7

Version: 1

Effective Time: 20111213

Physicians Total Care, Inc.

LEVETIRACETAM - levetiracetam tablet, film coated, extended release

Physicians Total Care, Inc.

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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

Warnings and Precautions (5.1) [04/2009]

Patient Counseling Information (17) [04/2009]

INDICATIONS AND USAGE

Levetiracetam extended-release tablets are an antiepileptic drug indicated for adjunctive therapy in the treatment of partial

onset seizures in patients ≥ 16 years of age with epilepsy (1)

DOSAGE AND ADMINISTRATION

Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in increments of 1000

mg every 2 weeks to a maximum recommended daily dose of 3000 mg (2).

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

DOSAGE FORMS AND STRENGTHS

500 mg white, film-coated extended-release tablet (3)

750 mg white, film-coated extended-release tablet (3)

CONTRAINDICATIONS

None (4)

WARNINGS AND PRECAUTIONS

Suicidal Behavior and Ideation (5.1)

Neuropsychiatric Adverse Reactions: Levetiracetam extended-release tablets cause somnolence, dizziness, and

behavioral abnormalities. The adverse reactions that may be seen in patients receiving levetiracetam extended-release

tablets are expected to be similar to those seen in patients receiving immediate-release levetiracetam tablets. (5.2)

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset seizures,

immediate-release levetiracetam causes somnolence and fatigue, coordination difficulties, and behavioral abnormalities

(e.g., psychotic symptoms, suicidal ideation, and other abnormalities). (5.2)

Withdrawal Seizures: Levetiracetam extended-release tablets must be gradually withdrawn. (5.3)

ADVERSE REACTIONS

Most common adverse reactions (difference in incidence rate is ≥ 5% between levetiracetam extended-release tablet-

treated patients and placebo-treated patients and occurred more frequently in levetiracetam extended-release tablet-

treated patients) include: somnolence and irritability (6.1).

To report SUSPECTED ADVERSE REACTIONS, contact TEVA USA, PHARMACOVIGILANCE at 1-888-838-

2872, X6351 or drug.safety@tevausa.com; or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

USE IN SPECIFIC POPULATIONS

To enroll in the North American Antiepileptic Drug Pregnancy Registry call (888) 233-2334 (toll free). (8.1)

A dose adjustment is recommended for patients with impaired renal function, based on the patient’s estimated

creatinine clearance (8.6).

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 12/2011

FULL PRESCRIBING INFORMATION: CONTENTS*

1 INDICATIONS AND USAGE

2 DOSAGE AND ADMINISTRATION

2.1 Adult Patients With Impaired Renal Function

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Suicidal Behavior and Ideation

5.2 Neuropsychiatric Adverse Reactions

5.3 Withdrawal Seizures

5.4 Hematologic Abnormalities

5.5 Hepatic Abnormalities

5.6 Laboratory Tests

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

6.2 Postmarketing Experience

7 DRUG INTERACTIONS

7.1 General Information

7.2 Phenytoin

7.3 Valproate

7.4 Other Antiepileptic Drugs

7.5 Oral Contraceptives

7.6 Digoxin

7.7 Warfarin

7.8 Probenecid

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Labor and Delivery

8.3 Nursing Mothers

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Use in Patients With Impaired Renal Function

9 DRUG ABUSE AND DEPENDENCE

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

13.2 Animal Toxicology and/or Pharmacology

14 CLINICAL STUDIES

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

16.2 Storage

17 PATIENT COUNSELING INFORMATION

Levetiracetam Extended-Release Tablets 500 mg Label Text

FULL PRESCRIBING INFORMATION

1 INDICATIONS AND USAGE

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

Levetiracetam extended-release tablets are indicated as adjunctive therapy in the treatment of partial

onset seizures in patients ≥ 16 years of age with epilepsy.

2 DOSAGE AND ADMINISTRATION

Treatment should be initiated with a dose of 1000 mg once daily. The daily dosage may be adjusted in

increments of 1000 mg every 2 weeks to a maximum recommended daily dose of 3000 mg.

