DIVALPROEX SODIUM - divalproex sodium tablet, film coated, extended release

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

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Active ingredient:
DIVALPROEX SODIUM (UNII: 644VL95AO6) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
State of Florida DOH Central Pharmacy
INN (International Name):
DIVALPROEX SODIUM
Composition:
VALPROIC ACID 500 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities). The efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies (
Product summary:
Divalproex Sodium Extended-release Tablets, USP are available containing divalproex sodium, USP equivalent to 250 mg or 500 mg of valproic acid. The 250 mg tablets are white, film-coated, round, unscored tablets debossed with M over 177 on one side of the tablet and blank on the other side. The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M 473 on one side of the tablet and blank on the other side. They are supplied by State of Florida DOH Central Pharmacy as follows: Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature.] PHARMACIST: Dispense a Medication Guide with each prescription. * Maalox® is a registered trademark of Novartis. † TitralacTM is a trademark of 3M.
Authorization status:
Abbreviated New Drug Application
Authorization number:
53808-0831-1

DIVALPROEX SODIUM - divalproex sodium tablet, film coated, extended release

State of Florida DOH Central Pharmacy

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MEDICATION GUIDE

DIVALPROEX SODIUM EXTENDED-RELEASE TABLETS, USP

(dye val′ proe ex soe′ dee um)

250 mg and 500 mg

Read this Medication Guide before you start taking divalproex sodium 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 divalproex sodium extended-release tablets?

Do not stop taking divalproex sodium extended-release tablets without first talking to your healthcare

provider.

Stopping divalproex sodium extended-release tablets suddenly can cause serious problems.

Divalproex sodium extended-release tablets can cause serious side effects, including:

Serious liver damage that can cause death, especially in children younger than 2 years old. The risk

of getting this serious liver damage is more likely to happen within the first 6 months of treatment.

Call your healthcare provider right away if you get any of the following symptoms:

nausea or vomiting that does not go away

loss of appetite

pain on the right side of your stomach (abdomen)

dark urine

swelling of your face

yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

Divalproex sodium extended-release tablets may harm your unborn baby.

If you take divalproex sodium extended-release tablets during pregnancy for any medical condition,

your baby is at risk for serious birth defects. The most common birth defects with divalproex

sodium extended-release tablets affect the brain and spinal cord and are called spina bifida or neural

tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this

medicine during pregnancy. These defects can begin in the first month, even before you know you

are pregnant. Other birth defects can happen.

Birth defects may occur even in children born to women who are not taking any medicines and do

not have other risk factors.

Taking folic acid supplements before getting pregnant and during early pregnancy can lower the

chance of having a baby with a neural tube defect.

If you take divalproex sodium extended-release tablets during pregnancy for any medical condition,

your child is at risk for having a lower IQ.

There may be other medicines to treat your condition that have a lower chance of causing birth

defects and decreased IQ in your child.

Women who are pregnant must not take divalproex sodium extended-release tablets to prevent

migraine headaches.

All women of childbearing age should talk to their healthcare provider about using other possible

treatments instead of divalproex sodium extended-release tablets. If the decision is made to use

divalproex sodium extended-release tablets, you should use effective birth control (contraception).

Tell your healthcare provider right away if you become pregnant while taking divalproex sodium

extended-release tablets. You and your healthcare provider should decide if you will continue to

take divalproex sodium extended-release tablets while you are pregnant.

Pregnancy Registry: If you become pregnant while taking divalproex sodium 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 antiepileptic drugs during pregnancy.

Inflammation of your pancreas that can cause death.

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

severe stomach pain that you may also feel in your back

nausea or vomiting that does not go away

Like other antiepileptic drugs, divalproex sodium extended-release tablets may cause suicidal

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

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) o other unusual changes in behavior or mood

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.

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

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

seizure medicine suddenly in a patient who has epilepsy can cause seizures that do 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.

What are divalproex sodium extended-release tablets?

Divalproex sodium extended-release tablets come in different dosage forms with different usages.

Divalproex Sodium Extended-release Tablets are prescription medicines used:

to treat manic episodes associated with bipolar disorder.

alone or with other medicines to treat:

complex partial seizures in adults and children 10 years of age and older

simple and complex absence seizures, with or without other seizure types

to prevent migraine headaches

Who should not take divalproex sodium extended-release tablets?

Do not take divalproex sodium extended-release tablets if you:

have liver problems

are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in

divalproex sodium extended-release tablets. See the end of this leaflet for a complete list of

ingredients in divalproex sodium extended-release tablets.

have a genetic problem called urea cycle disorder

are pregnant for the prevention of migraine headaches

What should I tell my healthcare provider before taking divalproex sodium extended-release tablets?

Before you take divalproex sodium extended-release tablets, tell your healthcare provider if you:

drink alcohol

are pregnant or breast-feeding. Divalproex sodium can pass into breast milk. Talk to your healthcare

provider about the best way to feed your baby if you take divalproex sodium extended-release

tablets.

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

have any other medical conditions

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

prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of

time.

Taking divalproex sodium extended-release tablets with certain other medicines can cause side effects or

affect how well they work. Do not start or stop other medicines without talking to your healthcare

provider.

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

each time you get a new medicine.

How should I take divalproex sodium extended-release tablets?

Take divalproex sodium extended-release tablets exactly as your healthcare provider tells you. Your

healthcare provider will tell you how much divalproex sodium to take and when to take it.

Your healthcare provider may change your dose.

Do not change your dose of divalproex sodium extended-release tablets without talking to your

healthcare provider.

Do not stop taking divalproex sodium extended-release tablets without first talking to your

healthcare provider. Stopping divalproex sodium extended-release tablets suddenly can cause

serious problems.

Swallow divalproex sodium extended-release tablets whole. Do not crush or chew divalproex

sodium extended-release tablets. Tell your healthcare provider if you can not swallow divalproex

sodium extended-release tablets whole. You may need a different medicine.

If you take too much divalproex sodium, call your healthcare provider or local Poison Control

Center right away.

What should I avoid while taking divalproex sodium extended-release tablets?

Divalproex sodium extended-release tablets can cause drowsiness and dizziness. Do not drink

alcohol or take other medicines that make you sleepy or dizzy while taking divalproex sodium

extended-release tablets, until you talk with your doctor. Taking divalproex sodium extended-

release tablets with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or

dizziness worse.

Do not drive a car or operate dangerous machinery until you know how divalproex sodium

extended-release tablets affect you. Divalproex sodium extended-release tablets can slow your

thinking and motor skills.

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

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

release tablets?”

Divalproex sodium extended-release tablets may cause other serious side effects including:

Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or

nose.

High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.

Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling

tired, confusion, coma.

Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and

peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or

throat, trouble swallowing or breathing.

Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less

than you normally would. Tell your doctor if you are not able to eat or drink as you normally do.

Your doctor may start you at a lower dose of divalproex sodium extended-release tablets.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of divalproex sodium extended-release tablets include:

nausea

headache

sleepiness

vomiting

weakness

tremor

dizziness

stomach pain

blurry vision

double vision

diarrhea

increased appetite

weight gain

hair loss

loss of appetite

problems with walking or coordination

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

information, ask your healthcare provider or pharmacist.

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

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

FDA-1088.

How should I store divalproex sodium extended-release tablets?

Store divalproex sodium extended-release tablets at 20° to 25°C (68° to 77°F).

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

General information about the safe and effective use of divalproex sodium extended-release tablets

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

use divalproex sodium extended-release tablets for a condition for which it was not prescribed. Do not

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

that you have. It may harm them.

This Medication Guide summarizes the most important information about divalproex sodium 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 divalproex sodium extended-release tablets that

is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in divalproex sodium extended-release tablets?

Active ingredient: divalproex sodium

Inactive ingredients: ammonium hydroxide, colloidal anhydrous silica, colloidal silicon dioxide, dibutyl

sebacate, ethylcellulose, hydroxyethyl cellulose, hypromellose, oleic acid, polydextrose, polyethylene

glycol, silicified microcrystalline cellulose, titanium dioxide and triacetin.

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

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive

Tallahassee, FL 32304

United States

Revised: 9/2013

Document Id: 970a776f-2cac-4d2e-be54-e10a3af85ec4

Set id: 326fc363-f0c6-4469-ba37-9b93ecb08da1

Version: 1

Effective Time: 20130910

State of Florida DOH Central Pharmacy

DIVALPROEX SODIUM - divalproex sodium tablet, film coated, extended release

State of Florida DOH Central Pharmacy

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HIGHLIGHTS OF PRESCRIBING INFORMATION

These highlights do not include all the information needed to use divalproex sodium extended-release tablets

safely and effectively. See full prescribing information for divalproex sodium extended-release tablets.

Divalproex Sodium Extended-release Tablets, USP for oral use

Initial U.S. Approval: 2000

WARNING: LIFE THREATENING ADVERSE REACTIONS

See full prescribing information for complete boxed warning

RECENT MAJOR CHANGES

Boxed Warning, Fetal Risk 06/2013

Indications and Usage, Important Limitations (1.4) 06/2013

Contraindications (4) 06/2013

Warnings and Precautions, Birth Defects (5.2) 06/2013

Warnings and Precautions, Decreased IQ (5.3) 06/2013

Warnings and Precautions, Use in Women of Childbearing Potential (5.4) 06/2013

Warning and Precautions, Medication Residue in the Stool (5.18) 02/2013

INDICATIONS AND USAGE

Divalproex sodium extended-release tablets are an anti-epileptic drug indicated for:

DOSAGE AND ADMINISTRATION

DOSAGE FORMS AND STRENGTHS

Tablets: 250 mg and 500 mg (3)

CONTRAINDICATIONS

Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the

age of 2 years are at considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and

perform liver function tests prior to therapy and at frequent intervals thereafter (5.1)

Teratogenicity, including neural tube defects (5.2)

Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3,

5.4 )

Pancreatitis, including fatal hemorrhagic cases (5.3)

Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features (1.1)

Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures;

adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2)

Prophylaxis of migraine headaches (1.3)

Divalproex sodium extended-release tablets are intended for once-a-day oral administration. Divalproex sodium

extended-release tablets should be swallowed whole and should not be crushed or chewed. (2.1, 2.2)

Mania: Initial dose is 25 mg/kg/day, increasing as rapidly as possible to achieve therapeutic response or desired

plasma level (2.1). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Complex Partial Seizures: Start at 10 to 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day to

achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing

information for conversion to monotherapy (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Absence Seizures: Start at 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day until seizure control

or limiting side effects (2.2). The maximum recommended dosage is 60 mg/kg/day (2.1, 2.2).

Migraine: The recommended starting dose is 500 mg/day for one week, thereafter increasing to 1000 mg/day (2.3).

Hepatic disease or significant hepatic dysfunction (4, 5.1)

Known hypersensitivity to the drug (4, 5.12)

Urea cycle disorders (4, 5.6)

WARNINGS AND PRECAUTIONS

ADVERSE REACTIONS

To report SUSPECTED ADVERSE REACTIONS, contact Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-

4-INFO-RX) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

DRUG INTERACTIONS

USE IN SPECIFIC POPULATIONS

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 9/2013

FULL PRESCRIBING INFORMATION: CONTENTS*

Pregnant patients treated for prophylaxis of migraine headaches (4, 8.1)

Hepatotoxicity; monitor liver function tests (5.1)

Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or

bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing

potential unless essential (5.2, 5.3, 5.4)

Pancreatitis; divalproex sodium extended-release tablets should ordinarily be discontinued (5.5)

Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium extended-release tablets, increase the

risk of suicidal thoughts or behavior (5.7)

Thrombocytopenia; monitor platelet counts and coagulation tests (5.8)

Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and

vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate

therapy (5.6, 5.9, 5.10)

Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia.

