DIVALPROEX SODIUM tablet, film coated, extended release

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

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Active ingredient:
DIVALPROEX SODIUM (UNII: 644VL95AO6) (VALPROIC ACID - UNII:614OI1Z5WI)
Available from:
American Health Packaging
INN (International Name):
DIVALPROEX SODIUM
Composition:
VALPROIC ACID 250 mg
Administration route:
ORAL
Prescription type:
PRESCRIPTION DRUG
Therapeutic indications:
Divalproex sodium extended-release tablets, USP are 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 Stu
Product summary:
Divalproex Sodium Extended-release Tablets USP, 250 mg are available as white to off-white, capsule-shaped, biconvex, film-coated tablets imprinted with "ZA47" on one side and the other side plain and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-310-01 Divalproex Sodium Extended-release Tablets USP, 500 mg are available as white to off-white, capsule-shaped, biconvex, film-coated tablets imprinted with "ZA48" on one side and the other side plain and are supplied as follows: Unit dose packages of 100 (10 x 10) NDC 68084-415-01 Storage Store at 20° to 25°C (68° to 77°F) [See USP Controlled Room Temperature]. FOR YOUR PROTECTION: Do not use if blister is torn or broken. Maalox ® is the registered trademark of Novartis Consumer Health. Trisogel ® is the registered trademark of Eli Lilly Corporation. Titralac ® is the registered trademark of 3M Pharmaceuticals
Authorization status:
Abbreviated New Drug Application
Authorization number:
68084-310-01, 68084-310-11, 68084-415-01, 68084-415-11

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

American Health Packaging

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MEDICATION GUIDE

8231001/0919

Divalproex Sodium (dye val PRO ex sew dee uhm)

Extended-release Tablets, USP

Read this Medication Guide before you start taking divalproex sodium 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?

Do not stop taking divalproex sodium without first talking to your healthcare provider.

Stopping divalproex sodium suddenly can cause serious problems.

Divalproex sodium 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 may harm your unborn baby.

If you take divalproex sodium 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 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 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. If the

decision is made to use divalproex sodium, you should use effective birth control (contraception).

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

You and your healthcare provider should decide if you will continue to take divalproex sodium while

you are pregnant.

Pregnancy Registry : If you become pregnant while taking divalproex sodium, 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 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 without first talking to a healthcare provider. Stopping divalproex sodium

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 is divalproex sodium?

Divalproex sodium come in different dosage forms with different usages.

Divalproex sodium extended-release tablets are prescription medicines used:

to treat manic episodes associated with bipolar disorder.

alone or with other medicines to treat:

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

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

to prevent migraine headaches

Who should not take divalproex sodium?

Do not take divalproex sodium 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. See the end of this leaflet for a complete list of ingredients in divalproex sodium.

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?

Before you take divalproex sodium, 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.

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 nonprescription

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

Taking divalproex sodium 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?

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

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

Your healthcare provider may change your dose.

Do not change your dose of divalproex sodium without talking to your healthcare provider.

Do not stop taking divalproex sodium without first talking to your healthcare provider. Stopping

divalproex sodium suddenly can cause serious problems.

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

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

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

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

right away.

What should I avoid while taking divalproex sodium?

Divalproex sodium can cause drowsiness and dizziness. Do not drink alcohol or take other medicines

that make you sleepy or dizzy while taking divalproex sodium, until you talk with your doctor.

Taking divalproex sodium 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 affects

you. Divalproex sodium can slow your thinking and motor skills.

What are the possible side effects of divalproex sodium?

See "What is the most important information I should know about divalproex sodium?"

Divalproex sodium 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.

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

The common side effects of divalproex sodium 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. 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?

Store divalproex sodium extended-release tablets at 20° to 25°C (68° to 77°F) [See USP Controlled

Room Temperature].

Keep divalproex sodium and all medicines out of the reach of children.

General information about the safe and effective use of divalproex sodium

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

divalproex sodium for a condition for which it was not prescribed. Do not give divalproex sodium 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. If you would

like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare

provider for information about divalproex sodium that is written for health professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

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

Active ingredient: divalproex sodium, USP

Inactive ingredients: hydroxypropyl cellulose, hypromellose, lecithin, magnesium stearate, polyethylene

glycol, polyvinyl alcohol (partially hydrolyzed), silicon dioxide, talc, titanium dioxide and xanthan gum.

