DIVALPROEX SODIUM tablet, 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:
Aphena Pharma Solutions - Tennessee, LLC
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, 250 mg are available as white to off-white, round, coated tablets with imprinting “AN 755” on one side and plain on the other side. Each divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 250 mg of valproic acid in the following package sizes: Bottles of 100:                                    NDC 65162-755-10 Bottles of 500:                                    NDC 65162-755-50 Divalproex sodium extended-release tablets USP, 500 mg are available as white to off-white, capsule shaped, coated tablets with imprinting “AN 757” on one side and plain on the other side. Each divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 500 mg of valproic acid in the following packaging sizes: Bottles of 100:                                    NDC 65162-757-10 Bottles of 500:                                    NDC 65162-757-50 Recommended Storage: Store tablets at 20° to 25°C (68° to 77°F); excursions permitted between 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].
Authorization status:
Abbreviated New Drug Application
Authorization number:
71610-311-53, 71610-311-60, 71610-311-70

DIVALPROEX SODIUM- divalproex sodium tablet, extended release

Aphena Pharma Solutions - Tennessee, LLC

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MEDICATION GUIDE

Divalproex (dye val’ proe ex) Sodium Extended-Release Tablets, USP

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 that 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 that affect the

structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra)

on the bottom of the penis can also 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 lower IQ.

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

defects, decreased IQ, or other disorders in your child.

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

migraine headaches.

All women of childbearing age (including girls from the start of puberty) 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 toll-free 1-

888-233-2334 or by visiting the website, http://www.aedpregnancyregistry.org/. 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)

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 will not stop (status

epilepticus).

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

actions, your healthcare provider may check for other causes.

What are divalproex sodium extended-release tablets?

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

have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-

Huttenlocher syndrome)

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 taking it to prevent migraine headaches and are either pregnant or may become pregnant because

you are not using effective birth control (contraception).

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:

have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)

drink alcohol

are pregnant or breastfeeding. 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 extended-release tablets 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 cannot swallow divalproex sodium

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

If you take too much divalproex sodium extended-release tablets, 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 can cause serious side effects including:

Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due

to bleeding or bleeding from your mouth 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); excursions permitted

between 15° to 30°C (59° to 86°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, go to www.amneal.com or call 1-877-835-5472.

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

Active ingredient: divalproex sodium, USP

Inactive ingredients:

ammonium hydroxide, ethyl acrylate and methyl methacrylate co-polymer dispersion, hypromellose,

iron oxide, isopropyl alcohol, lactose monohydrate, macrogol, magnesium stearate, microcrystalline

cellulose, n-butyl alcohol, polyvinyl alcohol, propylene glycol, shellac, silicon dioxide, talc, and

titanium dioxide.

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

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad 382220, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 03-2019-06

Revised: 8/2019

Document Id: 5972f31b-7143-4432-ae2e-96d8508ceb05

34391-3

Set id: fe30c8da-0ae4-48d0-9c0f-9b9d0d726904

Version: 1

Effective Time: 20190812

Aphena Pharma Solutions - Tennessee, LLC

DIVALPROEX SODIUM- divalproex sodium tablet, extended release

Aphena Pharma Solutions - Tennessee, LLC

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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, for oral use

Initial U.S. Approval: 2000

WARNING: LIFE THREATENING ADVERSE REACTIONS

See full prescribing information for complete boxed warning.

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

age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely,

and perform serum liver testing prior to therapy and at frequent intervals thereafter (5.1)

Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ (5.2, 5.3, 5.4)

Pancreatitis, including fatal hemorrhagic cases (5.5)

RECENT MAJOR CHANGES

Boxed Warning, Fetal Risk 2/2019

Indications and Usage, Important Limitations (1.4) 2/2019

Contraindications (4) 2/2019

Warnings and Precautions, Use in Women 2/2019

of Childbearing Potential (5.4)

INDICATIONS AND USAGE

Divalproex sodium extended-release tablets are indicated for:

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)

DOSAGE AND ADMINISTRATION

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 mg/kg/day to 15 mg/kg/day, increasing at 1 week intervals by 5 mg/kg/day 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 1 week intervals by 5 mg/kg/day 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 1 week, thereafter increasing to 1,000 mg/day (2.3).

DOSAGE FORMS AND STRENGTHS

Tablets: 250 mg and 500 mg (3)

CONTRAINDICATIONS

Hepatic disease or significant hepatic dysfunction (4, 5.1)

Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1)

Suspected POLG-related disorder in children under two years of age (4, 5.1)

Known hypersensitivity to the drug (4, 5.12)

Urea cycle disorders (4, 5.6)

Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective

contraception (4, 8.1)

WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS

Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1)

Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure; should not be used to

treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of

childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise

unacceptable (5.2, 5.3, 5.4)

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

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

suicidal thoughts or behavior (5.7)

Bleeding and other hematopoietic disorders; 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)

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue

divalproex sodium extended-release (5.12)

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

regular monitoring for fluid and nutritional intake (5.14)

ADVERSE REACTIONS

Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia,

anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspnea,

dyspepsia, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia,

nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal,

thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss (6.1, 6.2, 6.3).