2.1 Adult Patients With Impaired Renal Function

Levetiracetam extended-release tablet dosing must be individualized according to the patient's renal

function status. Recommended doses and adjustment for dose for adults are shown in Table 1. To use

this dosing table, an estimate of the patient's creatinine clearance (CL ) in mL/min is needed. CL in

mL/min may be estimated from serum creatinine (mg/dL) determination using the following formula:

Table 1: Dosing Adjustment Regimen For Adult Patients

With Impaired Renal Function

Group

Creatinine Clearance

(mL/min/1.73 m )

Dosage

(mg)

Frequency

Normal

> 80

1000 to

3000

Every 24

Mild

50 to 80

1000 to

2000

Every 24

Moderate

30 to 50

500 to

1500

Every 24

Severe

< 30

500 to

1000

Every 24

3 DOSAGE FORMS AND STRENGTHS

Levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release tablets

imprinted with “TV/7795” with black ink on one side and plain on the other and contain 500 mg

levetiracetam.

Levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release tablets

imprinted with “TV/7796” with black ink on one side and plain on the other and contain 750 mg

levetiracetam.

4 CONTRAINDICATIONS

None

5 WARNINGS AND PRECAUTIONS

5.1 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 1000

Patients

Drug

Patients

with

Events

Per 1000

Patients

Relative Risk:

Incidence of

Events in Drug

Patients/Incidence

in Placebo

Patients

Risk

Difference:

Additional

Drug

Patients with

Events Per

1000

Patients

Epilepsy

Psychiatric 5.7

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.

Patients, their caregivers, and families should be informed that AEDs increase the risk of suicidal

thoughts and behavior and should be advised of the need to be alert for the emergence or worsening of

the signs and symptoms of depression, any unusual changes in mood or behavior, or the emergence of

suicidal thoughts, behavior, or thoughts about self-harm. Behaviors of concern should be reported

immediately to healthcare providers.

5.2 Neuropsychiatric Adverse Reactions

LevetiracetamExtended-ReleaseTablets

In some patients experiencing partial onset seizures, levetiracetam extended-release tablets cause

somnolence, dizziness, and behavioral abnormalities.

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

onset seizures, 7.8% of levetiracetam extended-release tablet-treated patients experienced somnolence

compared to 2.5% of placebo-treated patients. Dizziness was reported in 5.2% of levetiracetam

extended-release tablet-treated patients compared to 2.5% of placebo-treated patients.

A total of 6.5% of levetiracetam extended-release tablet-treated patients experienced non-psychotic

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

patients. Irritability was reported in 6.5% of levetiracetam extended-release tablet-treated patients.

Aggression was reported in 1.3% of levetiracetam extended-release tablet-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 tablet controlled

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

Immediate-ReleaseLevetiracetamTablets

In controlled trials of immediate-release levetiracetam tablets in patients experiencing partial onset

seizures, immediate-release levetiracetam tablets cause the occurrence of central nervous system

adverse reactions that can be classified into the following categories: 1) somnolence and fatigue, 2)

coordination difficulties, and 3) behavioral abnormalities.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.8% of

immediate-release levetiracetam tablet-treated patients reported somnolence, compared to 8.4% of

placebo patients. There was no clear dose response up to 3000 mg/day.

In controlled trials of adult patients with epilepsy experiencing partial onset seizures, 14.7% of treated

patients reported asthenia, compared to 9.1% of placebo patients.

A total of 3.4% of immediate-release levetiracetam tablet-treated patients experienced coordination

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

patients.

Somnolence, asthenia and coordination difficulties occurred most frequently within the first 4 weeks of

treatment.

In controlled trials of patients with epilepsy experiencing partial onset seizures, 5 (0.7%) immediate-

release levetiracetam tablet-treated patients experienced psychotic symptoms compared to 1 (0.2%)

placebo patient.

A total of 13.3% of immediate-release levetiracetam tablet patients experienced other behavioral

symptoms (reported as aggression, agitation, anger, anxiety, apathy, depersonalization, depression,

emotional lability, hostility, irritability, etc.) compared to 6.2% of placebo patients.