Each tablet is imprinted with black pharmaceutical ink which contains: ammonium hydroxide, ferrosoferric

oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.

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

The product's labeling may have been updated. For latest package insert, please call American Health

Packaging at 1-800-707-4621.

Distributed by:

American Health Packaging

Columbus, OH 43217

8231001/0919

Revised: 11/2019

Document Id: 9649003d-78a1-9fbe-e053-2995a90a6313

34391-3

Set id: a8ba3986-1ded-44a8-8d10-d0f252a07794

Version: 6

Effective Time: 20191101

American Health Packaging

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

American Health Packaging

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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 of Childbearing Potential ( 5.4)

2/2019

INDICATIONS AND USAGE

Divalproex sodium extended-release tablets, USP 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 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve

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

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

Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day until seizure control or

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

Migraine: The recommended starting dose is 500 mg/day for 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

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 tablets should ordinarily be discontinued ( 5.5)

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

risk of suicidal thoughts or behavior ( 5.7)

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 tablets ( 5.12)

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

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

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 Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779

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)

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

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

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 tablets ( 7.2)

Topiramate: Hyperammonemia and encephalopathy ( 5.10, 7.3)

USE IN SPECIFIC POPULATIONS

Pregnancy: Divalproex sodium extended-release tablets 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 Postmarketing Experience

7. DRUG INTERACTIONS

7.1 Effects of Coadministered 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 tablets are

used in this patient group, it should be used with extreme caution and as a sole agent. The

benefits of therapy should be weighed against the risks. The incidence of fatal

hepatotoxicity decreases considerably in progressively older patient groups.

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 tablets are

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 tablets 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 tablets 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

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)].

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

Counseling Information ( 17)].

Pancreatitis

Cases of life-threatening pancreatitis have been reported in both children and adults

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

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

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

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

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

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

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

1. INDICATIONS AND USAGE

1.1 Mania

Divalproex sodium extended-release tablets, USP are 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, USP 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, USP 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 tablet is 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 tablet 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 tablet has not been systematically studied as initial therapy.

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

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

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

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

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

mg/kg/day can be made.

The probability of thrombocytopenia increases significantly at total trough valproate plasma

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

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

reactions.

Conversion to Monotherapy

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

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

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

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

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

mg/kg/day can be made.

Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2

weeks. This reduction may be started at initiation of divalproex sodium extended-release tablet therapy,

or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The

speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be

monitored closely during this period for increased seizure frequency.

Adjunctive Therapy

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

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

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

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

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

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

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

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

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

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

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

Interactions ( 7)].

Simple and Complex Absence Seizures

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

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

dosage is 60 mg/kg/day.

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

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

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

serum concentrations [see Clinical Pharmacology ( 12.3)].

As divalproex sodium extended-release tablet 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 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

Total Daily Dose (mg)

Divalproex Sodium Extended-release Tablets

(mg)

to 625

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

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 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

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.

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,

capsule-shaped tablets imprinted with "ZA47". Each divalproex sodium extended-release tablet contains

divalproex sodium equivalent to 250 mg of valproic acid.

Divalproex Sodium Extended-release Tablets USP, 500 mg are available as white to off-white,

capsule-shaped tablets imprinted with "ZA48". Each divalproex sodium extended-release tablet contains

divalproex sodium 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.

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 tablets are used in this patient group, it should be used with extreme caution

and as a sole agent. The benefits of therapy should be weighed against the risks. 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 tablets are 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 tablets 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 tablets 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 to110]), 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 tablets should ordinarily be discontinued. Alternative

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

Warning].

5.6 Urea Cycle Disorders

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

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

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

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

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

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

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

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

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

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

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

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

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

and Precautions ( 5.10)].

5.7 Suicidal Behavior and Ideation

Antiepileptic drugs (AEDs), including divalproex sodium extended-release tablets, increase the risk of

suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any

AED for any indication should be monitored for the emergence or worsening of depression, suicidal

thoughts or behavior, and/or any unusual changes in mood or behavior.