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

To report SUSPECTED ADVERSE REACTIONS, contact Amneal Pharmaceuticals at 1-877-835-5472 or FDA at

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

DRUG INTERACTIONS

Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, 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 dosage adjustment are indicated whenever enzyme-

inducing or inhibiting drugs are introduced or withdrawn (7.1)

Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: Monitoring of valproate concentrations

is recommended (7.1)

Co-administration 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)

Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose

(7.2)

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

concomitantly with divalproex sodium extended-release (7.2)

Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

USE IN SPECIFIC POPULATIONS

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

decreased IQ and neurodevelopmental disorders (5.2, 5.3, 8.1)

Pediatric: Children under the age of two 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)

See 17 for PATIENT COUNSELING INFORMATION and Medication Guide.

Revised: 3/2019

FULL PRESCRIBING INFORMATION: CONTENTS*

WARNING: LIFE THREATENING ADVERSE REACTIONS

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

2.3 Migraine

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

Extended-Release Tablets

2.5 General Dosing Advice

2.6 Dosing in Patients Taking Rufinamide

3 DOSAGE FORMS AND STRENGTHS

4 CONTRAINDICATIONS

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

5.2 Structural 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 Bleeding and Other Hematopoietic Disorders

5.9 Hyperammonemia

5.10 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use

5.11 Hypothermia

5.12 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

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

6.4 Post-Marketing Experience

7 DRUG INTERACTIONS

7.1 Effects of Co-Administered Drugs on Valproate Clearance

7.2 Effects of Valproate on Other Drugs

7.3 Topiramate

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy

8.2 Lactation

8.3 Females and Males of Reproductive Potential

8.4 Pediatric Use

8.5 Geriatric Use

8.6 Effect of Disease

10 OVERDOSAGE

11 DESCRIPTION

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action

12.2 Pharmacodynamics

12.3 Pharmacokinetics

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, and Impairment of Fertility

14 CLINICAL STUDIES

14.1 Mania

14.2 Epilepsy

14.3 Migraine

15 REFERENCES

16 HOW SUPPLIED/STORAGE AND HANDLING

17 PATIENT COUNSELING INFORMATION

FULL PRESCRIBING INFORMATION

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

WARNING: LIFE THREATENING ADVERSE REACTIONS

Hepatotoxicity

General Population: Hepatic failure resulting in fatalities has occurred in patients receiving

valproate and its derivatives. These incidents usually have occurred during the first six

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. Serum liver tests should be

performed prior to therapy and at frequent intervals thereafter, especially during the first

six months [see Warnings and Precautions (5.1)].

Children under the age of two 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 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. The incidence of fatal hepatotoxicity decreases

considerably in progressively older patient groups.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute

liver failure and resultant deaths in patients with hereditary neurometabolic syndromes

caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g.,

Alpers Huttenlocher Syndrome). Divalproex sodium extended-release is contraindicated in

patients known to have mitochondrial disorders caused by POLG mutations and children

under two years of age who are clinically suspected of having a mitochondrial disorder [see

Contraindications (4)]. In patients over two years of age who are clinically suspected of

having a hereditary mitochondrial disease, divalproex sodium extended-release should only

be used after other anticonvulsants have failed. This older group of patients should be

closely monitored during treatment with divalproex sodium extended-release for the

development of acute liver injury with regular clinical assessments and serum liver testing.

POLG mutation screening should be performed in accordance with current clinical practice

[see Warnings and Precautions (5.1)].

Fetal Risk

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

Counseling Information (17)].

Pancreatitis

Valproate can cause major congenital malformations, particularly neural tube defects (e.g.,

spina bifida). In addition, valproate can cause decreased IQ scores and

neurodevelopmental disorders following in utero exposure.

Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant

women and in women of childbearing potential who are not using effective contraception

[see Contraindications (4)]. Valproate should not be used to treat women with epilepsy or

bipolar disorder who are pregnant or who plan to become pregnant unless other

medications have failed to provide adequate symptom control or are otherwise

unacceptable.

Valproate should not be administered to a woman of childbearing potential unless other

medications have failed to provide adequate symptom control or are otherwise

unacceptable. In such situations, effective contraception should be used [see Warnings and

Precautions (5.2, 5.3, 5.4)].

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.

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, neurodevelopmental disorders, neural tube defects,

and other major congenital malformations, which may occur very early in pregnancy, valproate should

not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become

pregnant unless other medications have failed to provide adequate symptom control or are otherwise

unacceptable. Valproate should not be administered to a woman of childbearing potential unless other

medications have failed to provide adequate symptom control or are otherwise unacceptable

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

Information (17)].

For prophylaxis of migraine headaches, divalproex sodium extended-release tablets are contraindicated

in women who are pregnant and in women of childbearing potential who are not using effective

contraception [see Contraindications (4)].