5.3 Withdrawal Seizures

Antiepileptic drugs, including levetiracetam extended-release tablets, should be withdrawn gradually to

minimize the potential of increased seizure frequency.

5.4 Hematologic Abnormalities

Although there were no obvious hematologic abnormalities observed in treated patients in the

levetiracetam extended-release tablet controlled study, the limited number of patients makes any

conclusion tentative. The data from the partial seizure patients in the immediate-release levetiracetam

tablet controlled studies should be considered to be relevant for levetiracetam extended-release tablet-

treated patients.

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 tablet-treated patients. A total of 3.2% of treated and 1.8% of placebo patients had

at least one possibly significant (≤ 2.8 x 10 /L) decreased WBC, and 2.4% of treated and 1.4% of

placebo patients had at least one possibly significant (≤ 1.0 x 10 /L) decreased neutrophil count. Of the

treated patients with a low neutrophil count, all but one rose towards or to baseline with continued

treatment. No patient was discontinued secondary to low neutrophil counts.

5.5 Hepatic Abnormalities

There were no meaningful changes in mean liver function tests (LFT) in the levetiracetam extended-

release tablet controlled trial. No patients were discontinued from the controlled trial for LFT

abnormalities.

There were no meaningful changes in mean liver function tests (LFT) in controlled trials of immediate-

release levetiracetam tablets in adult patients; lesser LFT abnormalities were similar in drug and

placebo-treated patients in controlled trials (1.4%). No patients were discontinued from controlled trials

for LFT abnormalities except for 1 (0.07%) adult epilepsy patient receiving open treatment.

5.6 Laboratory Tests

Although effects on laboratory tests were not clinically significant with levetiracetam extended-release

tablet treatment, it is expected that the data from immediate-release levetiracetam tablets controlled

studies would be considered relevant for levetiracetam extended-release tablet-treated patients.

Although most laboratory tests are not systematically altered with immediate-release levetiracetam

tablet treatment, there have been relatively infrequent abnormalities seen in hematologic parameters and

liver function tests.

6 ADVERSE REACTIONS

6.1 Clinical Studies Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed

in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug

and may not reflect the rates observed in practice.

The prescriber should be aware that the adverse reaction incidence figures in the following table,

obtained when levetiracetam extended-release tablets were added to concurrent AED therapy, cannot be

used to predict the frequency of adverse experiences in the course of usual medical practice where

patient characteristics and other factors may differ from those prevailing during clinical studies.

Similarly, the cited frequencies cannot be directly compared with figures obtained from other clinical

investigations involving different treatments, uses, or investigators. An inspection of these frequencies,

however, does provide the prescriber with one basis to estimate the relative contribution of drug and

non-drug factors to the adverse reaction incidences in the population studied.

Levetiracetam Extended-Release Tablets

In the well-controlled clinical study using levetiracetam extended-release tablets in patients with partial

onset seizures, the most frequently reported adverse reactions in patients receiving levetiracetam

extended-release tablets in combination with other AEDs, not seen at an equivalent frequency among

placebo-treated patients, were irritability and somnolence.

Table 3 lists treatment-emergent adverse reactions that occurred in at least 5% of epilepsy patients

treated with levetiracetam extended-release tablets participating 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. Adverse reactions were

usually mild to moderate in intensity.

Table 3: Incidence (%) of Treatment-Emergent Adverse

Reactions in the Placebo-Controlled, Add-on Study by

Body System (Adverse Reactions Occurred in at Least

5% of Levetiracetam Extended-Release Tablet-Treated

Patients and Occurred More Frequently Than Placebo-

Treated Patients)

Body

Sys tem/Advers e

Reaction

Levetiracetam

Extended-Releas e

Tablets (N = 77) %

Placebo (N = 79)

%

Gas trointes tinal

Dis orders

Nausea

Infections and

Infes tations

Influenza

Nasopharyngitis

Nervous System

Dis orders

Somnolence

Dizziness

Ps ychiatric

Dis orders

Irritability

Discontinuation Or Dose Reduction In The Levetiracetam Extended-Release Tablets Well-Controlled

Clinical Study

In the well-controlled clinical study using levetiracetam extended-release tablets, 5.2% of patients

receiving levetiracetam extended-release tablets and 2.5% receiving placebo discontinued as a result of

an adverse event. The adverse reactions that resulted in discontinuation and that occurred more

frequently in levetiracetam extended-release tablet-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 tablet-treated patient and no placebo-treated patients.