Pooled analyses of 199 placebo-controlled clinical trials (mono- and adjunctive therapy) of 11 different

AEDs showed that patients randomized to one of the AEDs had approximately twice the risk (adjusted

Relative Risk 1.8, 95% CI:1.2, 2.7) of suicidal thinking or behavior compared to patients randomized to

placebo. In these trials, which had a median treatment duration of 12 weeks, the estimated incidence rate

of suicidal behavior or ideation among 27,863 AED-treated patients was 0.43%, compared to 0.24%

among 16,029 placebo-treated patients, representing an increase of approximately one case of suicidal

thinking or behavior for every 530 patients treated. There were four suicides in drug-treated patients in

the trials and none in placebo-treated patients, but the number is too small to allow any conclusion about

drug effect on suicide.

The increased risk of suicidal thoughts or behavior with AEDs was observed as early as one week

after starting drug treatment with AEDs and persisted for the duration of treatment assessed.

Because most trials included in the analysis did not extend beyond 24 weeks, the risk of suicidal

thoughts or behavior beyond 24 weeks could not be assessed.

The risk of suicidal thoughts or behavior was generally consistent among drugs in the data analyzed.

The finding of increased risk with AEDs of varying mechanisms of action and across a range of

indications suggests that the risk applies to all AEDs used for any indication. The risk did not vary

substantially by age (5 to 100 years) in the clinical trials analyzed.

Table 2 shows absolute and relative risk by indication for all evaluated AEDs.

Table 2 Risk by indication for antiepileptic drugs in the pooled analysis

Indication

Placebo Patients

with Events Per

1,000 Patients

Drug Patients

with Events Per

1,000 Patients

Relative Risk:

Incidence of Events in

Drug Patients/Incidence

in Placebo Patients

Risk Difference:

Additional Drug

Patients with

Events Per 1,000

Patients

Epilepsy

Psychiatric

Other

Total

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

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

epilepsy and psychiatric indications.

Anyone considering prescribing divalproex sodium extended-release tablets or any other AED must

balance the risk of suicidal thoughts or behavior with the risk of untreated illness. Epilepsy and many

other illnesses for which AEDs are prescribed are themselves associated with morbidity and mortality

and an increased risk of suicidal thoughts and behavior. Should suicidal thoughts and behavior emerge

during treatment, the prescriber needs to consider whether the emergence of these symptoms in any

given patient may be related to the illness being treated.

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

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

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

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

immediately to healthcare providers.

5.8 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 tablets 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 tablets in the

treatment of manic episodes associated with bipolar disorder.

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

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

than the placebo incidence.

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

Treated Patients During Placebo-Controlled Trials of Acute Mania

Adverse Event

Divalproex Sodium Extended-release

Tablets

(n=338)

Placebo

(n=263)

Somnolence

Dyspepsia

Nausea

Vomiting

Diarrhea

Dizziness

Pain

Abdominal pain

Accidental injury

Asthenia

Pharyngitis

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

extended-release tablets-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.

Musculoskeletal System:

Arthrosis, Myalgia.

*

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

sodium extended-release tablets: headache

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 tablets 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 tablets-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 tablets-treated patients and for which the incidence was greater than in the placebo

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

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

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

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

antiepilepsy drugs.

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

Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures

Body System/Event

Divalproex Sodium Delayed-release

Tablets (%)

Placebo (%)

(n = 77)

(n = 70)

Body as a Whole

Headache

Asthenia

Fever

Gastrointestinal System

Nausea

Vomiting

Abdominal pain

Diarrhea

Anorexia

Dyspepsia

Constipation

Nervous System

Somnolence

Tremor

Dizziness

Diplopia

Amblyopia/Blurred Vision

Ataxia

Nystagmus

Emotional Lability

Thinking Abnormal

Amnesia

Respiratory System

Flu Syndrome

Infection

Bronchitis

Rhinitis

Other

Alopecia

Weight Loss

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

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

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

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

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

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

antiepilepsy drugs.