This adverse reaction can also occur in patients using concomitant topiramate (5.11)

Multi-organ hypersensitivity reaction; discontinue divalproex sodium extended-release tablets (5.12)

Somnolence in the elderly can occur. Divalproex sodium extended-release tablets dosage should be increased slowly

and with regular monitoring for fluid and nutritional intake (5.14)

Most common adverse reactions (reported > 5%) reported in adult studies are nausea, somnolence, dizziness,

vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain,

alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred vision, ataxia, nystagmus, emotional

lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema,

insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).

The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults (8.4).

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase

valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased

monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme-

inducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)

Coadministration of valproate can affect the pharmacokinetics of other drugs (e.g., diazepam, ethosuximide,

lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)

Dosage adjustment of amitriptyline/nortriptyline, warfarin, and zidovudine may be necessary if used concomitantly

with divalproex sodium extended-release tablets (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

Pregnancy: Divalproex sodium extended-release tablets can cause congenital malformations including neural tube

defects and decreased IQ (5.2, 5.3, 8.1)

Pediatric: Children under the age of 2 years are at considerably higher risk of fatal hepatotoxicity (5.1, 8.4)

Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence

(5.14, 8.5)

BOXED WARNING

1 INDICATIONS AND USAGE

1.1 Mania

1.2 Epilepsy

1.3 Migraine

1.4 Important Limitations

2 DOSAGE AND ADMINISTRATION

2.1 Mania

2.2 Epilepsy

Complex Partial Seizures

Monotherapy (Initial Therapy)

Conversion to Monotherapy

Adjunctive Therapy

Simple and Complex Absence Seizures

2.3 Migraine

2.4 Conversion from Divalproex Sodium Delayed-release Tablets to Divalproex Sodium Extended-

release Tablets

Dosing in Elderly Patients

Dose Related Adverse Reactions

G.I. Irritation

Compliance

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

5.2 Birth Defects

5.3 Decreased IQ Following in utero Exposure

5.4 Use in Women of Childbearing Potential

5.5 Pancreatitis

5.6 Urea Cycle Disorders

5.7 Suicidal Behavior and Ideation

5.8 Thrombocytopenia

5.9 Hyperammonemia

5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

5.11 Hypothermia

5.12 Multi-Organ Hypersensitivity Reactions

5.13 Interaction with Carbapenem Antibiotics

5.14 Somnolence in the Elderly

5.15 Monitoring: Drug Plasma Concentration

5.16 Effect on Ketone and Thyroid Function Tests

5.17 Effect on HIV and CMV Viruses Replication

5.18 Medication Residue in the Stool

6 ADVERSE REACTIONS

6.1 Mania

6.2 Epilepsy

6.3 Migraine

Mania

Epilepsy

Gas trointes tinal

CNS Effects

Dermatologic

Ps ychiatric

Mus culos keletal

Hematologic

Hepatic

Endocrine

Pancreatic

Metabolic

Genitourinary

Special Senses

Other

7 DRUG INTERACTIONS

7.1 Effects of Coadministered Drugs on Valproate Clearance

As pirin

Carbapenem Antibiotics

Felbamate

Rifampin

Antacids

Chlorpromazine

Haloperidol

Cimetidine and Ranitidine

7.2 Effects of Valproate on Other Drugs

Amitriptyline/Nortriptyline

Carbamazepine/carbamazepine-10,11-Epoxide

Clonazepam

Diazepam

Ethos uximide

Lamotrigine

Phenobarbital

Phenytoin

Tolbutamide

Warfarin

Zidovudine

Acetaminophen

Clozapine

Lithium

Lorazepam

Oral Contraceptive Steroids

7.3 Topiramate

8 USE IN SPECIFIC POPULATIONS

Pregnancy Category D

Pregnancy Category X

Pregnancy Registry

Fetal Risk Summary

Clinical Considerations

Human

Animal

8.3 Nursing Mothers

8.4 Pediatric Use

Pediatric Clinical Trials

Juvenile Animal Toxicology

8.5 Geriatric Use

Liver Disease

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

Epilepsy

Mania

Absorption/Bioavailability

Conversion from Divalproex Sodium Delayed-release Tablets to Divalproex Sodium

Extended-release Tablets

Protein Binding

CNS Distribution

Metabolism

Elimination

Pediatric

Elderly

Effect of Sex

Effect of Race

Liver Disease

Renal Disease

13 NONCLINICAL TOXICOLOGY

Carcinogenesis

Mutagenesis

Fertility

14 CLINICAL STUDIES

14.1 Mania

14.2 Epilepsy

14.3 Migraine

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

17.1 Hepatotoxicity

17.2 Pancreatitis

17.3 Birth Defects and Decreased IQ

17.4 Suicidal Thinking and Behavior

17.5 Hyperammonemia

17.6 CNS Depression

17.7 Multi-Organ Hypersensitivity Reaction

17.8 Medication Residue in the Stool

FULL PRESCRIBING INFORMATION

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

BOXED WARNING

BOXED WARNING

WARNING: LIFE THREATENING ADVERSE REACTIONS

Hepatotoxicity: Hepatic failure resulting in fatalities has occurred in patients receiving

valproate and its derivatives. Children under the age of 2 years are at a considerably

increased risk of developing fatal hepatotoxicity, especially those on multiple

anticonvulsants, those with congenital metabolic disorders, those with severe seizure

disorders accompanied by mental retardation, and those with organic brain disease. When

divalproex sodium extended-release tablets are used in this patient group, it should be used

with extreme caution and as a sole agent. The benefits of therapy should be weighed against

the risks. The incidence of fatal hepatotoxicity decreases considerably in progressively

older patient groups.

These incidents usually have occurred during the first 6 months of treatment. Serious or

fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness,

lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure

control may also occur. Patients should be monitored closely for appearance of these

symptoms. Liver function tests should be performed prior to therapy and at frequent

intervals thereafter, especially during the first 6 months [see Warnings and Precautions (5.1)].

Pancreatitis: Cases of life threatening pancreatitis have been reported in both children and

adults receiving valproate. Some of the cases have been described as hemorrhagic with a

rapid progression from initial symptoms to death. Cases have been reported shortly after

initial use as well as after several years of use. Patients and guardians should be warned

that abdominal pain, nausea, vomiting and/or anorexia can be symptoms of pancreatitis that

require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily

be discontinued. Alternative treatment for the underlying medical condition should be

initiated as clinically indicated [see Warnings and Precautions (5.5)].

1 INDICATIONS AND USAGE

1.1 Mania

Divalproex sodium extended-release tablets are a valproate and are indicated for the treatment of acute

manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic

episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood.

Fetal Risk: Valproate can cause major congenital malformations, particularly neural tube defects

(e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero

exposure.

Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see

Valproate should only be used to treat pregnant women with epilepsy or

bipolar disorder if other medications have failed to control their symptoms or are otherwise

unacceptable.

Contraindications (4)].

Valproate should not be administered to a woman of childbearing potential unless the drug is

essential to the management of her medical condition. This is especially important when valproate

use is considered for a condition not usually associated with permanent injury or death (e.g.,

migraine). Women should use effective contraception while using valproate [see Warnings and

Precautions (5.2, 5.3, 5.4)].

A Medication Guide describing the risks of valproate is available for patients [see Patient

Counseling Information (17)].

Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep,

flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is

characterized by the criteria for a manic episode in conjunction with those for a major depressive

episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of divalproex sodium extended-release tablets is based in part on studies of divalproex

sodium delayed-release tablets in this indication, and was confirmed in a 3-week trial with patients

meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for

acute mania [see Clinical Studies (14.1)].

The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been

demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use divalproex

sodium extended-release tablets for extended periods should continually reevaluate the long-term risk-

benefits of the drug for the individual patient.

1.2 Epilepsy

Divalproex sodium extended-release tablets are indicated as monotherapy and adjunctive therapy in the

treatment of adult patients and pediatric patients down to the age of 10 years with complex partial

seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium

extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of

simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in

adults and children 10 years of age or older with multiple seizure types that include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness

accompanied by certain generalized epileptic discharges without other detectable clinical signs.

Complex absence is the term used when other signs are also present.

1.3 Migraine

Divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches.

There is no evidence that divalproex sodium extended-release tablets are useful in the acute treatment

of migraine headaches.

1.4 Important Limitations

Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital

malformations, which may occur very early in pregnancy, valproate should not be administered to a

woman of childbearing potential unless the drug is essential to the management of her medical condition

[see Warnings and Precautions (5.2, 5.3, 5.4), Use in Specific Populations (8.1), and Patient Counseling

Information (17.3)].

Divalproex sodium extended-release tablets are contraindicated for prophylaxis of migraine headaches

in women who are pregnant.

2 DOSAGE AND ADMINISTRATION

Divalproex sodium extended-release tablets are an extended-release product intended for once-a-day

oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should

not be crushed or chewed.

2.1 Mania

Divalproex sodium extended-release tablets are administered orally. The recommended initial dose is

25 mg/kg/day given once daily. The dose should be increased as rapidly as possible to achieve the

lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma

concentrations. In a placebo-controlled clinical trial of acute mania or mixed type, patients were dosed

to a clinical response with a trough plasma concentration between 85 and 125 mcg/mL. The maximum

recommended dosage is 60 mg/kg/day.

There is no body of evidence available from controlled trials to guide a clinician in the longer term

management of a patient who improves during divalproex sodium extended-release tablet treatment of an

acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute

response in mania is desirable, both for maintenance of the initial response and for prevention of new

manic episodes, there are no data to support the benefits of divalproex sodium extended-release tablets

in such longer-term treatment (i.e., beyond 3 weeks).

2.2 Epilepsy

Divalproex sodium extended-release tablets are administered orally, and must be swallowed whole. As

divalproex sodium extended-release tablets dosage is titrated upward, concentrations of clonazepam,

diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may

be affected [see Drug Interactions (7.2)].

Complex Partial Seizures

For adults and children 10 years of age or older.

Monotherapy (Initial Therapy)

Divalproex sodium extended-release tablets have not been systematically studied as initial therapy.

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10

mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at

daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels

should be measured to determine whether or not they are in the usually accepted therapeutic range (50

to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60

mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma

concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure

control with higher doses should be weighed against the possibility of a greater incidence of adverse

reactions.

Conversion to Monotherapy

Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10

mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at

daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels

should be measured to determine whether or not they are in the usually accepted therapeutic range (50

to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60

mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by

approximately 25% every 2 weeks. This reduction may be started at initiation of divalproex sodium

extended-release tablets therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely

to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly

variable, and patients should be monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

Divalproex sodium extended-release tablets may be added to the patient's regimen at a dosage of 10 to

15 mg/kg/day. The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical

response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If

satisfactory clinical response has not been achieved, plasma levels should be measured to determine

whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No

recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made.

In a study of adjunctive therapy for complex partial seizures in which patients were receiving either

carbamazepine or phenytoin in addition to valproate, no adjustment of carbamazepine or phenytoin

dosage was needed [see Clinical Studies (14.2)]. However, since valproate may interact with these or

other concurrently administered AEDs as well as other drugs, periodic plasma concentration

determinations of concomitant AEDs are recommended during the early course of therapy [see Drug

Interactions (7)].