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 tablets 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 mg/kg/day to 15 mg/kg/day. The dosage should be increased by 5

mg/kg/week 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 mcg/mL 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 mg/kg/day to 15 mg/kg/day. The dosage should be increased by 5

mg/kg/week 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 mcg/mL 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

mg/kg/day to 15 mg/kg/day. The dosage may be increased by 5 mg/kg/week 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 mcg/mL 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 mg/kg/day 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 mcg/mL 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 1 week, thereafter increasing to 1,000 mg

once daily. Although doses other than 1,000 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 mg/day to 1,000 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

Divalproex Sodium Extended-Release Tablets

Total Daily Dose (mg)

(mg)

500* to 625

750* to 875

1,000

1,000* to 1,125

1,250

1,250 to 1,375

1,500

1,500 to 1,625

1,750

1,750

2,000

1,875 to 2,000

2,250

2,125 to 2,250

2,500

2,375

2,750

2,500 to 2,750

3,000

2,875

3,250

3,000 to 3,125

3,500

* 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.

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

sodium delayed-release tablets doses above 3,125 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 mcg/mL 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.

2.6 Dosing in Patients Taking Rufinamide

Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a

low dose, and titrate to a clinically effective dose [see Drug Interactions (7.2)].

3 DOSAGE FORMS AND STRENGTHS

Divalproex sodium extended-release tablets USP, 250 mg are available as white to off-white, round,

coated tablets with imprinting “AN 755” on one side and plain on the other side. Each divalproex sodium

extended-release tablet, USP contains divalproex sodium, USP equivalent to 250 mg of valproic acid.

Divalproex sodium extended-release tablets USP, 500 mg are available as white to off-white, capsule

shaped, coated tablets with imprinting “AN 757” on one side and plain on the other side. Each

divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 500 mg

of valproic acid.

4 CONTRAINDICATIONS

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 known to have

mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g.,

Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a

POLG-related disorder [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)].

For use in prophylaxis of migraine headaches: Divalproex sodium extended-release tablets are

contraindicated in women who are pregnant and in women of childbearing potential who are not

using effective contraception [see Warnings and Precautions (5.2, 5.3, 5.4) and Use in Specific

Populations (8.1)].

5 WARNINGS AND PRECAUTIONS

5.1 Hepatotoxicity

General Information on Hepatotoxicity

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

usually have occurred during the first six 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. Serum liver tests should be performed prior to

therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy.

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. See below, “Patients with Known or Suspected

Mitochondrial Disease.”

Experience has indicated that children under the age of two years are at a considerably increased risk of

developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex

sodium extended-release 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. In progressively older patient

groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases

considerably.

Patients with Known or Suspected Mitochondrial Disease

Divalproex sodium extended-release is contraindicated in patients known to have mitochondrial

disorders caused by POLG mutations and children under two years of age who are clinically suspected

of having a mitochondrial disorder [see Contraindications (4)]. Valproate-induced acute liver failure and

liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by

mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher

Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver

failure in patients with these syndromes have been identified in children and adolescents.

POLG-related disorders should be suspected in patients with a family history or suggestive symptoms

of a POLG-related disorder, including but not limited to unexplained encephalopathy, refractory

epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor

regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, ophthalmoplegia, or

complicated migraine with occipital aura. POLG mutation testing should be performed in accordance

with current clinical practice for the diagnostic evaluation of such disorders. The A467T and W748S

mutations are present in approximately 2/3 of patients with autosomal recessive POLG-related

disorders.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial

disease, divalproex sodium extended-release should only be used after other anticonvulsants have

failed. This older group of patients should be closely monitored during treatment with divalproex

sodium extended-release for the development of acute liver injury with regular clinical assessments and

serum liver test monitoring.

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 Structural 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, hypospadias, limb malformations). The rate of

congenital malformations among babies born to mothers using valproate is about four times 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 [see Use in Specific

Populations (8.1)].

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)].

5.4 Use in Women of Childbearing Potential

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders 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 other medications have failed to

provide adequate symptom control or are otherwise unacceptable. This is especially important when

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

as prophylaxis of migraine headaches [see Contraindications (4)]. Women should use effective

contraception while using valproate.

Women of childbearing potential should be counseled regularly regarding the relative risks and

benefits of valproate use during pregnancy. This is especially important for women planning a

pregnancy and for girls at the onset of puberty; 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 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 2 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 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 is 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 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, 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 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 Bleeding and Other Hematopoietic Disorders

Valproate is associated with dose-related thrombocytopenia. 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. Valproate use has also been associated

with decreases in other cell lines and myelodysplasia.

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

abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von

Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended

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

sodium extended-release be monitored for blood counts and coagulation parameters prior to planned

surgery and during pregnancy [see Use in Specific Populations (8.1)]. 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 reaction is not due to a pharmacokinetic interaction. 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 Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan

Hypersensitivity Reactions

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan

Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening.

DRESS typically, although not exclusively, presents with fever, rash, and/or lymphadenopathy, in

association with other organ system involvement, such as hepatitis, nephritis, hematological

abnormalities, myocarditis, or myositis sometimes resembling an acute viral infection. Eosinophilia is

often present. Because this disorder is variable in its expression, other organ systems not noted here

may be involved. It is important to note that early manifestations of hypersensitivity, such as fever or

lymphadenopathy, may be present even though rash is not evident. If such signs or symptoms are present,

the patient should be evaluated immediately. Valproate should be discontinued and not be resumed if an

alternative etiology for the signs or symptoms cannot be established.