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

Controlled Trial of Valproate Monotherapy for Complex Partial Seizures

Body System/Event

High Dose (%)

Low Dose (%)

(n = 131)

(n = 134)

Body as a Whole

Asthenia

Digestive System

Nausea

Diarrhea

Vomiting

Abdominal pain

Anorexia

Dyspepsia

Hemic/Lymphatic System

Thrombocytopenia

Ecchymosis

Metabolic/Nutritional

Weight Gain

Peripheral Edema

Nervous System

Tremor

Somnolence

Dizziness

Insomnia

*

Nervousness

Amnesia

Nystagmus

Depression

Respiratory System

Infection

Pharyngitis

Dyspnea

Skin and Appendages

Alopecia

Special Senses

Amblyopia/Blurred Vision

Tinnitus

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

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.

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

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

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

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

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

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

was greater than that for placebo patients.

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

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

Patients Taking Placebo

Body System Event

Divalproex Sodium Extended-release

Tablets

Placebo

(N=122)

(N=115)

Gastrointestinal System

Nausea

Dyspepsia

Diarrhea

Vomiting

Abdominal Pain

Nervous System

Somnolence

Other

Infection

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

divalproex sodium extended-release tablets-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:

T innitus.

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

*

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

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

asthenia and flu syndrome.

placebo patients.

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

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

Body System Reaction

Divalproex Sodium Delayed-release

Tablets

Placebo

(n=202)

(n=81)

Gastrointestinal System

Nausea

Dyspepsia

Diarrhea

Vomiting

Abdominal pain

Increased appetite

Nervous System

Asthenia

Somnolence

Dizziness

Tremor

Other

Weight gain

Back pain

Alopecia

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

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

Body as a Whole:

Chest pain.

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:

*

The following adverse reactions occurred in greater than 5% of divalproex sodium delayed-release tablets-

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

syndrome and pharyngitis.

Pruritus.

Urogenital System:

Metrorrhagia.

6.4 Postmarketing Experience

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

delayed-release tablets. Because these reactions are reported voluntarily from a population of uncertain

size, it is not always possible to reliably estimate their frequency or establish a causal relationship to

drug exposure.

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 Coadministered 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 coadministration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to

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

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

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

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

the presence of aspirin. Whether or not the interaction observed in this study applies to adults is

unknown, but caution should be observed if valproate and aspirin are to be coadministered.

Carbapenem Antibiotics

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

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

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

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

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

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

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 coadministration 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 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 coadministered with rifampin.

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

Antacids

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

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

of valproate.

Chlorpromazine

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

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

valproate.

Haloperidol

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

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

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

7.2 Effects of Valproate on Other Drugs

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

glucuronosyltransferases.

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

coadministration on the pharmacokinetics or pharmacodynamics of several commonly prescribed

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

Drugs for which a potentially important valproate interaction has been observed

Amitriptyline/Nortriptyline

Administration of a single oral 50 mg dose of amitriptyline to 15 normal volunteers (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 coadministration of valproate and CBZ to epileptic patients.

Clonazepam

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

absence type seizures.

Diazepam

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

Coadministration of valproate (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 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.

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 coadministration (a 165% increase). The dose of lamotrigine should

be reduced when coadministered with valproate. Serious skin reactions (such as Stevens-Johnson

syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and

valproate administration. See lamotrigine package insert for details on lamotrigine dosing with

concomitant valproate administration.

Phenobarbital

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

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

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

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

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

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

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

possible, and the barbiturate dosage decreased, if appropriate.

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

Phenytoin

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

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

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

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

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

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

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

clinical situation.

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 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 coadministered with

clozapine.

Lithium

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

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

Lorazepam

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

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

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 tablets, during pregnancy.

Encourage women who are taking divalproex sodium extended-release tablets 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/.

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 9-11% 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. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy

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

and phenytoin (108 [95% C.I. 104–112]). 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]: 1.7-4.9) 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%-7.5%) in valproate-exposed

children and 1.5% (95% CI: 1.5%-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 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 and any potential adverse effects on the breastfed child from

divalproex sodium 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, Warnings and Precautions ( 5.1)]. When divalproex sodium extended-release tablets

are used in this patient group, it should be used with extreme caution and as a sole agent. The benefits

of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has

indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older

patient groups.