Simple and Complex Absence Seizures

The recommended initial dose is 15 mg/kg/day, increasing at one week intervals by 5 to 10 mg/kg/day

until seizures are controlled or side effects preclude further increases. The maximum recommended

dosage is 60 mg/kg/day.

A good correlation has not been established between daily dose, serum concentrations, and therapeutic

effect. However, therapeutic valproate serum concentration for most patients with absence seizures is

considered to range from 50 to 100 mcg/mL. Some patients may be controlled with lower or higher

serum concentrations [see Clinical Pharmacology (12.3)].

As divalproex sodium extended-release tablets dosage is titrated upward, blood concentrations of

phenobarbital and/or phenytoin may be affected [see Drug Interactions (7.2)].

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to

prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant

hypoxia and threat to life.

2.3 Migraine

Divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches in

adults.

The recommended starting dose is 500 mg once daily for one week, thereafter increasing to 1000 mg

once daily. Although doses other than 1000 mg once daily of divalproex sodium extended-release

tablets have not been evaluated in patients with migraine, the effective dose range of divalproex sodium

delayed-release tablets in these patients is 500 to 1000 mg/day. As with other valproate products, doses

of divalproex sodium extended-release tablets should be individualized and dose adjustment may be

necessary. If a patient requires smaller dose adjustments than that available with divalproex sodium

extended-release tablets, divalproex sodium delayed-release tablets should be used instead.

2.4 Conversion from Divalproex Sodium Delayed-release Tablets to Divalproex Sodium

Extended-release Tablets

In adult patients and pediatric patients 10 years of age or older with epilepsy previously receiving

divalproex sodium delayed-release tablets, divalproex sodium extended-release tablets should be

administered once daily using a dose 8% to 20% higher than the total daily dose of divalproex sodium

delayed-release tablets (Table 1). For patients whose divalproex sodium delayed-release tablets total

daily dose cannot be directly converted to divalproex sodium extended-release tablets, consideration

may be given at the clinician’s discretion to increase the patient’s divalproex sodium delayed-release

tablets total daily dose to the next higher dosage before converting to the appropriate total daily dose of

divalproex sodium extended-release tablets.

Table 1. Dose Conversion

Divalproex Sodium Delayed-release Tablets

Total Daily Dose (mg)

Divalproex Sodium Extended-release Tablets

(mg)

500 to 625

750 to 875

1000

1000 to 1125

1250

1250 to 1375

1500

1500 to 1625

1750

1750

2000

1875 to 2000

2250

2125 to 2250

2500

2375

2750

2500 to 2750

3000

2875

3250

3000 to 3125

3500

There is insufficient data to allow a conversion factor recommendation for patients with divalproex

sodium delayed-release tablets doses above 3125 mg/day. Plasma valproate C

concentrations for

divalproex sodium extended-release tablets on average are equivalent to divalproex sodium delayed-

release tablets, but may vary across patients after conversion. If satisfactory clinical response has not

been achieved, plasma levels should be measured to determine whether or not they are in the usually

accepted therapeutic range (50 to 100 mcg/mL) [see Clinical Pharmacology (12.2)].

2.5 General Dosing Advice

Dosing in Elderly Patients

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in

the elderly, the starting dose should be reduced in these patients. Starting doses in the elderly lower

than 250 mg can only be achieved by the use of divalproex sodium delayed-release tablets. Dosage

should be increased more slowly and with regular monitoring for fluid and nutritional intake,

dehydration, somnolence, and other adverse reactions. Dose reductions or discontinuation of valproate

should be considered in patients with decreased food or fluid intake and in patients with excessive

somnolence. The ultimate therapeutic dose should be achieved on the basis of both tolerability and

clinical response [see Warnings and Precautions (5.14), Use in Specific Populations (8.5) and Clinical

Pharmacology (12.3)].

Dose Related Adverse Reactions

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be

dose related. The probability of thrombocytopenia appears to increase significantly at total valproate

concentrations of ≥ 110 mcg/mL (females) or ≥ 135 mcg/mL (males) [see Warnings and Precautions

(5.8)]. The benefit of improved therapeutic effect with higher doses should be weighed against the

possibility of a greater incidence of adverse reactions.

G.I. Irritation

Patients who experience G.I. irritation may benefit from administration of the drug with food or by

slowly building up the dose from an initial low level.

Compliance

Patients should be informed to take divalproex sodium extended-release tablets every day as prescribed.

If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a

dose is skipped, the patient should not double the next dose.

3 DOSAGE FORMS AND STRENGTHS

These total daily doses of divalproex sodium delayed-release tablets cannot be directly converted to an 8% to

20% higher total daily dose of divalproex sodium extended-release tablets because the required dosing strengths

of divalproex sodium extended-release tablets are not available. Consideration may be given at the clinician’s

discretion to increase the patient’s divalproex sodium delayed-release tablets total daily dose to the next higher

dosage before converting to the appropriate total daily dose of divalproex sodium extended-release tablets.

The 250 mg tablets are white, film-coated, round, biconvex, unscored tablets debossed with M over

177 on one side of the tablet and blank on the other side. Each tablet contains divalproex sodium

equivalent to 250 mg of valproic acid.

The 500 mg tablets are white, film-coated, oval, biconvex, unscored tablets debossed with M 473 on

one side of the tablet and blank on the other side. Each tablet contains divalproex sodium equivalent to

500 mg of valproic acid.

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents

usually have occurred during the first 6 months of treatment. Serious or fatal hepatotoxicity may be

preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and

vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be

monitored closely for appearance of these symptoms. Liver function tests should be performed prior to

therapy and at frequent intervals thereafter, especially during the first 6 months. However, healthcare

providers should not rely totally on serum biochemistry since these tests may not be abnormal in all

instances, but should also consider the results of careful interim medical history and physical

examination.

Caution should be observed when administering valproate products to patients with a prior history of

hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic

disorders, those with severe seizure disorders accompanied by mental retardation, and those with

organic brain disease may be at particular risk. Experience has indicated that children under the age of 2

years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the

aforementioned conditions. When divalproex sodium extended-release tablets are used in this patient

group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be

weighed against the risks. Above this age group, experience in epilepsy has indicated that the incidence

of fatal hepatotoxicity decreases considerably in progressively older patient groups.

The drug should be discontinued immediately in the presence of significant hepatic dysfunction,

suspected or apparent. In some cases, hepatic dysfunction has progressed in spite of discontinuation of

drug [see Boxed Warning and Contraindications (4)].

5.2 Birth Defects

Valproate can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show

that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g.,

craniofacial defects, cardiovascular malformations and malformations involving various body systems).

The rate of congenital malformations among babies born to mothers using valproate is about 4 times

Divalproex sodium extended-release tablets should not be administered to patients with hepatic

disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)].

Divalproex sodium extended-release tablets are contraindicated in patients with known

hypersensitivity to the drug [see Warnings and Precautions (5.12)].

Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle

disorders [see Warnings and Precautions (5.6)].

Divalproex sodium extended-release tablets are contraindicated for use in prophylaxis of

migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific

Populations (8.1)].

higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of

pregnancy decreases the risk for congenital neural tube defects in the general population.

5.3 Decreased IQ Following in utero Exposure

Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological

studies have indicated that children exposed to valproate in utero have lower cognitive test scores than

children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs. The largest

of these studies

is a prospective cohort study conducted in the United States and United Kingdom that

found that children with prenatal exposure to valproate (n = 62) had lower IQ scores at age 6 (97 [95%

C.I. 94 to 101]) than children with prenatal exposure to the other antiepileptic drug monotherapy

treatments evaluated: lamotrigine (108 [95% C.I. 105 to 110]), carbamazepine (105 [95% C.I. 102 to

108]), and phenytoin (108 [95% C.I. 104 to 112]). It is not known when during pregnancy cognitive

effects in valproate-exposed children occur. Because the women in this study were exposed to

antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was related to a particular

time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence

supports the conclusion that valproate exposure in utero can cause decreased IQ in children.

In animal studies, offspring with prenatal exposure to valproate had malformations similar to those seen

in humans and demonstrated neurobehavioral deficits [see Use in Specific Populations (8.1)].

Valproate use is contraindicated during pregnancy in women being treated for prophylaxis of migraine

headaches. Women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant

should not be treated with valproate unless other treatments have failed to provide adequate symptom

control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during

pregnancy may still outweigh the risks.

5.4 Use in Women of Childbearing Potential

Because of the risk to the fetus of decreased IQ and major congenital malformations (including neural

tube defects), which may occur very early in pregnancy, valproate should not be administered to a

woman of childbearing potential unless the drug is essential to the management of her medical

condition. This is especially important when valproate use is considered for a condition not usually

associated with permanent injury or death (e.g., migraine). Women should use effective contraception

while using valproate. Women who are planning a pregnancy should be counseled regarding the

relative risks and benefits of valproate use during pregnancy, and alternative therapeutic options should

be considered for these patients [see Boxed Warning and Use in Specific Populations (8.1)].

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status

epilepticus with resulting maternal and fetal hypoxia and threat to life.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of

pregnancy decreases the risk for congenital neural tube defects in the general population. It is not

known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving

valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to

conception and during pregnancy should be routinely recommended for patients using valproate.

5.5 Pancreatitis

Cases of life threatening pancreatitis have been reported in both children and adults receiving valproate.

Some of the cases have been described as hemorrhagic with rapid progression from initial symptoms to

Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6

years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):24 4 -252.

death. Some cases have occurred shortly after initial use as well as after several years of use. The rate

based upon the reported cases exceeds that expected in the general population and there have been

cases in which pancreatitis recurred after rechallenge with valproate. In clinical trials, there were two

cases of pancreatitis without alternative etiology in 2,416 patients, representing 1,044 patient-years

experience. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or

anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is

diagnosed, divalproex sodium extended-release tablets should ordinarily be discontinued. Alternative

treatment for the underlying medical condition should be initiated as clinically indicated [see Boxed

Warning].

5.6 Urea Cycle Disorders

Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle

disorders (UCD). Hyperammonemic encephalopathy, sometimes fatal, has been reported following

initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic

abnormalities, particularly ornithine transcarbamylase deficiency. Prior to the initiation of divalproex

sodium extended-release tablets therapy, evaluation for UCD should be considered in the following

patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with

a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or

history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic

extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a

family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms

of UCD. Patients who develop symptoms of unexplained hyperammonemic encephalopathy while

receiving valproate therapy should receive prompt treatment (including discontinuation of valproate

therapy) and be evaluated for underlying urea cycle disorders [see Contraindications (4) and Warnings

and Precautions (5.10)].

5.7 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including divalproex sodium 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 divalproex sodium 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.

5.8 Thrombocytopenia

The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be

dose related. In a clinical trial of valproate as monotherapy in patients with epilepsy, 34/126 patients

(27%) receiving approximately 50 mg/kg/day on average, had at least one value of platelets ≤ 75 x

10 /L. Approximately half of these patients had treatment discontinued, with return of platelet counts to

normal. In the remaining patients, platelet counts normalized with continued treatment. In this study, the

probability of thrombocytopenia appeared to increase significantly at total valproate concentrations of ≥

110 mcg/mL (females) or ≥ 135 mcg/mL (males). The therapeutic benefit which may accompany the

higher doses should therefore be weighed against the possibility of a greater incidence of adverse

effects.