Comparison Of Gender, Age And Race

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

the distribution of adverse experience reports by gender, age and race.

Table 4 lists the adverse reactions seen in the well-controlled studies of immediate-release

levetiracetam tablets in adult patients experiencing partial onset seizures. Although the pattern of

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

seen in partial onset seizure well-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.

Immediate-Release Levetiracetam Tablets

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

other AEDs in adults with partial onset seizures, the most frequently reported adverse reactions, not

seen at an equivalent frequency among placebo-treated patients, were somnolence, asthenia, infection

and dizziness.

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

treated with immediate-release levetiracetam tablets participating 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. Adverse reactions were

usually mild to moderate in intensity.

Table 4: Incidence (%) of Treatment-Emergent Adverse

Reactions in Placebo-Controlled, Add-on Studies in Adults

Experiencing Partial Onset Seizures by Body System

(Adverse Reactions Occurred in at Least 1% of Immediate-

Release Levetiracetam Tablet-Treated Patients and

Occurred More Frequently Than Placebo-Treated Patients)

Body System/Adverse

Reaction

Immediate-Releas e

LevetiracetamTablets

(N = 769) %

Placebo

(N = 439)

%

Body as a Whole

Asthenia

Headache

Infection

Pain

Digestive System

Anorexia

Nervous System

Somnolence

Dizziness

Depression

Nervousness

Ataxia

Vertigo

Amnesia

Anxiety

Hostility

Paresthesia

Emotional Lability

Respiratory System

Pharyngitis

Rhinitis

Cough Increased

Sinusitis

Special Senses

Diplopia

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

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

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

6.2 Postmarketing Experience

In addition to the adverse reactions listed above for immediate-release levetiracetam tablets [see Adverse

Reactions (6.1)], the following adverse events have been identified during postapproval use of

immediate-release levetiracetam tablets. Because these events 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, hepatic

failure, hepatitis, leukopenia, neutropenia, pancreatitis, pancytopenia (with bone marrow suppression

identified in some of these cases), thrombocytopenia and weight loss. Alopecia has been reported with

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

immediate-release levetiracetam tablets were discontinued.

7 DRUG INTERACTIONS

7.1 General Information

In vitro data on metabolic interactions indicate that levetiracetam extended-release tablets are 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.

Levetiracetam circulates largely unbound (< 10% bound) to plasma proteins; clinically significant

interactions with other drugs through competition for protein binding sites are therefore unlikely.

Potential pharmacokinetic interactions were assessed in clinical pharmacokinetic studies (phenytoin,

valproate, oral contraceptive, digoxin, warfarin, probenecid) and through pharmacokinetic screening

with immediate-release levetiracetam tablets in the placebo-controlled clinical studies in epilepsy

patients. The following are the results of these studies. The potential for drug interactions for

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

release levetiracetam tablets.

7.2 Phenytoin

Immediate-release levetiracetam tablets (3000 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.

7.3 Valproate

Immediate-release levetiracetam tablets (1500 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.

7.4 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.

7.5 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.

7.6 Digoxin

Immediate-release levetiracetam tablets (1000 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.

7.7 Warfarin

Immediate-release levetiracetam tablets (1000 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.

7.8 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 1000 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.

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Teratogenic Effects

Pregnancy category C

There are no adequate and well-controlled studies in pregnant women. In animal studies, levetiracetam

produced evidence of developmental toxicity, including teratogenic effects, at doses similar to or

greater than human therapeutic doses. Levetiracetam extended-release tablets should be used during

pregnancy only if the potential benefit justifies the potential risk to the fetus.