Younger children, especially those receiving enzyme inducing drugs, will require larger maintenance

doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3

months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults.

Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid

concentration. Interpretation of valproic acid concentrations in children should include consideration of

factors that affect hepatic metabolism and protein binding.

Pediatric Clinical Trials

Divalproex sodium 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 tablets for the indications of mania (150 patients aged 10 to 17

years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients

aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). Efficacy was

not established for either the treatment of migraine or the treatment of mania. The most common drug-

related adverse reactions (reported > 5% and twice the rate of placebo) reported in the controlled

pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and

rash.

The remaining five trials were long term safety studies. Two six month pediatric studies were

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

indication of mania (292 patients aged 10 to 17 years). Two 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 Capsules (Sprinkle) 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 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 over dosage. Because

naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with

caution in patients with epilepsy.

11. DESCRIPTION

Divalproex sodium is a stable coordination compound comprised of sodium valproate and valproic acid

in a 1:1 molar relationship. 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.

Each divalproex sodium extended-release tablet, USP intended for oral administration contains 250 mg

or 500 mg of divalproex sodium equivalent to 250 mg or 500 mg of valproic acid. In addition, each

tablet contains the following inactive ingredients: hydroxypropyl cellulose, hypromellose, lecithin,

magnesium stearate, polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), silicon dioxide, talc,

titanium dioxide and xanthan gum. Each tablet is imprinted with black pharmaceutical ink which contains:

ammonium hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol and

shellac.

The Product meets USP Dissolution Test 8.

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 to 100 mcg/mL of total valproate,

although some patients may be controlled with lower or higher plasma concentrations.

Mania

In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough

plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration ( 2.1)].

12.3 Pharmacokinetics

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 tablets

is less than that of divalproex sodium delayed-release tablets. In five multiple-dose studies in healthy

subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and nonfasting

conditions, divalproex sodium extended-release tablets given once daily produced an average

bioavailability of 89% relative to an equal total daily dose of divalproex sodium delayed-release

tablets given BID, TID, or QID. The median time to maximum plasma valproate concentrations (C

after divalproex sodium extended-release tablets administration ranged from 4 to 17 hours. After

multiple once-daily dosing of divalproex sodium extended-release tablets, the peak-to-trough

fluctuation in plasma valproate concentrations was 10 to 20% lower than that of regular divalproex

sodium delayed-release tablets given BID, TID, or QID.

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

release Tablets

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

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

randomized, crossover studies, multiple daily doses of divalproex sodium delayed-release tablets were

compared to 8 to 20% higher once-daily doses of divalproex sodium extended-release tablets. In these

two studies, divalproex sodium extended-release tablets and divalproex sodium delayed-release tablets

regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of

bioavailability). Additionally, valproate C

was lower, and C

was either higher or not different,

for divalproex sodium extended-release tablets relative to divalproex sodium delayed-release tablets

regimens (see Table 8).

Table 8 Bioavailability of Divalproex Sodium Extended-release Tablets Relative to Divalproex

Sodium Delayed-release Tablets When Divalproex Sodium Extended-release Tablets Dose is 8 to

20% Higher

Study Population

Regimens

Relative Bioavailability

Divalproex Sodium Extended-release Tablets

vs.

Divalproex Sodium Delayed-release Tablets

AUC

C

C

Healthy Volunteers

(N=35)

1,000 & 1,500 mg Divalproex Sodium

Extended-release Tablets

875 & 1,250 mg Divalproex Sodium Delayed-

release Tablets

1.059

0.882

1.173

Patients with epilepsy on

concomitant enzyme-

inducing antiepilepsy

drugs

(N=64)

1,000 to 5,000 mg Divalproex Sodium

Extended- release Tablets

875 to 4,250 mg Divalproex Sodium Delayed-

release Tablets

1.008

0.899

1.022

Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine

were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate

bioavailability when converting between divalproex sodium delayed-release tablets and divalproex

sodium extended-release tablets.