Because of reports of thrombocytopenia, inhibition of the secondary phase of platelet aggregation, and

abnormal coagulation parameters, (e.g., low fibrinogen), platelet counts and coagulation tests are

recommended before initiating therapy and at periodic intervals. It is recommended that patients

receiving divalproex sodium extended-release tablets be monitored for platelet count and coagulation

parameters prior to planned surgery. Evidence of hemorrhage, bruising, or a disorder of

hemostasis/coagulation is an indication for reduction of the dosage or withdrawal of therapy.

5.9 Hyperammonemia

Hyperammonemia has been reported in association with valproate therapy and may be present despite

normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in

mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be

measured. Hyperammonemia should also be considered in patients who present with hypothermia [see

Warnings and Precautions (5.11)]. If ammonia is increased, valproate therapy should be discontinued.

Appropriate interventions for treatment of hyperammonemia should be initiated, and such patients should

undergo investigation for underlying urea cycle disorders [see Contraindications (4) and Warnings and

Precautions (5.6, 5.10)].

During the placebo-controlled pediatric mania trial, one (1) in twenty (20) adolescents (5%) treated with

valproate developed increased plasma ammonia levels compared to no (0) patients treated with placebo.

Asymptomatic elevations of ammonia are more common and when present, require close monitoring of

plasma ammonia levels. If the elevation persists, discontinuation of valproate therapy should be

considered.

5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

Concomitant administration of topiramate and valproate has been associated with hyperammonemia with

or without encephalopathy in patients who have tolerated either drug alone. Clinical symptoms of

hyperammonemic encephalopathy often include acute alterations in level of consciousness and/or

cognitive function with lethargy or vomiting. Hypothermia can also be a manifestation of

hyperammonemia [see Warnings and Precautions (5.11)]. In most cases, symptoms and signs abated with

discontinuation of either drug. This adverse event is not due to a pharmacokinetic interaction. It is not

known if topiramate monotherapy is associated with hyperammonemia. Patients with inborn errors of

metabolism or reduced hepatic mitochondrial activity may be at an increased risk for hyperammonemia

with or without encephalopathy. Although not studied, an interaction of topiramate and valproate may

exacerbate existing defects or unmask deficiencies in susceptible persons. In patients who develop

unexplained lethargy, vomiting, or changes in mental status, hyperammonemic encephalopathy should be

considered and an ammonia level should be measured [see Contraindications (4) and Warnings and

Precautions (5.6, 5.9)].

5.11 Hypothermia

Hypothermia, defined as an unintentional drop in body core temperature to < 35°C (95°F), has been

reported in association with valproate therapy both in conjunction with and in the absence of

hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate with

valproate after starting topiramate treatment or after increasing the daily dose of topiramate [see Drug

Interactions (7.3)]. Consideration should be given to stopping valproate in patients who develop

hypothermia, which may be manifested by a variety of clinical abnormalities including lethargy,

confusion, coma, and significant alterations in other major organ systems such as the cardiovascular and

respiratory systems. Clinical management and assessment should include examination of blood ammonia

levels.

5.12 Multi-Organ Hypersensitivity Reactions

Multi-organ hypersensitivity reactions have been rarely reported in close temporal association to the

initiation of valproate therapy in adult and pediatric patients (median time to detection 21 days: range 1 to

40 days). Although there have been a limited number of reports, many of these cases resulted in

hospitalization and at least one death has been reported. Signs and symptoms of this disorder were

diverse; however, patients typically, although not exclusively, presented with fever and rash associated

with other organ system involvement. Other associated manifestations may include lymphadenopathy,

hepatitis, liver function test abnormalities, hematological abnormalities (e.g., eosinophilia,

thrombocytopenia, neutropenia), pruritus, nephritis, oliguria, hepato-renal syndrome, arthralgia, and

asthenia. Because the disorder is variable in its expression, other organ system symptoms and signs, not

noted here, may occur. If this reaction is suspected, valproate should be discontinued and an alternative

treatment started. Although the existence of cross sensitivity with other drugs that produce this

syndrome is unclear, the experience amongst drugs associated with multi-organ hypersensitivity would

indicate this to be a possibility.

5.13 Interaction with Carbapenem Antibiotics

Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may

reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.

Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate

concentrations drop significantly or seizure control deteriorates [see Drug Interactions (7.1)].

5.14 Somnolence in the Elderly

In a double-blind, multicenter trial of valproate in elderly patients with dementia (mean age = 83 years),

doses were increased by 125 mg/day to a target dose of 20 mg/kg/day. A significantly higher proportion

of valproate patients had somnolence compared to placebo, and although not statistically significant,

there was a higher proportion of patients with dehydration. Discontinuations for somnolence were also

significantly higher than with placebo. In some patients with somnolence (approximately one-half), there

was associated reduced nutritional intake and weight loss. There was a trend for the patients who

experienced these events to have a lower baseline albumin concentration, lower valproate clearance,

and a higher BUN. In elderly patients, dosage should be increased more slowly and with regular

monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions. Dose

reductions or discontinuation of valproate should be considered in patients with decreased food or fluid

intake and in patients with excessive somnolence [see Dosage and Administration (2.4)].

5.15 Monitoring: Drug Plasma Concentration

Since valproate may interact with concurrently administered drugs which are capable of enzyme

induction, periodic plasma concentration determinations of valproate and concomitant drugs are

recommended during the early course of therapy [see Drug Interactions (7)].

5.16 Effect on Ketone and Thyroid Function Tests

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation

of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate. The clinical

significance of these is unknown.

5.17 Effect on HIV and CMV Viruses Replication

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses

under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the

relevance of these in vitro findings is uncertain for patients receiving maximally suppressive

antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results

from regular monitoring of the viral load in HIV infected patients receiving valproate or when

following CMV infected patients clinically.

5.18 Medication Residue in the Stool

There have been rare reports of medication residue in the stool. Some patients have had anatomic

(including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit

times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended

that plasma valproate levels be checked in patients who experience medication residue in the stool, and

patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be

considered.

6 ADVERSE REACTIONS

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

observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of

another drug and may not reflect the rates observed in practice. Information on pediatric adverse

reactions is presented in section 8.

6.1 Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two 3-

week placebo-controlled clinical trials of divalproex sodium extended-release tablets in the treatment

of manic episodes associated with bipolar disorder.

Table 3 summarizes those adverse reactions reported for patients in these trials where the incidence

rate in the divalproex sodium extended-release tablet-treated group was greater than 5% and greater

than the placebo incidence.

Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-release Tablet-

Treated Patients During Placebo-Controlled Trials of Acute Mania

Adverse Event

Divalproex Sodium Extended-release Tablets

(n = 338)

Placebo

(n = 263)

Somnolence

Dyspepsia

Nausea

Vomiting

Diarrhea

Dizziness

Pain

Abdominal pain

Accidental injury

Asthenia

Pharyngitis

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

the divalproex sodium extended-release tablet-treated patients in controlled clinical trials:

Body as a Whole: Back Pain, Flu Syndrome, Infection, Infection Fungal.

Cardiovascular System: Hypertension.

Digestive System: Constipation, Dry Mouth, Flatulence.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral Edema.

Musculoskeletal System: Myalgia.

Nervous System: Abnormal Gait, Hypertonia, Tremor.

Respiratory System: Rhinitis.

Skin and Appendages: Pruritus, Rash.

Special Senses: Conjunctivitis.

Urogenital System: Urinary Tract Infection, Vaginitis.

6.2 Epilepsy

*

The following adverse reactions/event occurred at an equal or greater incidence for placebo than for divalproex

sodium extendedrelease tablets: headache

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures,

divalproex sodium delayed-release tablets were generally well tolerated with most adverse reactions

rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the

divalproex sodium delayed-release tablet-treated patients (6%), compared to 1% of placebo-treated

patients.

Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium

delayed-release tablet-treated patients and for which the incidence was greater than in the placebo

group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures.

Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to

determine whether the following adverse reactions can be ascribed to divalproex sodium delayed-

release tablets alone, or the combination of divalproex sodium delayed-release tablets and other

antiepilepsy drugs.

Table 4 Adverse Reactions Reported by > 5% of Patients Treated with Valproate During

Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Event

Divalproex Sodium Delayed-

release Tablets (%)

(n = 77)

Placebo (%)

(n = 70)

Body as a Whole

Headache

Asthenia

Fever

Gastrointestinal System

Nausea

Vomiting

Abdominal Pain

Diarrhea

Anorexia

Dyspepsia

Constipation

Nervous System

Somnolence

Tremor

Dizziness

Diplopia

Amblyopia/Blurred Vision

Ataxia

Nystagmus

Emotional Lability

Thinking Abnormal

Amnesia

Respiratory System

Flu Syndrome

Infection

Bronchitis

Rhinitis

Other

Alopecia

Weight Loss

Table 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high

dose valproate group, and for which the incidence was greater than in the low dose group, in a

controlled trial of divalproex sodium delayed-release tablets monotherapy treatment of complex partial

seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the

trial, it is not possible, in many cases, to determine whether the following adverse reactions can be

ascribed to divalproex sodium delayed-release tablets alone, or the combination of valproate and other

antiepilepsy drugs.

Table 5 Adverse Reactions Reported by > 5% of Patients in the High Dose Group in the

Controlled Trial of Valproate Monotherapy for Complex Partial Seizures

Body System/Event

High Dose (%)

(n = 131)

Low Dose (%)

(n = 134)

Body as a Whole

Asthenia

Digestive System

Nausea

Diarrhea

Vomiting

Abdominal Pain

Anorexia

Dyspepsia

Hemic/Lymphatic System

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

Nervousness

Amnesia

Nystagmus

Depression

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

*

Headache was the only adverse event that occurred in ≥ 5% of patients in the high dose group and at an equal or

The following additional adverse reactions were reported by greater than 1% but less than 5% of the

358 patients treated with valproate in the controlled trials of complex partial seizures:

Body as a Whole: Back pain, chest pain, malaise.

Cardiovascular System: Tachycardia, hypertension, palpitation.

Digestive System: Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal

abscess.

Hemic and Lymphatic System: Petechia.

Metabolic and Nutritional Disorders: SGOT increased, SGPT increased.

Musculoskeletal System: Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System: Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal

dreams, personality disorder.

Respiratory System: Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages: Rash, pruritus, dry skin.

Special Senses: Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System: Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

6.3 Migraine

Based on two placebo-controlled clinical trials and their long-term extension, valproate was generally

well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients

exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is

compared to a rate of 5% for the 81 placebo patients. Including the long- term extension study, the

adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated

patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence

(1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Table 6 includes those adverse reactions reported for patients in the placebo-controlled trial where the

incidence rate in the divalproex sodium extended-release tablets-treated group was greater than 5% and

was greater than that for placebo patients.

Table 6 Adverse Reactions Reported by > 5% of Divalproex Sodium Extended-release Tablet-

Treated Patients During the Migraine Placebo-Controlled Trial with a Greater Incidence than

Patients Taking Placebo

Body System Event

Divalproex Sodium Extended-release Tablets

(n = 122)

Placebo

(n = 115)

Gastrointestinal System

Nausea

Dyspepsia

Diarrhea

Vomiting

Abdominal Pain

Nervous System

Somnolence

Other

Infection

greater incidence in the low dose group.

*

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

divalproex sodium extended-release tablet-treated patients and with a greater incidence than placebo in

the placebo-controlled clinical trial for migraine prophylaxis:

Body as a Whole: Accidental injury, viral infection.

Digestive System: Increased appetite, tooth disorder.

Metabolic and Nutritional Disorders: Edema, weight gain.

Nervous System: Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.

Respiratory System: Pharyngitis, rhinitis.