Oral administration of levetiracetam to female rats throughout pregnancy and lactation led to increased

incidences of minor fetal skeletal abnormalities and retarded offspring growth pre- and/or postnatally at

doses ≥ 350 mg/kg/day (approximately equivalent to the maximum recommended human dose of 3000

mg [MRHD] on a mg/m basis) and with increased pup mortality and offspring behavioral alterations at a

dose of 1800 mg/kg/day (6 times the MRHD on a mg/m basis). The developmental no effect dose was

70 mg/kg/day (0.2 times the MRHD on a mg/m basis). There was no overt maternal toxicity at the doses

used in this study.

Oral administration of levetiracetam to pregnant rabbits during the period of organogenesis resulted in

increased embryofetal mortality and increased incidences of minor fetal skeletal abnormalities at doses

≥ 600 mg/kg/day (approximately 4 times MRHD on a mg/m basis) and in decreased fetal weights and

increased incidences of fetal malformations at a dose of 1800 mg/kg/day (12 times the MRHD on a

mg/m basis). The developmental no effect dose was 200 mg/kg/day (1.3 times the MRHD on a mg/m

basis). Maternal toxicity was also observed at 1800 mg/kg/day.

When levetiracetam was administered orally to pregnant rats during the period of organogenesis, fetal

weights were decreased and the incidence of fetal skeletal variations was increased at a dose of 3600

mg/kg/day (12 times the MRHD). 1200 mg/kg/day (4 times the MRHD) was a developmental no effect

dose. There was no evidence of maternal toxicity in this study.

Treatment of rats with levetiracetam during the last third of gestation and throughout lactation produced

no adverse developmental or maternal effects at oral doses of up to 1800 mg/kg/day (6 times the MRHD

on a mg/m basis).

Pregnancy Registry

To provide information regarding the effects of in utero exposure to levetiracetam extended-release

tablets, physicians are advised to recommend that pregnant patients taking levetiracetam extended-

release tablets enroll in the North American Antiepileptic Drug (NAAED) pregnancy registry. This can

be done by calling the toll free number 1-888-233-2334, and must be done by the patients themselves.

Information on the registry can also be found at the website http://www.aedpregnancyregistry.org/.

8.2 Labor and Delivery

The effect of levetiracetam extended-release tablets on labor and delivery in humans is unknown.

8.3 Nursing Mothers

Levetiracetam is excreted in breast milk. Because of the potential for serious adverse reactions in

nursing infants from levetiracetam extended-release tablets, a decision should be made whether to

discontinue nursing or discontinue the drug, taking into account the importance of the drug to the

mother.

8.4 Pediatric Use

Safety and effectiveness of levetiracetam extended-release tablets in patients below the age of 16 years

have not been established.

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.

Of the total number of subjects in clinical studies of immediate-release levetiracetam tablets, 347 were

65 and over. No overall differences in safety were observed between these subjects and younger

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

adequately assess the effectiveness of immediate-release levetiracetam tablets in these patients.

A study in 16 elderly subjects (age 61 to 88 years) with oral administration of single dose and multiple

twice-daily doses of immediate-release levetiracetam tablets for 10 days showed no pharmacokinetic

differences related to age alone.

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.

8.6 Use in Patients With Impaired Renal Function

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

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

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

levetiracetam tablets. Caution should be taken in dosing patients with moderate and severe renal

impairment and in patients undergoing hemodialysis. The dosage should be reduced in patients with

impaired renal function receiving levetiracetam extended-release tablets [see Clinical Pharmacology

(12.3) and Dosage and Administration (2.1)].

Clearance of immediate-release levetiracetam tablets is decreased in patients with renal impairment and

is correlated with creatinine clearance.

9 DRUG ABUSE AND DEPENDENCE

The abuse and dependence potential of levetiracetam extended-release tablets has not been evaluated in

human studies.

10 OVERDOSAGE

Signs, Symptoms And Laboratory Findings Of Acute Overdosage In Humans

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

to those seen with immediate-release levetiracetam tablets.

The highest known dose of oral immediate-release levetiracetam received in the clinical development

program was 6000 mg/day. Other than drowsiness, there were no adverse reactions in the few known

cases of overdose in clinical trials. Cases of somnolence, agitation, aggression, depressed level of

consciousness, respiratory depression and coma were observed with immediate-release levetiracetam

tablet overdoses in postmarketing use.

Treatment Or 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.