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

24

max

min

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 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

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

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

mg. Once daily administration of divalproex sodium extended-release tablets in pediatric patients (10 to

17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in

adults.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be

reduced compared to younger adults (age range: 22 to 26 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 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 equal 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 tablets for the treatment of acute mania is

based in part on studies establishing the effectiveness of divalproex sodium delayed-release tablets for

this indication. Divalproex sodium extended-release tablet's effectiveness was confirmed in one

randomized, double-blind, placebo-controlled, parallel group, 3 week, multicenter study. The study was

designed to evaluate the safety and efficacy of divalproex sodium extended-release tablets in the

treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a

current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were

hospitalized for acute mania, were enrolled into this study. Divalproex sodium extended-release tablets

were initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then

adjusted to achieve plasma valproate concentrations in the range of 85 to 125 mcg/mL. Mean daily

divalproex sodium extended-release tablets 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 tablets were significantly more effective than placebo in reduction

of the MRS total score.

14.2 Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in

isolation or in association with other seizure types was established in two controlled trials.

In one, 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 tablets or placebo. Randomized

patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 9 Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks

Add on Treatment

Number of Patients

Bas eline

Incidence

Experimental

Incidence

Divalproex Sodium Delayed-release

Tablets

Placebo

14.5

11.5

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an

effective treatment is shifted to the left of the curve for placebo. This Figure shows that the proportion

of patients achieving any particular level of improvement was consistently higher for valproate than for

placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial

seizure rate compared to 23% of patients treated with placebo.

Figure 1

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

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

tablets monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123

mcg/mL in the low dose and high dose groups, respectively.

The following Table presents the findings for all patients randomized who had at least one post-

randomization assessment.

Table 10 Monotherapy Study Median Incidence of CPS per 8 Weeks

Treatment

Number of Patients

Baseline Incidence

Randomized Phase

Incidence

High dose Valproate

13.2

10.7

Low dose Valproate

14.2

13.8

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in

complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy

study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency),

while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a

more effective treatment is shifted to the left of the curve for a less effective treatment. This Figure

shows that the proportion of patients achieving any particular level of reduction was consistently higher

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

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

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 tablets in the prophylactic

treatment of migraine headache. This trial recruited patients with a history of migraine headaches with

or without aura occurring on average twice or more a month for the preceding three months. Patients

with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed

in the trial if they were deemed to be practicing an effective method of contraception.

Patients who experienced ≥ 2 migraine headaches in the 4 week baseline period were randomized in a

1:1 ratio to divalproex sodium extended-release tablets or placebo and treated for 12 weeks. Patients

initiated treatment on 500 mg once daily for one week, and were then increased to 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 tablets-

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 tablets (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 tablets group, versus 0.6 from a baseline mean of 4.2 in

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

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,

capsule-shaped, biconvex, film-coated tablets imprinted with "ZA47" on one side and the other side

plain and are supplied as follows:

Unit dose packages of 100 (10 x 10) NDC 68084-310-01

Divalproex Sodium Extended-release Tablets USP, 500 mg are available as white to off-white,

capsule-shaped, biconvex, film-coated tablets imprinted with "ZA48" on one side and the other side

plain and are supplied as follows:

Unit dose packages of 100 (10 x 10) NDC 68084-415-01

Storage

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

FOR YOUR PROTECTION: Do not use if blister is torn or broken.

Maalox

is the registered trademark of Novartis Consumer Health.

Trisogel

is the registered trademark of Eli Lilly Corporation.

Titralac

is the registered trademark of 3M Pharmaceuticals

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 tablets 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 tablets, 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)].

PACKAGING INFORMATION

American Health Packaging unit dose blisters (see How Supplied section) contain drug product from

BluePoint Laboratories as follows:

(250 mg / 100 UD) NDC 68084-310-01 packaged from NDC 68001-105

(500 mg / 100 UD) NDC 68084-415-01 packaged from NDC 68001-106

Distributed by:

American Health Packaging

Columbus, OH 43217

8231001/0919

MEDICATION GUIDE

8231001/0919

Divalproex Sodium (dye val PRO ex sew dee uhm)

Extended-release Tablets, USP

Read this Medication Guide before you start taking divalproex sodium 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?