Skin and Appendages: Rash.

Special Senses: Tinnitus.

Table 7 includes those adverse reactions reported for patients in the placebo-controlled trials where

the incidence rate in the valproate-treated group was greater than 5% and was greater than that for

placebo patients.

Table 7 Adverse Reactions Reported by > 5% of Valproate-Treated Patients During Migraine

Placebo-Controlled Trials with a Greater Incidence than Patients Taking Placebo

Body System Reaction

Divalproex Sodium

Delayed-release Tablets

(n = 202)

Placebo

(n = 81)

Gastrointestinal System

Nausea

Dyspepsia

Diarrhea

Vomiting

Abdominal Pain

Increased Appetite

Nervous System

Asthenia

Somnolence

Dizziness

Tremor

Other

Weight Gain

Back Pain

Alopecia

The following additional adverse reactions were reported by greater than 1% but not more than 5% of

the 202 valproate-treated patients in the controlled clinical trials:

Body as a Whole: Chest pain.

The following adverse reactions occurred in greater than 5% of divalproex sodium extended-release tablet-

treated patients and at a greater incidence for placebo than for divalproex sodium extended-release tablets:

asthenia and flu syndrome.

*

The following adverse events occurred in greater than 5% of divalproex sodium delayed-release tablet-treated

patients and at a greater incidence for placebo than for divalproex sodium delayed-release tablets: flu syndrome

and pharyngitis.

Cardiovascular System: Vasodilatation.

Digestive System: Constipation, dry mouth, flatulence, and stomatitis.

Hemic and Lymphatic System: Ecchymosis.

Metabolic and Nutritional Disorders: Peripheral edema.

Musculoskeletal System: Leg cramps.

Nervous System: Abnormal dreams, confusion, paresthesia, speech disorder, and thinking

abnormalities.

Respiratory System: Dyspnea, and sinusitis.

Skin and Appendages: Pruritus.

Urogenital System: Metrorrhagia.

6.4 Other Patient Populations

Mania

The following adverse reactions not listed previously were reported by greater than 1% of divalproex

sodium delayed-release tablet treated patients and with a greater incidence than placebo in placebo-

controlled trials of manic episodes associated with bipolar disorder:

Body as a Whole: Chills, chills and fever, drug level increased, neck rigidity.

Cardiovascular System: Arrhythmia, hypotension, postural hypotension.

Digestive System: Dysphagia, fecal incontinence, gastroenteritis, glossitis, gum hemorrhage, mouth

ulceration.

Hemic and Lymphatic System: Anemia, bleeding time increased, leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia.

Musculoskeletal System: Arthrosis.

Nervous System: Agitation, catatonic reaction, dysarthria, hallucinations, hypokinesia, psychosis,

reflexes increased, sleep disorder, tardive dyskinesia.

Respiratory System: Hiccup.

Skin and Appendages: Discoid lupus erythematosus, erythema nodosum, furunculosis, maculopapular

rash, seborrhea, sweating, vesiculobullous rash.

Special Senses: Conjunctivitis, dry eyes, eye disorder, eye pain, photophobia, taste perversion.

Urogenital System: Cystitis, menstrual disorder.

Epileps y

Adverse reactions that have been reported with all dosage forms of valproate from epilepsy trials,

spontaneous reports, and other sources are listed below by body system.

Gas trointes tinal

The most commonly reported side effects at the initiation of therapy are nausea, vomiting, and

indigestion. These effects are usually transient and rarely require discontinuation of therapy. Diarrhea,

abdominal cramps, and constipation have been reported. Both anorexia with some weight loss and

increased appetite with weight gain have also been reported. The administration of delayed-release

divalproex sodium may result in reduction of gastrointestinal side effects in some patients.

CNS Effects

Sedative effects have occurred in patients receiving valproate alone but occur most often in patients

receiving combination therapy. Sedation usually abates upon reduction of other antiepileptic medication.

Tremor (may be dose related), hallucinations, ataxia, headache, nystagmus, diplopia, asterixis, "spots

before eyes", dysarthria, dizziness, confusion, hypesthesia, vertigo, incoordination, and parkinsonism

have been reported with the use of valproate. Rare cases of coma have occurred in patients receiving

valproate alone or in conjunction with phenobarbital. In rare instances encephalopathy with or without

fever has developed shortly after the introduction of valproate monotherapy without evidence of

hepatic dysfunction or inappropriately high plasma valproate levels. Although recovery has been

described following drug withdrawal, there have been fatalities in patients with hyperammonemic

encephalopathy, particularly in patients with underlying urea cycle disorders [see Warnings and

Precautions (5.6)].

Several reports have noted reversible cerebral atrophy and dementia in association with valproate

therapy.

Dermatologic

Transient hair loss, skin rash, photosensitivity, generalized pruritus, erythema multiforme, and Stevens-

Johnson Syndrome. Rare cases of toxic epidermal necrolysis have been reported including a fatal case

in a 6 month old infant taking valproate and several other concomitant medications. An additional case of

toxic epidermal necrosis resulting in death was reported in a 35 year old patient with AIDS taking

several concomitant medications and with a history of multiple cutaneous drug reactions. Serious skin

reactions have been reported with concomitant administration of lamotrigine and valproate [see Drug

Interactions (7.2)].

Ps ychiatric

Emotional upset, depression, psychosis, aggression, hyperactivity, hostility, and behavioral

deterioration.

Mus culos keletal

Weakness.

Hematologic

Thrombocytopenia and inhibition of the secondary phase of platelet aggregation may be reflected in

altered bleeding time, petechiae, bruising, hematoma formation, epistaxis, and frank hemorrhage [see

Warnings and Precautions (5.8) and Drug Interactions (7)]. Relative lymphocytosis, macrocytosis,

hypofibrinogenemia, leukopenia, eosinophilia, anemia including macrocytic with or without folate

deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute

intermittent porphyria.

Hepatic

Minor elevations of transaminases (e.g., SGOT and SGPT) and LDH are frequent and appear to be dose

related. Occasionally, laboratory test results include increases in serum bilirubin and abnormal changes

in other liver function tests. These results may reflect potentially serious hepatotoxicity [see Warnings

and Precautions (5.1)].

Endocrine

Irregular menses, secondary amenorrhea, breast enlargement, galactorrhea, and parotid gland swelling.

Abnormal thyroid function tests [see Warnings and Precautions (5.16)].

There have been rare spontaneous reports of polycystic ovary disease. A cause and effect relationship

has not been established.

Pancreatic

Acute pancreatitis including fatalities [see Warnings and Precautions (5.5)].

Metabolic

Hyperammonemia [see Warnings and Precautions (5.9, 5.10)], hyponatremia, and inappropriate ADH

secretion .

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Decreased carnitine concentrations have been reported although the clinical relevance is undetermined.

Hyperglycinemia has occurred and was associated with a fatal outcome in a patient with preexistent

nonketotic hyperglycinemia.

Genitourinary

Enuresis and urinary tract infection.

Special Senses

Hearing loss, either reversible or irreversible, has been reported; however, a cause and effect

relationship has not been established. Ear pain has also been reported.

Other

Allergic reaction, anaphylaxis, edema of the extremities, lupus erythematosus, bone pain, cough

increased, pneumonia, otitis media, bradycardia, cutaneous vasculitis, fever, and hypothermia [see

Warnings and Precautions (5.11)].

There have been reports of developmental delay, autism and/or autism spectrum disorder in the

offspring of women exposed to valproate during pregnancy.

7 DRUG INTERACTIONS

7.1 Effects of Coadministered Drugs on Valproate Clearance

Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of

glucuronosyltransferases, may increase the clearance of valproate. For example, phenytoin,

carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients

on monotherapy will generally have longer half-lives and higher concentrations than patients receiving

polytherapy with antiepilepsy drugs.

In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be

expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated

oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-

oxidation.

Because of these changes in valproate clearance, monitoring of valproate and concomitant drug

concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn.

The following list provides information about the potential for an influence of several commonly

prescribed medications on valproate pharmacokinetics. The list is not exhaustive nor could it be, since

new interactions are continuously being reported.

Drugs for Which a Potentially Important Interaction has Been Observed

As pirin

A study involving the coadministration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to

pediatric patients (n = 6) revealed a decrease in protein binding and an inhibition of metabolism of

valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to

valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-

keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in

the presence of aspirin.

Whether or not the interaction observed in this study applies to adults is unknown, but caution should be

observed if valproate and aspirin are to be coadministered.

Carbapenem Antibiotics

A clinically significant reduction in serum valproic acid concentration has been reported in patients

receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete

list) and may result in loss of seizure control. The mechanism of this interaction is not well understood.

Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy.

Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid

concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13)].

Felbamate

A study involving the coadministration of 1200 mg/day of felbamate with valproate to patients with

epilepsy (n = 10) revealed an increase in mean valproate peak concentration by 35% (from 86 to 115

mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2400 mg/day increased the mean

valproate peak concentration to 133 mcg/mL (another 16% increase). A decrease in valproate dosage

may be necessary when felbamate therapy is initiated.

Rifampin

A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of

daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Valproate dosage adjustment may be necessary when it is coadministered with rifampin.

Drugs for Which Either no Interaction or a Likely Clinically Unimportant Interaction has Been

Obs erved

Antacids

A study involving the coadministration of valproate 500 mg with commonly administered antacids

(Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption

of valproate.

Chlorpromazine

A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients

already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of

valproate.

Haloperidol

A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already

receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and

glucuronosyltransferases.

The following list provides information about the potential for an influence of valproate

coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed

medications. The list is not exhaustive, since new interactions are continuously being reported.

Drugs for Which a Potentially Important Valproate Interaction has Been Observed

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (ten males and five

females) who received valproate (500 mg BID) resulted in a 21% decrease in plasma clearance of

amitriptyline and a 34% decrease in the net clearance of nortriptyline. Rare post-marketing reports of

concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been

received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity.

Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with

amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the

presence of valproate.

Carbamazepine/carbamazepine-10,11-Epoxide

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11-epoxide

(CBZ-E) increased by 45% upon coadministration of valproate and CBZ to epileptic patients.

Clonazepam

The concomitant use of valproate and clonazepam may induce absence status in patients with a history of

absence type seizures.

Diazepam

Valproate displaces diazepam from its plasma albumin binding sites and inhibits its metabolism.

Coadministration of valproate (1500 mg daily) increased the free fraction of diazepam (10 mg) by 90%

in healthy volunteers (n = 6). Plasma clearance and volume of distribution for free diazepam were

reduced by 25% and 20%, respectively, in the presence of valproate. The elimination half-life of

diazepam remained unchanged upon addition of valproate.

Ethos uximide

Valproate inhibits the metabolism of ethosuximide. Administration of a single ethosuximide dose of

500 mg with valproate (800 to 1600 mg/day) to healthy volunteers (n = 6) was accompanied by a 25%

increase in elimination half-life of ethosuximide and a 15% decrease in its total clearance as compared

to ethosuximide alone. Patients receiving valproate and ethosuximide, especially along with other

anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

Lamotrigine

In a steady-state study involving ten healthy volunteers, the elimination half-life of lamotrigine

increased from 26 to 70 hours with valproate coadministration (a 165% increase). The dose of

lamotrigine should be reduced when coadministered with valproate. Serious skin reactions (such as

Stevens-Johnson Syndrome and toxic epidermal necrolysis) have been reported with concomitant

lamotrigine and valproate administration. See lamotrigine package insert for details on lamotrigine

dosing with concomitant valproate administration.