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 extended-release tablets are an antiepileptic drug available as 500 mg and 750 mg (white)

extended-release tablets for oral administration.

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

acetamide. Levetiracetam is chemically unrelated to existing antiepileptic drugs (AEDs). It has the

following structural formula:

C H N O M.W. 170.21

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

soluble in water (104.0 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:

dibutyl sebacate, ethylcellulose, hydrogenated castor oil powder, hypromellose, magnesium stearate,

microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide. The imprinting ink

contains iron oxide black and shellac glaze.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

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

antiepileptic activity of levetiracetam was assessed in a number of animal models of epileptic seizures.

Levetiracetam did not inhibit single seizures induced by maximal stimulation with electrical current or

different chemoconvulsants and showed only minimal activity in submaximal stimulation and in threshold

tests. Protection was observed, however, against secondarily generalized activity from focal seizures

induced by pilocarpine and kainic acid, two chemoconvulsants that induce seizures that mimic some

features of human complex partial seizures with secondary generalization. Levetiracetam also displayed

inhibitory properties in the kindling model in rats, another model of human complex partial seizures,

both during kindling development and in the fully kindled state. The predictive value of these animal

models for specific types of human epilepsy is uncertain.

In vitro and in vivo recordings of epileptiform activity from the hippocampus have shown that

levetiracetam inhibits burst firing without affecting normal neuronal excitability, suggesting that

levetiracetam may selectively prevent hypersynchronization of epileptiform burst firing and propagation

of seizure activity.

Levetiracetam at concentrations of up to 10 μM did not demonstrate binding affinity for a variety of

known receptors, such as those associated with benzodiazepines, GABA (gamma-aminobutyric acid),

glycine, NMDA (N-methyl-D-aspartate), re-uptake sites, and second messenger systems. Furthermore,

in vitro studies have failed to find an effect of levetiracetam on neuronal voltage-gated sodium or T-

type calcium currents and levetiracetam does not appear to directly facilitate GABAergic

neurotransmission. However, in vitro studies have demonstrated that levetiracetam opposes the activity

of negative modulators of GABA- and glycine-gated currents and partially inhibits N-type calcium

currents in neuronal cells.

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,

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.

12.3 Pharmacokinetics

Overview

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

immediate-release tablets. The pharmacokinetics (AUC and C

) were shown to be dose proportional

after single dose administration of 1000 mg, 2000 mg, and 3000 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.

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 (AUC

) was similar

to extent of exposure after multiple dose immediate-release tablets intake. C

and C

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 (T

) 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

0-24

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 Use in Specific Populations (8.6) and Dosage and Administration (2.1)].

Pharmacokinetic 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. The

pharmacokinetics of immediate-release levetiracetam are linear over the dose range of 500 to 5000 mg.

Levetiracetam and its major metabolite are less than 10% bound to plasma proteins; clinically significant

interactions with other drugs through competition for protein binding sites are therefore unlikely.

Potential pharmacokinetic interactions of or with immediate-release levetiracetam were assessed in

clinical pharmacokinetic studies (phenytoin, valproate, warfarin, digoxin, oral contraceptive,

probenecid) and through pharmacokinetic screening in the placebo-controlled clinical studies in

epilepsy patients [see Drug Interactions (7)]. The potential for drug interactions for extended-release

levetiracetam is expected to be similar to that with immediate-release levetiracetam.

Special 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

Safety and effectiveness of levetiracetam extended-release tablets in patients below the age of 16 years

have not been established.

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.

Renal Impairment

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

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

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

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

levetiracetam 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.

Dosage should be reduced in patients with impaired renal function receiving levetiracetam; immediate-

release levetiracetam should be given to patients on dialysis [see Dosage and Administration (2.1)].

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.

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 1800 mg/kg/day.

The highest dose corresponds to 6 times the maximum recommended daily human dose (MRHD) of

3000 mg on a mg/m basis and it also provided systemic exposure (AUC) approximately 6 times that

achieved in humans receiving the MRHD. There was no evidence of carcinogenicity. A study was

conducted in which mice received levetiracetam in the diet for 80 weeks at doses of 60, 240 and 960

mg/kg/day (high dose is equivalent to 2 times the MRHD on a mg/m or exposure basis). Although no

evidence for carcinogenicity was seen, the potential for a carcinogenic response has not been fully

evaluated in that species because adequate doses have not been studied.