Do not stop taking divalproex sodium without first talking to your healthcare provider.

Stopping divalproex sodium suddenly can cause serious problems.

Divalproex sodium 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 may harm your unborn baby.

If you take divalproex sodium 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 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 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. If the

decision is made to use divalproex sodium, you should use effective birth control

(contraception).

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

You and your healthcare provider should decide if you will continue to take divalproex sodium

while you are pregnant.

Pregnancy Registry : If you become pregnant while taking divalproex sodium, 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 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 without first talking to a healthcare provider. Stopping divalproex

sodium 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 is divalproex sodium?

Divalproex sodium come in different dosage forms with different usages.

Divalproex sodium extended-release tablets are prescription medicines used:

to treat manic episodes associated with bipolar disorder.

alone or with other medicines to treat:

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

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

to prevent migraine headaches

Who should not take divalproex sodium?

Do not take divalproex sodium 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. See the end of this leaflet for a complete list of ingredients in divalproex

sodium.

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?

Before you take divalproex sodium, 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.

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

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

of time.

Taking divalproex sodium 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?

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

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

Your healthcare provider may change your dose.

Do not change your dose of divalproex sodium without talking to your healthcare provider.

Do not stop taking divalproex sodium without first talking to your healthcare provider.

Stopping divalproex sodium suddenly can cause serious problems.

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

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

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

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

Center right away.

What should I avoid while taking divalproex sodium?

Divalproex sodium can cause drowsiness and dizziness. Do not drink alcohol or take other

medicines that make you sleepy or dizzy while taking divalproex sodium, until you talk with your

doctor. Taking divalproex sodium 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 affects

you. Divalproex sodium can slow your thinking and motor skills.

What are the possible side effects of divalproex sodium?

See "What is the most important information I should know about divalproex sodium?"

Divalproex sodium 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.

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

The common side effects of divalproex sodium 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. 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?

Store divalproex sodium extended-release tablets at 20° to 25°C (68° to 77°F) [See USP Controlled

Room Temperature].

Keep divalproex sodium and all medicines out of the reach of children.

General information about the safe and effective use of divalproex sodium

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

use divalproex sodium for a condition for which it was not prescribed. Do not give divalproex sodium

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. If you

would like more information, talk with your healthcare provider. You can ask your pharmacist or

healthcare provider for information about divalproex sodium that is written for health professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

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

Active ingredient: divalproex sodium, USP

Inactive ingredients: hydroxypropyl cellulose, hypromellose, lecithin, magnesium stearate,

polyethylene glycol, polyvinyl alcohol (partially hydrolyzed), silicon dioxide, talc, titanium dioxide and

xanthan gum. Each tablet is imprinted with black pharmaceutical ink which contains: ammonium

hydroxide, ferrosoferric oxide, isopropyl alcohol, n-butyl alcohol, propylene glycol and shellac.

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

The product's labeling may have been updated. For latest package insert, please call American Health

Packaging at 1-800-707-4621.

Distributed by:

American Health Packaging

Columbus, OH 43217

8231001/0919

Package/Label Display Panel – Carton – 250 mg

NDC 68084- 310-01

Once-Daily Dosing

Divalproex Sodium

Extended-release Tablets, USP

250 mg*

(Valproic Acid Activity)

100 Tablets (10 x 10)

Rx Only

PHARMACIST: Dispense with the accompanying Medication

Guide to each patient.

*Each Tablet Contains:

Divalproex sodium, USP equivalent to valproic acid 250 mg

Usual Dosage: See package insert for full prescribing

information.

Store at 20º to 25ºC (68º to 77ºF); excursions permitted

between 15º to 30ºC (59º to 86ºF) [see USP Controlled

Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or

broken.