Phenobarbital

Valproate was found to inhibit the metabolism of phenobarbital. Coadministration of valproate (250 mg

BID for 14 days) with phenobarbital to normal subjects (n = 6) resulted in a 50% increase in half-life

and a 30% decrease in plasma clearance of phenobarbital (60 mg single dose). The fraction of

phenobarbital dose excreted unchanged increased by 50% in presence of valproate.

There is evidence for severe CNS depression, with or without significant elevations of barbiturate or

valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be

closely monitored for neurological toxicity. Serum barbiturate concentrations should be obtained, if

possible, and the barbiturate dosage decreased, if appropriate.

Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Phenytoin

Valproate displaces phenytoin from its plasma albumin binding sites and inhibits its hepatic metabolism.

Coadministration of valproate (400 mg TID) with phenytoin (250 mg) in normal volunteers (n = 7) was

associated with a 60% increase in the free fraction of phenytoin. Total plasma clearance and apparent

volume of distribution of phenytoin increased 30% in the presence of valproate. Both the clearance and

apparent volume of distribution of free phenytoin were reduced by 25%.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the

combination of valproate and phenytoin. The dosage of phenytoin should be adjusted as required by the

clinical situation.

Tolbutamide

From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when

added to plasma samples taken from patients treated with valproate. The clinical relevance of this

displacement is unknown.

Warfarin

In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%. The therapeutic

relevance of this is unknown; however, coagulation tests should be monitored if valproate therapy is

instituted in patients taking anticoagulants.

Zidovudine

In six patients who were seropositive for HIV, the clearance of zidovudine (100 mg q8h) was

decreased by 38% after administration of valproate (250 mg or 500 mg q8h); the half-life of zidovudine

was unaffected.

Drugs for Which Either no Interaction or a Likely Clinically Unimportant Interaction has Been

Obs erved

Acetaminophen

Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was

concurrently administered to three epileptic patients.

Clozapine

In psychotic patients (n = 11), no interaction was observed when valproate was coadministered with

clozapine.

Lithium

Coadministration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male

volunteers (n = 16) had no effect on the steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male

volunteers (n = 9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Oral Contraceptive Steroids

Administration of a single dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to six women

on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

7.3 Topiramate

Concomitant administration of valproate and topiramate has been associated with hyperammonemia with

and without encephalopathy [see Contraindications (4) and Warnings and Precautions (5.6, 5.9, 5.10)].

Concomitant administration of topiramate with valproate has also been associated with hypothermia in

patients who have tolerated either drug alone. It may be prudent to examine blood ammonia levels in

patients in whom the onset of hypothermia has been reported [see Warnings and Precautions (5.9, 5.11)].

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

Pregnancy Category D

For epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions

(5.2 and 5.3)].

Pregnancy Category X

For prophylaxis of migraine headaches [see Contraindications (4)].

Pregnancy Registry

To collect information on the effects of in utero exposure to divalproex sodium extended-release

tablets, physicians should encourage pregnant patients taking divalproex sodium extended-release

tablets to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be

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

the registry can be found at the website, http://www.aedpregnancyregistry.org/.

Fetal Risk Summary

All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or

other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any

indication increases the risk of congenital malformations, particularly neural tube defects, but also

malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations).

The risk of major structural abnormalities is greatest during the first trimester; however, other serious

developmental effects can occur with valproate use throughout pregnancy. The rate of congenital

malformations among babies born to epileptic mothers who used valproate during pregnancy has been

shown to be about 4 times higher than the rate among babies born to epileptic mothers who used other

anti-seizure monotherapies.

Several published epidemiological studies have indicated that children exposed to valproate in utero

have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no

antiepileptic drugs in utero [see Warnings and Precautions (5.3)].

In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to

those seen in humans and demonstrated neurobehavioral deficits.

Clinical Considerations

Neural tube defects are the congenital malformation most strongly associated with maternal

Data

Human

There is an extensive body of evidence demonstrating that exposure to valproate in utero increases the

risk of neural tube defects and other structural abnormalities. Based on published data from the CDC’s

National Birth Defects Prevention Network, the risk of spina bifida in the general population is about

0.06% to 0.07%. The risk of spina bifida following in utero valproate exposure has been estimated to

be approximately 1% to 2%.

In one study using NAAED Pregnancy Registry data, 16 cases of major malformations following

valproate use. The risk of spina bifida following in utero valproate exposure is generally

estimated as 1% to 2%, compared to an estimated general population risk for spina bifida of about

0.06% to 0.07% (6 to 7 in 10,000 births).

Valproate can cause decreased IQ scores in children whose mothers were treated with valproate

during pregnancy.

Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which

may occur very early in pregnancy:

Valproate should not be administered to a woman of childbearing potential unless the drug is

essential to the management of her medical condition. This is especially important when

valproate use is considered for a condition not usually associated with permanent injury or

death (e.g., migraine).

Valproate is contraindicated during pregnancy in women being treated for prophylaxis of

migraine headaches.

Valproate should not be used to treat women with epilepsy or bipolar disorder who are

pregnant or who plan to become pregnant unless other treatments have failed to provide

adequate symptom control or are otherwise unacceptable. In such women, the benefits of

treatment with valproate during pregnancy may still outweigh the risks. When treating a

pregnant woman or a woman of childbearing potential, carefully consider both the potential

risks and benefits of treatment and provide appropriate counseling.

To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this

can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even

minor seizures may pose some hazard to the developing embryo or fetus. However,

discontinuation of the drug may be considered prior to and during pregnancy in individual cases if

the seizure disorder severity and frequency do not pose a serious threat to the patient.

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to

pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first

trimester of pregnancy decreases the risk for congenital neural tube defects in the general

population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring

of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid

supplementation both prior to conception and during pregnancy should be routinely recommended

for patients using valproate.

Patients taking valproate may develop clotting abnormalities [see Warnings and Precautions (5.8)].

A patient who had low fibrinogen when taking multiple anticonvulsants including valproate gave

birth to an infant with afibrinogenemia who subsequently died of hemorrhage. If valproate is used

in pregnancy, the clotting parameters should be monitored carefully.

Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and

Precautions (5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in utero have also

been reported following maternal use of valproate during pregnancy.

prenatal valproate exposure were reported among offspring of 149 enrolled women who used valproate

during pregnancy. Three of the 16 cases were neural tube defects; the remaining cases included

craniofacial defects, cardiovascular malformations and malformations of varying severity involving

other body systems. The NAAED Pregnancy Registry has reported a major malformation rate of 10.7%

(95% C.I. 6.3% to 16.9%) in the offspring of women exposed to an average of 1000 mg/day of

valproate monotherapy during pregnancy (dose range 500 to 2000 mg/day). The major malformation rate

among the internal comparison group of 1,048 epileptic women who received any other antiepileptic

drug monotherapy during pregnancy was 2.9% (95% CI 2% to 4.1%). These data show a 4-fold

increased risk for any major malformation (Odds Ratio 4; 95% CI 2.1 to 7.4) following valproate

exposure in utero compared to the risk following exposure in utero to any other antiepileptic drug

monotherapy.

Published epidemiological studies have indicated that children exposed to valproate in utero have lower

IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs

in utero. The largest of these studies is a prospective cohort study conducted in the United States and

United Kingdom that found that children with prenatal exposure to valproate (n = 62) had lower IQ

scores at age 6 (97 [95% C.I. 94 to 101]) than children with prenatal exposure to the other anti-epileptic

drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105 to 110]), carbamazepine (105

[95% C.I. 102 to 108]) and phenytoin (108 [95% C.I. 104 to 112]). It is not known when during

pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study

were exposed to antiepileptic drugs throughout pregnancy, whether the risk for decreased IQ was

related to a particular time period during pregnancy could not be assessed.

Although all of the available studies have methodological limitations, the weight of the evidence

supports a causal association between valproate exposure in utero and subsequent adverse effects on

cognitive development.

There are published case reports of fatal hepatic failure in offspring of women who used valproate

during pregnancy.

Animal

In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal

structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following

treatment of pregnant animals with valproate during organogenesis at clinically relevant doses

(calculated on a body surface area basis). Valproate induced malformations of multiple organ systems,

including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal

neural tube defects have been reported following valproate administration during critical periods of

organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral

abnormalities (including cognitive, locomotor, and social interaction deficits) and brain

histopathological changes have also been reported in mice and rat offspring exposed prenatally to

clinically relevant doses of valproate.

8.3 Nursing Mothers

Valproate is excreted in human milk. Caution should be exercised when valproate is administered to a

nursing woman.

8.4 Pediatric Use

Experience has indicated that pediatric patients under the age of 2 years are at a considerably increased

risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed

Warning and Warnings and Precautions (5.1)]. When valproate is used in this patient group, it should be

used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the

risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal

hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme inducing drugs, will require larger maintenance

doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3

months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid

concentration. Interpretation of valproic acid concentrations in children should include consideration of

factors that affect hepatic metabolism and protein binding.

Pediatric Clinical Trials

Divalproex sodium delayed-release tablets were studied in seven pediatric clinical trials.

Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of

divalproex sodium extended-release tablets for the indications of mania (150 patients aged 10 to 17

years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients

aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). Efficacy was

not established for either the treatment of migraine or the treatment of mania. The most common drug-

related adverse reactions (reported > 5% and twice the rate of placebo) reported in the controlled

pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and

rash.

The remaining five trials were long-term safety studies. Two 6-month pediatric studies were conducted

to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of

mania (292 patients aged 10 to 17 years). Two 12-month pediatric studies were conducted to evaluate

the long-term safety of divalproex sodium extended-release tablets for the indication of migraine (353

patients aged 12 to 17 years). One 12-month study was conducted to evaluate the safety of divalproex

sodium delayed-release capsules in the indication of partial seizures (169 patients aged 3 to 10 years).

In these seven clinical trials, the safety and tolerability of divalproex sodium delayed-release tablets in

pediatric patients were shown to be comparable to those in adults [see Adverse Reactions (6)].

Juvenile Animal Toxicology

In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal

dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats

treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these

findings was less than the maximum recommended human dose on a mg/m basis.

8.5 Geriatric Use

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania

associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater

than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury,

infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events. It is not clear

whether these events indicate additional risk or whether they result from preexisting medical illness and

concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for

somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these

patients, and dosage reductions or discontinuation should be considered in patients with excessive

somnolence [see Dosage and Administration (2.5)].

There is insufficient information available to discern the safety and effectiveness of valproate for the

prophylaxis of migraines in patients over 65.

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be

reduced compared to younger adults (age range: 22 to 26 years) [see Clinical Pharmacology (12.3)].

8.6 Effect of Disease

Liver Disease

[(See Boxed Warning, Contraindications (4), Warnings and Precautions (5) and Clinical Pharmacology

(12.3)]. Liver disease impairs the capacity to eliminate valproate.

10 OVERDOSAGE

Overdosage with valproate may result in somnolence, heart block, and deep coma. Fatalities have been

reported; however patients have recovered from valproate levels as high as 2120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem

hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric

lavage or emesis will vary with the time since ingestion. General supportive measures should be

applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage. Because

naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with

caution in patients with epilepsy.

11 DESCRIPTION

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic

acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5

equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-

propylpentanoate). Divalproex sodium has the following structure:

Divalproex sodium, USP occurs as a white crystalline powder with a characteristic odor.