Mutagenesis

Levetiracetam was not mutagenic in the Ames test or in mammalian cells in vitro in the Chinese hamster

ovary/HGPRT locus assay. It was not clastogenic in an in vitro analysis of metaphase chromosomes

obtained from Chinese hamster ovary cells or in an in vivo mouse micronucleus assay. The hydrolysis

product and major human metabolite of levetiracetam (ucb L057) was not mutagenic in the Ames test or

the in vitro mouse lymphoma assay.

Impairment Of Fertility

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

oral doses up to 1800 mg/kg/day (approximately 6 times the maximum recommended human dose on a

mg/m or exposure basis).

13.2 Animal Toxicology and/or Pharmacology

In animal studies, levetiracetam produced evidence of developmental toxicity at doses similar to or

greater than human therapeutic doses.

14 CLINICAL STUDIES

The effectiveness of the immediate-release formulation of levetiracetam as adjunctive therapy (added to

other antiepileptic drugs) in adults was established in three multicenter, randomized, double-blind,

placebo controlled clinical studies in 904 patients who had refractory partial onset seizures with or

without secondary generalization for at least two years and had taken two or more classical AEDs.

The effectiveness of levetiracetam extended-release tablets as adjunctive therapy (added to other

antiepileptic drugs) 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. Patients enrolled 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 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 levetiracetam extended-release tablets (2 x 500 mg tablets) (N = 79)

given once daily over a 12 week treatment period.

The primary efficacy endpoint 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 tablet 1000 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 has not been studied and is unknown.

16 HOW SUPPLIED/STORAGE AND HANDLING

16.1 How Supplied

Levetiracetam extended-release tablets are available as follows:

500 mg – white, oval-shaped, film-coated tablets imprinted with “TV/7795” with black ink on one side

and plain on the other, in bottles of 90.....NDC 54868-6316-0.

16.2 Storage

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

Dispense in a tight, light-resistant container as defined in the USP, with a child-resistant closure (as

required).

17 PATIENT COUNSELING INFORMATION

Patients and caregivers should be informed of the availability of a Medication Guide, and they should

be instructed to read the Medication Guide prior to taking levetiracetam extended-release tablets. The

Medication Guide may also obtained by calling 1-888-838-2872, MEDICAL AFFAIRS. Patients should

be instructed to take levetiracetam extended-release tablets only as prescribed.

Patients, their caregivers, and families should be counseled that AEDs, including levetiracetam

extended-release tablets, may increase the risk of suicidal thoughts and behavior and should be advised

of the need to be alert for the emergence or worsening of symptoms of depression, any unusual changes

in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.

Behaviors of concern should be reported immediately to healthcare providers.

Patients should be advised that levetiracetam extended-release tablets may cause 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, irritability and, in rare cases, psychotic symptoms.

Patients should be instructed to only take levetiracetam extended-release tablets as prescribed and to

swallow the tablets whole. They should not be chewed, broken, or crushed.

Patients should be advised to notify their physician if they become pregnant or intend to become

pregnant during therapy. Patients should be encouraged to enroll in the NAAED Pregnancy Registry if

they become pregnant. This registry is collecting information about the safety of antiepileptic drugs

during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 [see Use in Specific

Populations (8.1)].

Patients should be advised that levetiracetam extended-release tablets may cause dizziness and

somnolence. Accordingly, patients should be advised not to drive or operate heavy machinery or

engage in other hazardous activities until they have gained sufficient experience on levetiracetam

extended-release tablets to gauge whether they adversely affect their performance of these activities.

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. A 1/2011

Relabeling and Repackaging by:

Physicians Total Care, Inc.

Tulsa, Oklahoma 74146

MEDICATION GUIDE

Levetiracetam Extended-Release Tablets

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 in a very small number of people, about 1 in 500 people taking them.

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 are levetiracetam extended-release tablets?