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

The following serious adverse reactions are described below and elsewhere in the labeling:

Hepatic failure [see Warnings and Precautions (5.1)]

Birth defects [see Warnings and Precautions (5.2)]

Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]

Pancreatitis [see Warnings and Precautions (5.5)]

Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]

Suicidal behavior and ideation [see Warnings and Precautions (5.7)]

Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]

Hypothermia [see Warnings and Precautions (5.11)]

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity

reactions [see Warnings and Precautions (5.12)]

Somnolence in the elderly [see Warnings and Precautions (5.14)]

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

three week placebo-controlled clinical trials of divalproex sodium extended-release 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-treated group was greater than 5% and greater than the

placebo incidence.

Table 3. Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release-Treated

Patients During Placebo-Controlled Trials of Acute Mania

Adverse Event

Divalproex Sodium Extended-

Releas e

(n=338)

Placebo

(n=263)

Somnolence

Dyspepsia

Nausea

Vomiting

Diarrhea

Dizziness

Pain

Abdominal Pain

Accidental Injury

Asthenia

Pharyngitis

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

divalproex sodium extended-release: headache

The following additional adverse reactions were reported by greater than 1% of the divalproex sodium

extended-release-treated patients in controlled clinical trials:

Body as a Whole: Back Pain, Chills, Chills and Fever, Drug Level Increased, Flu Syndrome, Infection,

Infection Fungal, Neck Rigidity.

Cardiovascular System: Arrhythmia, Hypertension, Hypotension, Postural Hypotension.

Digestive System: Constipation, Dry Mouth, Dysphagia, Fecal Incontinence, Flatulence, Gastroenteritis,

Glossitis, Gum Hemorrhage, Mouth Ulceration.

Hemic and Lymphatic System: Anemia, Bleeding Time Increased, Ecchymosis, Leucopenia.

Metabolic and Nutritional Disorders: Hypoproteinemia, Peripheral Edema.

1

Musculoskeletal System: Arthrosis, Myalgia.

Nervous System: Abnormal Gait, Agitation, Catatonic Reaction, Dysarthria, Hallucinations, Hypertonia,

Hypokinesia, Psychosis, Reflexes Increased, Sleep Disorder, Tardive Dyskinesia, Tremor.

Respiratory System: Hiccup, Rhinitis.

Skin and Appendages: Discoid Lupus Erythematosus, Erythema Nodosum, Furunculosis, Maculopapular

Rash, Pruritus, Rash, Seborrhea, Sweating, Vesiculobullous Rash.

Special Senses: Conjunctivitis, Dry Eyes, Eye Disorder, Eye Pain, Photophobia, Taste Perversion.

Urogenital System: Cystitis, Urinary Tract Infection, Menstrual Disorder, Vaginitis.

6.2 Epilepsy

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

divalproex sodium delayed-release was 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-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-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 alone,

or the combination of divalproex sodium delayed-release 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 (%)

(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 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 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

1

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 greater incidence in the low dose group.

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-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-Treated

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

Taking Placebo

Body System Event

Divalproex Sodium Extended-

Releas e

(n=122)

Placebo

(n=115)

Gastrointestinal System

Nausea

Dyspepsia

Diarrhea

1

Vomiting

Abdominal Pain

Nervous System

Somnolence

Other

Infection

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

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

release: asthenia and flu syndrome.

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

divalproex sodium extended-release-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-

Releas e

(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 adverse reactions occurred in greater than 5% of divalproex sodium delayed-release-

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

1

syndrome and pharyngitis.

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.

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 Post-Marketing Experience

The following adverse reactions have been identified during post approval use of divalproex sodium

delayed-release. Because these reactions are reported voluntarily from a population of uncertain size, it

is not always possible to reliably estimate their frequency or establish a causal relationship to drug

exposure.

Dermatologic: Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic

epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric: Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance

in attention, learning disorder, and behavioral deterioration.

Neurologic: Paradoxical convulsion, parkinsonism

There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy

or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the

cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate

discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia

levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or

fully after valproate discontinuation.

Musculoskeletal: Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic: Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or

without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis,

and acute intermittent porphyria.

Endocrine: Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated

testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease,

decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.

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

Metabolism and nutrition: Weight gain.

Reproductive: Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male

infertility, and abnormal spermatozoa morphology.

Genitourinary: Enuresis and urinary tract infection.

Special Senses: Hearing loss.

Other: Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous

vasculitis.

7 DRUG INTERACTIONS

7.1 Effects of Co-Administered Drugs on Valproate Clearance

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

glucuronosyltransferases (such as ritonavir), 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

Aspirin

A study involving the co-administration 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 co-administered.

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)].

Estrogen-Containing Hormonal Contraceptives

Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result

in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should

monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen

containing products.

Felbamate

A study involving the co-administration of 1,200 mg/day of felbamate with valproate to patients with

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

115 mcg/mL) compared to valproate alone. Increasing the felbamate dose to 2,400 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 co-administered with rifampin.