Divalproex sodium extended-release 250 mg and 500 mg tablets are for oral administration. Divalproex

sodium extended-release tablets, USP contain divalproex sodium in a once-a-day extended-release

formulation equivalent to 250 mg or 500 mg of valproic acid.

Inactive Ingredients: ammonium hydroxide, colloidal anhydrous silica, colloidal silicon dioxide, dibutyl

sebacate, ethylcellulose, hydroxyethyl cellulose, hypromellose, oleic acid, polydextrose, polyethylene

glycol, silicified microcrystalline cellulose, titanium dioxide and triacetin.

Meets USP Dissolution Test 3.

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by

which valproate exerts its therapeutic effects have not been established. It has been suggested that its

activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

12.2 Pharmacodynamics

The relationship between plasma concentration and clinical response is not well documented. One

contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects

the clearance of the drug. Thus, monitoring of total serum valproate may not provide a reliable index of

the bioactive valproate species.

For example, because the plasma protein binding of valproate is concentration dependent, the free

fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than

expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and

renal diseases.

Epileps y

The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate,

although some patients may be controlled with lower or higher plasma concentrations.

Mania

In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough

plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration (2.1)].

12.3 Pharmacokinetics

Abs orption/Bioavailability

The absolute bioavailability of divalproex sodium extended-release tablets administered as a single

dose after a meal was approximately 90% relative to intravenous infusion.

When given in equal total daily doses, the bioavailability of divalproex sodium extended-release tablets

is less than that of divalproex sodium delayed-release tablets. In five multiple-dose studies in healthy

subjects (n = 82) and in subjects with epilepsy (n = 86), when administered under fasting and nonfasting

conditions, divalproex sodium extended-release tablets given once daily produced an average

bioavailability of 89% relative to an equal total daily dose of divalproex sodium delayed-release

tablets given BID, TID, or QID. The median time to maximum plasma valproate concentrations (C

after divalproex sodium extended-release tablets administration ranged from 4 to 17 hours. After

multiple once daily dosing of divalproex sodium extended-release tablets, the peak-to-trough

fluctuation in plasma valproate concentrations was 10% to 20% lower than that of regular divalproex

sodium delayed-release tablets given BID, TID, or QID.

Conversion from Divalproex Sodium Delayed-release Tablets to Divalproex Sodium Extended-

release Tablets

When divalproex sodium extended-release tablets are given in doses 8% to 20% higher than the total

daily dose of divalproex sodium delayed-release tablets, the two formulations are bioequivalent. In two

randomized, crossover studies, multiple daily doses of divalproex sodium delayed-release tablets were

compared to 8% to 20% higher once daily doses of divalproex sodium extended-release tablets. In

these two studies, divalproex sodium extended-release tablet and divalproex sodium delayed-release

tablet regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of

bioavailability). Additionally, valproate C

was lower, and C

was either higher or not different,

for divalproex sodium extended-release tablets relative to divalproex sodium delayed-release tablets

regimens (see Table 8).

Table 8. Bioavailability of Divalproex Sodium Extended-release Tablets Relative to Divalproex

Sodium Delayed-release Tablets When Divalproex Sodium Extended-release Tablets Dose is 8%

to 20% Higher

Study Population

Regimens

Relative

Bioavailability

Divalproex Sodium Extended-

release Tablets vs.

Divalproex Sodium Delayed-

Release Tablets

Healthy Volunteers

(n = 35)

1000 mg & 1500 mg

Divalproex Sodium Extended-

release Tablets vs.

875 mg & 1250 mg

Divalproex Sodium Delayed-

release Tablets

1.059

0.882 1.173

Patients with epilepsy on concomitant enzyme-

inducing antiepilepsy drugs

(n = 64)

1000 mg to 5000 mg

Divalproex Sodium Extended-

release Tablets vs.

875 mg to 4250 mg

Divalproex Sodium Delayed-

release Tablets

1.008

0.899 1.022

Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine

were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate

bioavailability when converting between divalproex sodium delayed-release tablets and divalproex

sodium extended-release tablets.

Dis tribution

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from

approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in

the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the

presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein bound drugs

(e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions (7.2)for more detailed

information on the pharmacokinetic interactions of valproate with other drugs].

CNS Distribution

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma

(about 10% of total concentration).

Metabolis m

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30% to 50% of

an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other

major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15% to

20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is

excreted unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not

increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma

protein binding. The kinetics of unbound drug are linear.

Elimination

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m and 11

L/1.73 m , respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6

L/hr/1.73 m and 92 L/1.73 m . Mean terminal half-life for valproate monotherapy ranged from 9 to 16

hours following oral dosing regimens of 250 mg to 1000 mg.

The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing

enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine,

phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate

clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant

antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age

Pediatric

The valproate pharmacokinetic profile following administration of divalproex sodium extended-release

tablets was characterized in a multiple dose, nonfasting, open-label, multicenter study in children and

adolescents. Divalproex sodium extended-release tablets once daily doses ranged from 250 mg to 1750

mg. Once daily administration of divalproex sodium extended-release tablets in pediatric patients (10 to

17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in

adults.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be

reduced compared to younger adults (age range: 22 to 26). Intrinsic clearance is reduced by 39%; the

free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see

Dosage and Administration (2.4)].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and

females (4.8 ± 0.17 and 4.7 ± 0.07 L/hr per 1.73 m , respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Effect of Disease

Liver Disease

Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate

was decreased by 50% in seven patients with cirrhosis and by 16% in four patients with acute hepatitis,

compared with six healthy subjects. In that study, the half-life of valproate was increased from 12 to 18

hours. Liver disease is also associated with decreased albumin concentrations and larger unbound

fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be

misleading since free concentrations may be substantially elevated in patients with hepatic disease

whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications (4),

Warnings and Precautions (5.1)].

Renal Disease

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal

failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate

concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with

renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total

concentrations may be misleading.

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenes is

Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the

maximum recommended human dose on a mg/m basis) for 2 years. The primary findings were an

increase in the incidence of subcutaneous fibrosarcomas in high dose male rats receiving valproate and

a dose related trend for benign pulmonary adenomas in male mice receiving valproate. The significance

of these findings for humans is unknown.

Mutagenes is

Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal

effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in

rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of

epileptic children taking valproate, but this association was not observed in another study conducted in

adults. There is some evidence that increased SCE frequencies may be associated with epilepsy. The

biological significance of an increase in SCE frequency is not known.

Fertility

Chronic toxicity studies of valproate in juvenile and adult rats and dogs demonstrated reduced

spermatogenesis and testicular atrophy at oral doses of 400 mg/kg/day or greater in rats (approximately

equivalent to or greater than the maximum recommended human dose (MRHD) on a mg/m basis) and 150

mg/kg/day or greater in dogs (approximately 1.4 times the MRHD or greater on a mg/m basis). Fertility

studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day

(approximately equal to the MRHD on a mg/m basis) for 60 days. The effect of valproate on testicular

development and on sperm production and fertility in humans is unknown.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium extended-release tablets for the treatment of acute mania is

based in part on studies establishing the effectiveness of divalproex sodium delayed-release tablets for

this indication. Divalproex sodium extended-release tablet’s effectiveness was confirmed in one

randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study. The study was

designed to evaluate the safety and efficacy of divalproex sodium extended-release tablets in the

treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a

current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were

hospitalized for acute mania, were enrolled into this study. Divalproex sodium extended-release tablets

were initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then

adjusted to achieve plasma valproate concentrations in the range of 85 to 125 mcg/mL. Mean daily

divalproex sodium extended-release tablet doses for observed cases were 2362 mg (range: 500 to

4,000), 2874 mg (range: 1,500 to 4,500), 2993 mg (range: 1,500 to 4,500), 3181 mg (range: 1,500 to

5,000), and 3353 mg (range: 1,500 to 5,500) at Days 1, 5, 10, 15, and 21, respectively. Mean valproate

concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5 mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21,

respectively. Patients were assessed on the Mania Rating Scale (MRS; score ranges from 0 to 52).

Divalproex sodium extended-release tablets were significantly more effective than placebo in reduction

of the MRS total score.

14.2 Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in

isolation or in association with other seizure types was established in two controlled trials.

In one, multiclinic, placebo-controlled study employing an add-on design, (adjunctive therapy) 144

patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of

monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma

concentrations within the "therapeutic range" were randomized to receive, in addition to their original

antiepilepsy drug (AED), either divalproex sodium delayed-release tablets or placebo. Randomized

patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 9. Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add-on

Treatment

Number of

Patients

Baseline

Incidence

Experimental

Incidence

Divalproex Sodium

Delayed-release Tablets

Placebo

14.5

11.5

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an

effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion

of patients achieving any particular level of improvement was consistently higher for valproate than for

placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial

seizure rate compared to 23% of patients treated with placebo.

Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level.

Fig ure 1.

The second study assessed the capacity of valproate to reduce the incidence of CPS when administered

as the sole AED. The study compared the incidence of CPS among patients randomized to either a high

or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this

study only if 1) they continued to experience two or more CPS per 4 weeks during an 8 to 12 week long

period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital,

or primidone) and 2) they made a successful transition over a 2 week interval to valproate. Patients

entering the randomized phase were then brought to their assigned target dose, gradually tapered off

their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients

randomized, however, completed the study. In patients converted to divalproex sodium delayed-release

tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123

mcg/mL in the low dose and high dose groups, respectively. The following Table presents the findings

for all patients randomized who had at least one post-randomization assessment.

Table 10. Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment

Number

of Patients

Baseline

Incidence

Randomized

Phase Incidence

High dose

Valproate

13.2

10.7

Low dose

Valproate

14.2

13.8

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a

more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure

shows that the proportion of patients achieving any particular level of reduction was consistently higher

Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05 level.

for high dose valproate than for low dose valproate. For example, when switching from carbamazepine,

phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of

patients experienced no change or a reduction in complex partial seizure rates compared to 54% of

patients receiving low dose valproate.

Fig ure 2.

Information on pediatric studies are presented in section 8.

14.3 Migraine

The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial

demonstrated the effectiveness of divalproex sodium extended-release tablets in the prophylactic

treatment of migraine headache. This trial recruited patients with a history of migraine headaches with

or without aura occurring on average twice or more a month for the preceding three months. Patients

with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed

in the trial if they were deemed to be practicing an effective method of contraception.

Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were randomized in a

1:1 ratio to divalproex sodium extended-release tablets or placebo and treated for 12 weeks. Patients

initiated treatment on 500 mg once daily for one week, and were then increased to 1000 mg once daily

with an option to permanently decrease the dose back to 500 mg once daily during the second week of

treatment if intolerance occurred. Ninety-eight of 114 divalproex sodium extended-release tablet-

treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least 2 weeks maintained

the 1000 mg once daily dose for the duration of their treatment periods. Treatment outcome was

assessed on the basis of reduction in 4-week migraine headache rate in the treatment period compared to

the baseline period.

Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with divalproex sodium

extended-release tablets (n = 122) or placebo (n = 115). Four patients were below the age of 18 and

three were above the age of 65. Two hundred and two patients (101 in each treatment group) completed

the treatment period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline

mean of 4.4 in the divalproex sodium extended-release tablets group, versus 0.6 from a baseline mean

of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 3).

Fig ure 3. Mean Reduction in 4 -Week Mig raine Headache Rates

16 HOW SUPPLIED/STORAGE AND HANDLING

Divalproex Sodium Extended-release Tablets, USP are available containing divalproex sodium, USP

equivalent to 250 mg or 500 mg of valproic acid.