The drug product contained in this package is from

NDC # 68001-105, BluePoint Laboratories.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

031001

0231001/0918A

Package/Label Display Panel – Blister – 250 mg

Once-Daily Dosing

Divalproex Sodium Extended-

release Tablet, USP

250 mg

Package/Label Display Panel – Carton – 500 mg

NDC 68084- 415-01

Once-Daily Dosing

Divalproex Sodium

Extended-release Tablets, USP

500 mg*

(Valproic Acid Activity)

100 Tablets (10 x 10)

Rx Only

PHARMACIST: Dispense with the accompanying Medication

Guide to each patient.

*Each Tablet Contains:

Divalproex sodium, USP equivalent to valproic acid 500 mg

Usual Dosage: See package insert for full prescribing

information.

Store at 20º to 25ºC (68º to 77ºF); excursions permitted

between 15º to 30ºC (59º to 86ºF) [see USP Controlled

Room Temperature].

Keep this and all drugs out of reach of children.

FOR YOUR PROTECTION: Do not use if blister is torn or

broken.

The drug product contained in this package is from

NDC # 68001-106, BluePoint Laboratories.

Packaged and Distributed by:

American Health Packaging

Columbus, Ohio 43217

041501

0241501/0918A

Package/Label Display Panel – Blister – 500 mg

Once-Daily Dosing

Divalproex Sodium Extended-

release Tablet, USP

500 mg

DIVALPROEX SODIUM

divalproex sodium tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 8 4-310 (NDC:6 8 0 0 1-10 5)

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

250 mg

Inactive Ingredients

Ingredient Name

Stre ng th

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

LECITHIN, SO YBEAN (UNII: 1DI56 QDM6 2)

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

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

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

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

XANTHAN GUM (UNII: TTV12P4NEE)

AMMO NIA (UNII: 5138 Q19 F1X)

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

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

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

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

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

white (WHITE TO OFF-WHITE)

S core

no sco re

S hap e

CAPSULE (CAPSULE)

S iz e

18 mm

Flavor

Imprint Code

ZA47

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 8 4-310 -0 1 10 0 in 1 BOX, UNIT-DOSE

11/15/20 13

1

NDC:6 8 0 8 4-310 -11

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 239

11/15/20 13

DIVALPROEX SODIUM

divalproex sodium tablet, film coated, extended release

Product Information

Product T ype

HUMAN PRESCRIPTION DRUG

Ite m Code (Source )

NDC:6 8 0 8 4-415(NDC:6 8 0 0 1-10 6 )

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

HYDRO XYPRO PYL CELLULO SE ( 16 0 0 0 0 0 WAMW) (UNII: RFW2ET6 71P)

HYPRO MELLO SE, UNSPECIFIED (UNII: 3NXW29 V3WO)

LECITHIN, SO YBEAN (UNII: 1DI56 QDM6 2)

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

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

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

SILICO N DIO XIDE (UNII: ETJ7Z6 XBU4)

TALC (UNII: 7SEV7J4R1U)

TITANIUM DIO XIDE (UNII: 15FIX9 V2JP)

XANTHAN GUM (UNII: TTV12P4NEE)

AMMO NIA (UNII: 5138 Q19 F1X)

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

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

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

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

SHELLAC (UNII: 46 N10 7B71O)

Product Characteristics

Color

white (WHITE TO OFF-WHITE)

S core

no sco re

S hap e

CAPSULE (CAPSULE)

S iz e

23mm

Flavor

Imprint Code

ZA48

Contains

Packag ing

#

Item Code

Package Description

Marketing Start Date

Marketing End Date

1

NDC:6 8 0 8 4-415-0 1 10 0 in 1 BOX, UNIT-DOSE

11/14/20 13

1

NDC:6 8 0 8 4-415-11

1 in 1 BLISTER PACK; Type 0 : No t a Co mbinatio n Pro duct

American Health Packaging

Marketing Information

Marke ting Cate gory

Application Numbe r or Monograph Citation

Marke ting Start Date

Marke ting End Date

ANDA

ANDA0 78 239

11/14/20 13

Labeler -

American Health Packaging (929561009)

Establishment

Name

Ad d re s s

ID/FEI

Busine ss Ope rations

American Health Packaging

9 29 56 10 0 9

repack(6 8 0 8 4-310 , 6 8 0 8 4-415)

Revised: 11/2019

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