Drugs for which either no interaction or a likely clinically unimportant interaction has been observed

Antacids

A study involving the co-administration 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 mg/day 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 mg/day 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 co-

administration 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 (10 males and 5

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 postmarketing 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 co-administration 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. Co-

administration of valproate (1,500 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.

Ethosuximide

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

500 mg with valproate (800 mg/day to 1,600 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 10 healthy volunteers, the elimination half-life of lamotrigine increased

from 26 to 70 hours with valproate co-administration (a 165% increase). The dose of lamotrigine

should be reduced when co-administered 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. Co-administration 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.

Co-administration 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.

Propofol

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce

the dose of propofol when co-administering with valproate. Monitor patients closely for signs of

increased sedation or cardiorespiratory depression.

Rufinamide

Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate.

Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate

(with the larger increases being seen in pediatric patients at high doses or concentrations of valproate).

Patients stabilized on rufinamide before being prescribed valproate should begin valproate therapy at a

low dose, and titrate to a clinically effective dose [see Dosage and Administration (2.6)]. Similarly,

patients on valproate should begin at a rufinamide dose lower than 10 mg/kg per day (pediatric patients)

or 400 mg per day (adults).

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 observed

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 co-administered with

clozapine.

Lithium

Co-administration 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.

Olanzapine

No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with

valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10)

caused 15% reduction in C

and 35% reduction in AUC of olanzapine.

Oral Contraceptive Steroids

Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 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 Registry

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

antiepileptic drugs (AEDs), including divalproex sodium extended-release, during pregnancy.

Encourage women who are taking divalproex sodium extended-release during pregnancy to enroll in the

North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334

or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.

Risk Summary

For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant

and in women of childbearing potential who are not using effective contraception [see Contraindications

(4)].

For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant

or who plan to become pregnant unless other medications have failed to provide adequate symptom

control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions (5.2, 5.3)].

Women with epilepsy who become pregnant while taking valproate should not discontinue valproate

abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to

life.

Maternal valproate use during pregnancy for any indication increases the risk of congenital

malformations, particularly neural tube defects including spina bifida, but also malformations involving

other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations,

hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which

no risk exists cannot be established. Valproate polytherapy with other AEDs has been associated with

an increased frequency of congenital malformations compared with AED monotherapy. 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 four times higher than the rate among babies born to epileptic mothers who used

other anti-seizure monotherapies [see Warnings and Precautions (5.2) and Data (Human)].

Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ

scores and a higher risk of neurodevelopmental disorders compared to children exposed to either

another AED in utero or to no AEDs in utero [see Warnings and Precautions (5.3) and Data (Human)].

An observational study has suggested that exposure to valproate products during pregnancy increases

the risk of autism spectrum disorders [see Data (Human)].

In animal studies, valproate administration during pregnancy resulted in fetal structural malformations

similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses

[see Data (Animal)].

There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants

following maternal use of valproate during pregnancy.

Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including

thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result

in hemorrhagic complications in the neonate including death [see Warnings and Precautions (5.1, 5.8)].

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 [see Warnings and

Precautions (5.2, 5.4)].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S.

general population, the estimated background risk of major birth defects and miscarriage in clinically

recognized pregnancies is 2% to 4% and 15% to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

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 [see Warnings and Precautions (5.4)].

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.

Maternal adverse reactions

Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia,

hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic

complications in the neonate including death [see Warnings and Precautions (5.8)]. If valproate is used in

pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the

mother, then these parameters should also be monitored in the neonate.

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.

Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy.

Data

Human

Neural tube defects and other structural abnormalities

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% (6 to 7 in 10,000 births) compared to the risk following in utero valproate exposure

estimated to be approximately 1% to 2% (100 to 200 in 10,000 births).

The NAAED Pregnancy Registry has reported a major malformation rate of 9% to 11% in the offspring

of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These

data show an up to a five-fold increased risk for any major malformation following valproate exposure

in utero compared to the risk following exposure in utero to other AEDs taken as monotherapy. The

major congenital malformations included cases of neural tube defects, cardiovascular malformations,

craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g.,

clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see

Warnings and Precautions (5.2)].

Effect on IQ and neurodevelopmental effects

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

IQ scores than children exposed to either another AED in utero or to no AEDs 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 AEDs

throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during

pregnancy could not be assessed [see Warnings and Precautions (5.3)].

Although 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

neurodevelopment, including increases in autism spectrum disorders. An observational study has

suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum

disorders. In this study, children born to mothers who had used valproate products during pregnancy had

2.9 times the risk (95% confidence interval [CI]: 1.7 to 4.9) of developing autism spectrum disorders

compared to children born to mothers not exposed to valproate products during pregnancy. The

absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6% to 7.5%) in valproate-exposed

children and 1.5% (95% CI: 1.5% to 1.6%) in children not exposed to valproate products. Because the

study was observational in nature, conclusions regarding a causal association between in utero valproate

exposure and an increased risk of autism spectrum disorder cannot be considered definitive.