The 250 mg tablets are white, film-coated, round, unscored tablets debossed with M over 177 on one

side of the tablet and blank on the other side.

The 500 mg tablets are white, film-coated, oval, unscored tablets debossed with M 473 on one side of

the tablet and blank on the other side.

They are supplied by State of Florida DOH Central Pharmacy as follows:

NDC

Strength

Quantity/Form

Color

Source

Prod.

Code

53808-

0831-1

500 mg

30 Tablets in a Blister

Pack

WHITE

0378-0473

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

PHARMACIST: Dispense a Medication Guide with each prescription.

* Maalox

is a registered trademark of Novartis.

Titralac

is a trademark of 3M.

17 PATIENT COUNSELING INFORMATION

See FDA-Approved Medication Guide

17.1 Hepatotoxicity

Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or

jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly

[see Warnings and Precautions (5.1)].

17.2 Pancreatitis

Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of

pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions

(5.5)].

17.3 Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential that use of valproate during pregnancy

increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to

use effective contraception while using valproate. When appropriate, counsel these patients about

alternative therapeutic options. This is particularly important when valproate use is considered for a

condition not usually associated with permanent injury or death. Advise patients to read the Medication

Guide, which appears as the last section of the labeling [see Warnings and Precautions (5.2, 5.3,

5.4)andUse in Specific Populations (8.1)].

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact

their doctor immediately if they think they are pregnant.

Encourage patients 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)].

17.4 Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including divalproex sodium 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.

Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare

providers [see Warnings and Precautions (5.7)].

17.5 Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and be told

to inform the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)].

17.6 CNS Depression

Since valproate products may produce CNS depression, especially when combined with another CNS

depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an

automobile or operating dangerous machinery, until it is known that they do not become drowsy from the

drug.

17.7 Multi-Organ Hypersensitivity Reaction

Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy,

etc.) may be drug-related and should be reported to the physician immediately [see Warnings and

Precautions (5.12)].

17.8 Medication Residue in the Stool

Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see

Warnings and Precautions (5.18)].

MEDICATION GUIDE

DIVALPROEX SODIUM EXTENDED-RELEASE TABLETS, USP

(dye val′ proe ex soe′ dee um)

250 mg and 500 mg

Read this Medication Guide before you start taking divalproex sodium 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 divalproex sodium extended-release

tablets?

Do not stop taking divalproex sodium extended-release tablets without first talking to your

healthcare provider.

Stopping divalproex sodium extended-release tablets suddenly can cause serious problems.

Divalproex sodium extended-release tablets can cause serious side effects, including:

Serious liver damage that can cause death, especially in children younger than 2 years old.

The risk of getting this serious liver damage is more likely to happen within the first 6 months of

treatment.

Call your healthcare provider right away if you get any of the following symptoms:

nausea or vomiting that does not go away

loss of appetite

pain on the right side of your stomach (abdomen)

dark urine

swelling of your face

yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

Divalproex sodium extended-release tablets may harm your unborn baby.

If you take divalproex sodium extended-release tablets during pregnancy for any medical

condition, your baby is at risk for serious birth defects. The most common birth defects with

divalproex sodium extended-release tablets affect the brain and spinal cord and are called spina

bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to

mothers who use this medicine during pregnancy. These defects can begin in the first month, even

before you know you are pregnant. Other birth defects can happen.

Birth defects may occur even in children born to women who are not taking any medicines and do

not have other risk factors.

Taking folic acid supplements before getting pregnant and during early pregnancy can lower the

chance of having a baby with a neural tube defect.

If you take divalproex sodium extended-release tablets during pregnancy for any medical

condition, your child is at risk for having a lower IQ.

There may be other medicines to treat your condition that have a lower chance of causing birth

defects and decreased IQ in your child.

Women who are pregnant must not take divalproex sodium extended-release tablets to prevent

migraine headaches.

All women of childbearing age should talk to their healthcare provider about using other

possible treatments instead of divalproex sodium extended-release tablets. If the decision is

made to use divalproex sodium extended-release tablets, you should use effective birth

Pregnancy Registry: If you become pregnant while taking divalproex sodium 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 antiepileptic drugs during pregnancy.

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

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

Do not stop divalproex sodium extended-release tablets without first talking to a healthcare

provider.

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

seizure medicine suddenly in a patient who has epilepsy can cause seizures that do 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.

What are divalproex sodium extended-release tablets?

Divalproex sodium extended-release tablets come in different dosage forms with different usages.

Divalproex Sodium Extended-release Tablets are prescription medicines used:

control (contraception).

Tell your healthcare provider right away if you become pregnant while taking divalproex sodium

extended-release tablets. You and your healthcare provider should decide if you will continue to

take divalproex sodium extended-release tablets while you are pregnant.

Inflammation of your pancreas that can cause death.

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

severe stomach pain that you may also feel in your back

nausea or vomiting that does not go away

Like other antiepileptic drugs, divalproex sodium extended-release tablets may cause

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

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) o other unusual changes in behavior or mood

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.

Who should not take divalproex sodium extended-release tablets?

Do not take divalproex sodium extended-release tablets if you:

What should I tell my healthcare provider before taking divalproex sodium extended-release

tablets ?

Before you take divalproex sodium extended-release tablets, tell your healthcare provider if you:

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

prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of

time.

Taking divalproex sodium extended-release tablets with certain other medicines can cause side effects

or affect how well they work. Do not start or stop other medicines without talking to your healthcare

provider.

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

pharmacist each time you get a new medicine.

How should I take divalproex sodium extended-release tablets?

to treat manic episodes associated with bipolar disorder.

alone or with other medicines to treat:

complex partial seizures in adults and children 10 years of age and older

simple and complex absence seizures, with or without other seizure types

to prevent migraine headaches

have liver problems

are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in

divalproex sodium extended-release tablets. See the end of this leaflet for a complete list of

ingredients in divalproex sodium extended-release tablets.

have a genetic problem called urea cycle disorder

are pregnant for the prevention of migraine headaches

drink alcohol

are pregnant or breast-feeding. Divalproex sodium can pass into breast milk. Talk to your

healthcare provider about the best way to feed your baby if you take divalproex sodium extended-

release tablets.

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

have any other medical conditions

Take divalproex sodium extended-release tablets exactly as your healthcare provider tells you.

Your healthcare provider will tell you how much divalproex sodium to take and when to take it.

Your healthcare provider may change your dose.

Do not change your dose of divalproex sodium extended-release tablets without talking to your

healthcare provider.

Do not stop taking divalproex sodium extended-release tablets without first talking to your

healthcare provider. Stopping divalproex sodium extended-release tablets suddenly can cause

serious problems.

Swallow divalproex sodium extended-release tablets whole. Do not crush or chew divalproex

sodium extended-release tablets. Tell your healthcare provider if you can not swallow divalproex

sodium extended-release tablets whole. You may need a different medicine.

What should I avoid while taking divalproex sodium extended-release tablets?

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

Divalproex sodium extended-release tablets may cause other serious side effects including:

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of divalproex sodium extended-release tablets include:

If you take too much divalproex sodium, call your healthcare provider or local Poison Control

Center right away.

Divalproex sodium extended-release tablets can cause drowsiness and dizziness. Do not drink

alcohol or take other medicines that make you sleepy or dizzy while taking divalproex sodium

extended-release tablets, until you talk with your doctor. Taking divalproex sodium extended-

release tablets with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness

or dizziness worse.

Do not drive a car or operate dangerous machinery until you know how divalproex sodium

extended-release tablets affect you. Divalproex sodium extended-release tablets can slow your

thinking and motor skills.

See “What is the most important information I should know about divalproex sodium

extended-release tablets?”

Low blood count: red or purple spots on your skin, bruising, bleeding from your mouth, teeth or

nose.

High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.

Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling

tired, confusion, coma.

Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and

peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or

throat, trouble swallowing or breathing.

Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink

less than you normally would. Tell your doctor if you are not able to eat or drink as you normally

do. Your doctor may start you at a lower dose of divalproex sodium extended-release tablets.

nausea

headache

sleepiness

vomiting

weakness

tremor

dizziness

stomach pain

blurry vision

double vision

diarrhea

increased appetite

weight gain

These are not all of the possible side effects of divalproex sodium extended-release tablets. For

more information, ask your healthcare provider or pharmacist.

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

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

800-FDA-1088.

How should I store divalproex sodium extended-release tablets?

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

General information about the safe and effective use of divalproex sodium extended-release

tablets

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

use divalproex sodium extended-release tablets for a condition for which it was not prescribed. Do not

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

that you have. It may harm them.

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

tablets that is written for health professionals.

For more information, call Mylan Pharmaceuticals Inc. at 1-877-446-3679 (1-877-4-INFO-RX).

What are the ingredients in divalproex sodium extended-release tablets?

Active ingredient: divalproex sodium

Inactive ingredients: ammonium hydroxide, colloidal anhydrous silica, colloidal silicon dioxide, dibutyl

sebacate, ethylcellulose, hydroxyethyl cellulose, hypromellose, oleic acid, polydextrose, polyethylene

glycol, silicified microcrystalline cellulose, titanium dioxide and triacetin.

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

Mylan Pharmaceuticals Inc.

Morgantown, WV 26505 U.S.A.

This Product was Repackaged By:

State of Florida DOH Central Pharmacy

104-2 Hamilton Park Drive

Tallahassee, FL 32304

United States

PRINCIPAL DISPLAY PANEL - 500 mg

NDC 53808-0831-1

Divalproex Sodium

Extended-release

Tablets, USP

500 mg*

hair loss

loss of appetite

problems with walking or coordination

Store divalproex sodium extended-release tablets at 20° to 25°C (68° to 77°F).

Valproic Acid Activity

PHARMACIST: Dispense the accompanying

Medication Guide to each patient.

Rx only 30 Tablets

*Each film-coated tablet contains

divalproex sodium, USP equivalent

to 500 mg of valproic acid.

Keep this and all medication out of the

reach of children.

Store at 20° to 25°C (68° to 77°F).[See

USP Controlled RoomTemperature.]

DIVALPROEX SODIUM

divalproex sodium tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:538 0 8 -0 8 31(NDC:0 378 -0 473)

Route of Administration

ORAL

Active Ingredient/Active Moiety

Ingredient Name

Basis of Strength

Stre ng th

DIVALPRO EX SO DIUM (UNII: 6 44VL9 5AO6 ) (VALPROIC ACID - UNII:6 14OI1Z5WI)

VALPROIC ACID

50 0 mg

Inactive Ingredients

Ingredient Name

Stre ng th

AMMO NIA (UNII: 5138 Q19 F1X)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

DIBUTYL SEBACATE (UNII: 4W5IH7FLNY)

ETHYLCELLULO SES (UNII: 7Z8 S9 VYZ4B)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

O LEIC ACID (UNII: 2UMI9 U37CP)

PO LYDEXTRO SE (UNII: VH2XOU12IE)

PO LYETHYLENE GLYCO LS (UNII: 3WJQ0 SDW1A)

State of Florida DOH Central Pharmacy

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

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

TRIACETIN (UNII: XHX3C3X6 73)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

OVAL

S iz e

21mm

Flavor

Imprint Code

M;473

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:538 0 8 -0 8 31-1

30 in 1 BLISTER PACK

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 7756 7

0 1/0 1/20 13

Labeler -

State of Florida DOH Central Pharmacy (829348114)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

State o f Flo rida DOH Central Pharmacy

8 29 348 114

re pa c k(538 0 8 -0 8 31)

Revised: 9/2013

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