Levetiracetam extended-release tablets are a prescription medicine taken by mouth that is used with

other medicines to treat partial onset seizures in people 16 years of age and older with epilepsy.

It is not known if levetiracetam extended-release tablets are safe or effective in people under 16 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.

500 mg levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release

tablets imprinted with “TV/7795” with black ink on one side and plain on the other.

750 mg levetiracetam extended-release tablets are white, oval-shaped, film-coated extended-release

tablets imprinted with “TV/7796” with black ink on one side and plain on the other.

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. The purpose of this registry is to collect information about the

safety of levetiracetam extended-release tablets and other antiepileptic medicine during pregnancy.

are breast feeding. Levetiracetam can pass into your milk and may harm your baby. You and your

healthcare provider should discuss whether you should take levetiracetam extended-release tablets

or breast feed; you should not do both.

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

nonprescription 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 prescribed.

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

when to take them. Levetiracetam extended-release tablets are usually taken once a day. Take

levetiracetam extended-release tablets at the same 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.

If you miss a dose of levetiracetam extended-release tablets, take it as soon as you remember. If it is

almost time for your next dose, just skip the missed dose. Take the next dose at your regular time.

Do not take two doses at the same time.

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?

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

release tablets?

Levetiracetam extended-release tablets can cause serious side effects.

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

problems with muscle coordination (problems walking and moving)

Common side effects seen in people who take levetiracetam extended-release tablets and other

formulations of levetiracetam include:

sleepiness

weakness

dizziness

infection

These side effects can happen at any time but happen more often within the first 4 weeks of treatment.

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, 20° to 25°C (68° to 77°F) away

from heat and light.

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

General information about 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 they were not prescribed. Do not

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

you have. They may harm them.

This Medication Guide summarizes the most important information about levetiracetam extended-release

tablets. If you would like more information, talk with your healthcare provider. You can ask your

pharmacist or healthcare provider for information about levetiracetam extended-release tablets that is

written for health professionals. You can also get information about levetiracetam extended-release

tablets by calling 1-888-838-2872, MEDICAL AFFAIRS.

What are the ingredients of levetiracetam extended-release tablets?

Levetiracetam extended-release tablet active ingredient: levetiracetam

Inactive ingredients: dibutyl sebacate, ethylcellulose, hydrogenated castor oil powder, hypromellose,

magnesium stearate, microcrystalline cellulose, polyethylene glycol, povidone, and titanium dioxide.

The imprinting ink contains iron oxide black and shellac glaze.

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

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

Manufactured In Israel By:

TEVA PHARMACEUTICAL IND. LTD.

Jerusalem, 91010, Israel

Manufactured For:

TEVA PHARMACEUTICALS USA

Sellersville, PA 18960

Rev. A 1/2011

PRINCIPAL DISPLAY PANEL

Levetiracetam Extended-Release Tablets 500 mg Label Text

LEVETIRACETAM

Extended-Releas e

Tablets

500 mg

Once Daily Dosing

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only

LEVETIRACETAM

levetiracetam tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:548 6 8 -6 316 (NDC:0 0 9 3-779 5)

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

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

ETHYLCELLULO SE ( 7 MPA.S) (UNII: H3UP1140 3C)

HYDRO GENATED CASTO R O IL (UNII: ZF9 4AP8 MEY)

HYPRO MELLO SE 2 9 10 ( 6 MPA.S) (UNII: 0 WZ8 WG20 P6 )

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

CELLULO SE, MICRO CRYSTALLINE (UNII: OP1R32D6 1U)

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

PO VIDO NE K3 0 (UNII: U725QWY32X)

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

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

FERRO SO FERRIC O XIDE (UNII: XM0 M8 7F357)

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

18 mm

Flavor

Imprint Code

TV;779 5

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:548 6 8 -6 316 -0

9 0 in 1 BOTTLE, PLASTIC

Marketing Information

Physicians Total Care, Inc.

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 9 1430

11/22/20 11

Labeler -

Physicians T otal Care, Inc. (194123980)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Physicians To tal Care, Inc.

19 41239 8 0

relabel, repack

Revised: 12/2011

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