Other

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

administration of valproate to pregnant animals during organogenesis at clinically relevant doses

(calculated on a body surface area [mg/m ] 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.

8.2 Lactation

Risk Summary

Valproate is excreted in human milk. Data in the published literature describe the presence of valproate

in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum

levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12

weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal

serum valproate levels. A published study in children up to six years of age did not report adverse

developmental or cognitive effects following exposure to valproate via breast milk [see Data (Human)].

There are no data to assess the effects of divalproex sodium delayed-release on milk production or

excretion.

Clinical Considerations

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

clinical need for divalproex sodium delayed-release and any potential adverse effects on the breastfed

child from divalproex sodium delayed-release or from the underlying maternal condition.

Monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or

bleeding. There have been reports of hepatic failure and clotting abnormalities in offspring of women

who used valproate during pregnancy [see Use in Specific Populations (8.1)].

Data

Human

In a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients

taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. In 4 patients

who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/mL

(range: 1.1 mcg/mL to 2.2 mcg/mL), which corresponded to 4.8% of the maternal plasma concentration

(range: 2.7% to 7.4%). Across all patients (7 of whom were taking other AEDs concomitantly), similar

results were obtained for breast milk concentration (1.8 mcg/mL, range: 0.4 mcg/mL to 3.9 mcg/mL) and

maternal plasma ratio (5.1%, range: 1.3% to 9.6%).

A published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during

maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). None of the mothers received

valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation.

Infant serum levels ranged from 0.7 mcg/mL to 1.5 mcg/mL. With maternal serum valproate levels near

or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. Similarly, in 2

published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of

infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively.

A prospective observational multicenter study evaluated the long-term neurodevelopmental effects of

AED use on children. Pregnant women receiving monotherapy for epilepsy were enrolled with

assessments of their children at ages 3 years and 6 years. Mothers continued AED therapy during the

breastfeeding period. Adjusted IQs measured at 3 years for breastfed and non-breastfed children were

93 (n=11) and 90 (n=24), respectively. At 6 years, the scores for breastfed and non-breastfed children

were 106 (n=11) and 94 (n=25), respectively (p=0.04). For other cognitive domains evaluated at 6

years, no adverse cognitive effects of continued exposure to an AED (including valproate) via breast

milk were observed.

8.3 Females and Males of Reproductive Potential

Contraception

Women of childbearing potential should use effective contraception while taking valproate [see Boxed

Warning, Warnings and Precautions (5.4), Drug Interactions (7), and Use in Specific Populations (8.1)].

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

with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications (4)].

Infertility

There have been reports of male infertility coincident with valproate therapy [see Adverse Reactions

(6.4)].

In animal studies, oral administration of valproate at clinically relevant doses resulted in adverse

reproductive effects in males [see Nonclinical Toxicology (13.1)].

8.4 Pediatric Use

Experience has indicated that pediatric patients under the age of two 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 divalproex sodium extended-release 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

concentrations. 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 was 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 for the indications of mania (150 patients aged 10 to 17 years, 76

of whom were on divalproex sodium extended-release) and migraine (304 patients aged 12 to 17 years,

231 of whom were on divalproex sodium extended-release). 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 six-month pediatric studies were

conducted to evaluate the long-term safety of divalproex sodium extended-release for the indication of

mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to

evaluate the long-term safety of divalproex sodium extended-release for the indication of migraine (353

patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of

divalproex sodium coated particles in 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 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

Liver disease impairs the capacity to eliminate valproate [(see Boxed Warning, Contraindications (4),

Warnings and Precautions (5.1), and Clinical Pharmacology (12.3)].

10 OVERDOSAGE

Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia.

Fatalities have been reported; however patients have recovered from valproate levels as high as 2,120

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 overdosage. 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 powder with a characteristic odor.

Divalproex sodium extended-release tablets USP, 250 mg and 500 mg are for oral administration.

Divalproex sodium extended-release tablets, USP contain divalproex sodium, USP in a once-a-day

extended-release formulation equivalent to 250 and 500 mg of valproic acid.

Inactive Ingredients

Divalproex sodium extended-release tablets USP, 250 mg and 500 mg: ammonium hydroxide, ethyl

acrylate and methyl methacrylate co-polymer dispersion, hypromellose, iron oxide, isopropyl alcohol,

lactose monohydrate, macrogol, magnesium stearate, microcrystalline cellulose, n-butyl alcohol,

polyvinyl alcohol, propylene glycol, shellac, silicon dioxide, talc, and titanium dioxide.

Meet USP Dissolution Test 10.

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.

Epilepsy

The therapeutic range in epilepsy is commonly considered to be 50 mcg/mL 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 mcg/mL and 125 mcg/mL [see Dosage and Administration (2.1)].

12.3 Pharmacokinetics

Absorption/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 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 given once daily produced an average bioavailability of 89%

relative to an equal total daily dose of divalproex sodium delayed-release given BID, TID, or QID. The

median time to maximum plasma valproate concentrations (C

) after divalproex sodium extended-

release administration ranged from 4 to 17 hours. After multiple once-daily dosing of divalproex

sodium extended-release, the peak-to-trough fluctuation in plasma valproate concentrations was 10% to

20% lower than that of regular divalproex sodium delayed-release given BID, TID, or QID.

Conversion from Divalproex Sodium Delayed-Release to Divalproex Sodium Extended-Release

When divalproex sodium extended-release is given in doses 8% to 20% higher than the total daily dose

of divalproex sodium delayed-release, the two formulations are bioequivalent. In two randomized,

crossover studies, multiple daily doses of divalproex sodium delayed-release were compared to 8% to

20% higher once-daily doses of divalproex sodium extended-release. In these two studies, divalproex

sodium extended-release and divalproex sodium delayed-release 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 relative to divalproex sodium delayed-release regimens (see Table 8).

Table 8. Bioavailability of Divalproex Sodium Extended-Release Tablets Relative to Divalproex

Sodium Delayed-Release When Divalproex Sodium Extended-Release Dose is 8 to 20% Higher

Study Population

Regimens

Relative Bioavailability

Divalproex Sodium

Extended-Release vs.

Divalproex Sodium

Delayed-Release

Healthy Volunteers (N=35)

1,000 mg & 1,500 mg

Divalproex Sodium

Extended-Release vs.

875 mg & 1,250 mg

Divalproex Sodium

Delayed-Release

1.059

0.882

1.173

Patients with epilepsy on

concomitant enzyme-

inducing antiepilepsy

drugs (N = 64)

1,000 mg to 5,000 mg

Divalproex Sodium

Extended-Release vs.

875 mg to 4,250 mg

Divalproex Sodium

Delayed-Release

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 and divalproex sodium

extended-release.

Distribution

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).

Metabolism

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 1,000 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

was characterized in a multiple-dose, non-fasting, open label, multi-center study in children and

adolescents. Divalproex sodium extended-release once daily doses ranged from 250 mg to 1,750 mg.

Once daily administration of divalproex sodium extended-release 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 years). 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 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis,

compared with 6 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), and

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, and Impairment of Fertility

Carcinogenesis

Valproate was administered orally to rats and mice at doses of 80 mg/kg/day and 170 mg/kg/day (less

than the maximum recommended human dose on a mg/m basis) for two 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.

Mutagenesis

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; this association was not observed in another study conducted in

adults.

Impairment of Fertility

In chronic toxicity studies in juvenile and adult rats and dogs administration of valproate resulted in

testicular atrophy and reduced spermatogenesis 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 equal to or greater than the MRHD

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.

14 CLINICAL STUDIES

14.1 Mania

The effectiveness of divalproex sodium extended-release 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’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 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 was 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 mcg/mL to 125 mcg/mL. Mean daily divalproex sodium

extended-release doses for observed cases were 2,362 mg (range: 500 to 4,000), 2,874 mg (range:

1,500 to 4,500), 2,993 mg (range: 1,500 to 4,500), 3,181 mg (range: 1,500 to 5,000) and 3,353 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 was 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, multi-clinic, 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 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

16.0

8.9*

Placebo

14.5

11.5

* Reduction from baseline statistically significantly greater for valproate than placebo at p ≤ 0.05 level.

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.

Figure 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 2 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 two 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

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

* Reduction from baseline statistically significantly greater for high dose than low dose at p ≤ 0.05

level.

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

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.

Figure 2

Information on pediatric studies is 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 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 or placebo and treated for 12 weeks. Patients initiated

treatment on 500 mg once daily for one week, and were then increased to 1,000 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-treated patients (86%)

and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 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 (N=122) or placebo (N=115). Four patients were below the age of 18 and 3 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 group, versus 0.6 from a baseline mean of 4.2 in the

placebo group. The treatment difference was statistically significant (see Figure 3).

Figure 3 Mean Reduction In 4-Week Migraine Headache Rates

15 REFERENCES

1. 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):244-252.

16 HOW SUPPLIED/STORAGE AND HANDLING

Divalproex sodium extended-release tablets USP, 250 mg are available as white to off-white, round,

coated tablets with imprinting “AN 755” on one side and plain on the other side. Each divalproex sodium

extended-release tablet, USP contains divalproex sodium, USP equivalent to 250 mg of valproic acid in

the following package sizes:

Bottles of 100: NDC 65162-755-10

Bottles of 500: NDC 65162-755-50

Divalproex sodium extended-release tablets USP, 500 mg are available as white to off-white, capsule

shaped, coated tablets with imprinting “AN 757” on one side and plain on the other side. Each

divalproex sodium extended-release tablet, USP contains divalproex sodium, USP equivalent to 500 mg

of valproic acid in the following packaging sizes:

Bottles of 100: NDC 65162-757-10

Bottles of 500: NDC 65162-757-50

Recommended Storage:

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

USP Controlled Room Temperature].

17 PATIENT COUNSELING INFORMATION

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

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)].

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)].

Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential (including girls beginning the onset of

puberty) that use of valproate during pregnancy increases the risk of birth defects, decreased IQ and

neurodevelopmental disorders in children who were exposed in utero. Advise women to use effective

contraception while taking 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 such as prophylaxis of migraine headache [see

Contraindications (4)]. 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) and Use in Specific Populations (8.1)].

Pregnancy Registry

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 women who are taking divalproex sodium extended-release to enroll in the North American

Antiepileptic Drug (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 or visit the website, http://www.aedpregnancyregistry.org/ [see Use in

Specific Populations (8.1)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including divalproex sodium extended-

release, may increase the risk of suicidal thoughts and behavior and 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)].

Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to

notify the prescriber if any of these symptoms occur [see Warnings and Precautions (5.9, 5.10)].

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.

Multiorgan Hypersensitivity Reactions

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)].

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)].

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad 382220, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 03-2019-07

MEDICATION GUIDE

Divalproex (dye val’ proe ex) Sodium Extended-Release Tablets, USP

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:

1. 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.

2. 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 that 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 that affect the structures

of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom

of the penis can also 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 lower IQ.

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

defects, decreased IQ, or other disorders in your child.

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

migraine headaches.

All women of childbearing age (including girls from the start of puberty) 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 toll-free 1-888-233-2334 or

by visiting the website, http://www.aedpregnancyregistry.org/. The purpose of this registry is to

collect information about the safety of antiepileptic drugs during pregnancy.

3. 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

4. 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)

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 will not stop (status

epilepticus).

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

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

What are divalproex sodium extended-release tablets?

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

have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-

Huttenlocher syndrome)

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 taking it to prevent migraine headaches and are either pregnant or may become pregnant because

you are not using effective birth control (contraception).

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:

have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher

syndrome)

drink alcohol

are pregnant or breastfeeding. 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 extended-release tablets 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 cannot swallow divalproex

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

If you take too much divalproex sodium extended-release tablets, 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 can cause serious side effects including:

Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints

due to bleeding or bleeding from your mouth 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); excursions permitted

between 15° to 30°C (59° to 86°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, go to www.amneal.com or call 1-877-835-5472.

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

Active ingredient: divalproex sodium, USP

Inactive ingredients:

ammonium hydroxide, ethyl acrylate and methyl methacrylate co-polymer dispersion, hypromellose,

iron oxide, isopropyl alcohol, lactose monohydrate, macrogol, magnesium stearate, microcrystalline

cellulose, n-butyl alcohol, polyvinyl alcohol, propylene glycol, shellac, silicon dioxide, talc, and

titanium dioxide.

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

Manufactured by:

Amneal Pharmaceuticals Pvt. Ltd.

Ahmedabad 382220, INDIA

Distributed by:

Amneal Pharmaceuticals LLC

Bridgewater, NJ 08807

Rev. 03-2019-06

Repackaging Information

Please reference the How Supplied section listed above for a description of individual tablets. This

drug product has been received by Aphena Pharma - TN in a manufacturer or distributor packaged

configuration and repackaged in full compliance with all applicable cGMP regulations. The package

configurations available from Aphena are listed below:

Count

500 mg

71610-311-53

71610-311-60

71610-311-70

Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-

resistant container as defined by USP. Keep this and all drugs out of the reach of children.

Repackaged by:

Cookeville, TN 38506

20190812JH

PRINCIPAL DISPLAY PANEL - 500 mg

NDC 71610-311 - Divalproex Sodium ER, USP 500 mg Tablets - Rx Only

DIVALPROEX SODIUM

divalproex sodium tablet, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:716 10 -311(NDC:6 516 2-757)

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)

ETHYL ACRYLATE (UNII: 71E6 178 C9 T)

METHACRYLIC ACID - METHYL METHACRYLATE CO PO LYMER ( 1:1) (UNII: 74G4R6 TH13)

HYPRO MELLO SES (UNII: 3NXW29 V3WO)

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

ISO PRO PYL ALCO HO L (UNII: ND2M416 30 2)

LACTO SE MO NO HYDRATE (UNII: EWQ57Q8 I5X)

PO LYETHYLENE GLYCO L, UNSPECIFIED (UNII: 3WJQ0 SDW1A)

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

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

BUTYL ALCO HO L (UNII: 8 PJ6 1P6 TS3)

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

PRO PYLENE GLYCO L (UNII: 6 DC9 Q16 7V3)

SHELLAC (UNII: 46 N10 7B71O)

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

Product Characteristics

Color

WHITE

S core

no sco re

S hap e

CAPSULE

S iz e

21mm

Flavor

Imprint Code

AN;757

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:716 10 -311-53

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

0 8 /0 2/20 19

2

NDC:716 10 -311-6 0

9 0 in 1 BOTTLE; Type 0 : No t a Co mbinatio n Pro duct

0 8 /0 2/20 19

3

NDC:716 10 -311-70

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

0 8 /0 2/20 19

Aphena Pharma Solutions - Tennessee, LLC

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA20 3730

0 6 /0 1/20 15

Labeler -

Aphena Pharma Solutions - T ennessee, LLC (128385585)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

Aphena Pharma So lutio ns - Tennessee, LLC

128 38 558 5

REPACK(716 10 -311)

Revised: 8/2019

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