Divalproex Sodium Extended Release

REMEDYREPACK INC.

FULL PRESCRIBING INFORMATION: CONTENTS*

• BOXED WARNING
• INDICATIONS & USAGE
• DOSAGE & ADMINISTRATION
• DOSAGE FORMS & STRENGTHS
• DIVALPROEX SODIUM EXTENDED RELEASE CONTRAINDICATIONS
• WARNINGS AND PRECAUTIONS
• DIVALPROEX SODIUM EXTENDED RELEASE ADVERSE REACTIONS
• DRUG INTERACTIONS
• USE IN SPECIFIC POPULATIONS
• OVERDOSAGE
• DIVALPROEX SODIUM EXTENDED RELEASE DESCRIPTION
• CLINICAL PHARMACOLOGY
• NONCLINICAL TOXICOLOGY
• CLINICAL STUDIES
• HOW SUPPLIED
• INFORMATION FOR PATIENTS
• PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

FULL PRESCRIBING INFORMATION

INDICATIONS & USAGE

DOSAGE & ADMINISTRATION

DOSAGE FORMS & STRENGTHS

DIVALPROEX SODIUM EXTENDED RELEASE CONTRAINDICATIONS

• ?Divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [seeWarnings and Precautions (5.1)].

• ?Divalproex sodium extended-release tablets are contraindicated in patients with known hypersensitivity to the drug [seeWarnings and Precautions (5.10)].

• ?Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders [seeWarnings and Precautions (5.4)].

• ?

WARNINGS AND PRECAUTIONS

5.4 Urea Cycle Disorders
Contraindications (4) Warnings and Precautions (5.7)

5.5 Suicidal Behavior and Ideation





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





5.6 Thrombocytopenia



5.7 Hyperammonemia
Warnings and Precautions (5.9)Contraindications (4)Warnings and Precautions (5.45.8)



5.8 Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
Warnings and Precautions (5.9)Contraindications (4)Warnings and Precautions (5.7)

5.9 Hypothermia
Drug Interactions (7.3)

5.10 Multi-Organ Hypersensitivity Reactions


5.11 Interaction with Carbapenem Antibiotics
Drug Interactions (7.1)

5.12 Somnolence in the Elderly
Dosage and Administration (2.4)

5.13 Monitoring: Drug Plasma Concentration
Drug Interactions (7)

5.14 Effect on Ketone and Thyroid Function Tests



5.15 Effect on HIV and CMV Viruses Replication

DIVALPROEX SODIUM EXTENDED RELEASE ADVERSE REACTIONS

6 ADVERSE REACTIONS


6.1 Mania



*
Adverse EventDivalproex Sodium Extended-ReleasePlaceboTablets(N = 263)(N = 338)*














6.2 Epilepsy




Body System/EventDivalproex Sodium Delayed-Placebo (%)Release Tablets (%)(N = 70)(N = 77)Body as a WholeGastrointestinal SystemNervous SystemRespiratory SystemOther

*
Body System/EventHigh Dose (%)Low Dose (%)(N = 131)(N = 134)Body as a WholeDigestive SystemHemic/Lymphatic SystemMetabolic/NutritionalNervous SystemRespiratory SystemSkin and AppendagesAlopecia*















6.3 Migraine



*
Body System EventDivalproex Sodium Extended-releasePlaceboTablets(N = 115)(N = 122)Gastrointestinal SystemNervous SystemOther*











*
Body System ReactionDivalproex SodiumPlaceboDelayed-release Tablets(N = 81)(N = 202)Gastrointestinal SystemNervous SystemOther*













6.4 Other Patient Populations

Mania













Epilepsy


Gastrointestinal


CNS Effects
Warnings and Precautions (5.4)


Dermatologic
Drug Interactions (7)

Psychiatric


Musculoskeletal


Hematologic
Warnings and Precautions (5.6)Drug Interactions (7)

Hepatic
Warnings and Precautions (5.1)

Endocrine
Warnings and Precautions (5.13)


Pancreatic
Warnings and Precautions (5.3)

Metabolic
Warnings and Precautions (5.7)




Genitourinary


Special Senses


Other

DRUG INTERACTIONS

7 DRUG INTERACTIONS

7.1 Effects of Coadministered Drugs on Valproate Clearance





Drugs for Which a Potentially Important Interaction has Been Observed

Aspirin



Carbapenem Antibiotics
Warnings and Precautions (5.11)

Felbamate


Rifampin


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

Antacids


Chlorpromazine


Haloperidol


Cimetidine and Ranitidine


7.2 Effects of Valproate on Other Drugs



Drugs for Which a Potentially Important Valproate Interaction has Been Observed

Amitriptyline/Nortriptyline


Carbamazepine/carbamazepine-10,11-Epoxide


Clonazepam


Diazepam


Ethosuximide


Lamotrigine


Phenobarbital




Phenytoin



Tolbutamide


Warfarin


Zidovudine


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

Acetaminophen


Clozapine


Lithium


Lorazepam


Oral Contraceptive Steroids


7.3 Topiramate
Contraindications (4)Warnings and Precautions (5.75.8)Warnings and Precautions (5.75.9)

USE IN SPECIFIC POPULATIONS

8 USE IN SPECIFIC POPULATIONS

8.1 Pregnancy



Human Data



Neural Tube Defects




Other Adverse Pregnancy Effects
Warnings and Precautions (5.6)
Warnings and Precautions (5.1)

Animal Data




Registry


8.3 Nursing Mothers



8.4 Pediatric Use


Mania




Migraine Prophylaxis



Epilepsy


Pediatric Safety


Safety Studies-Mania

Safety Study-Controlled Mania Trial




Adverse Reaction- Preferred TermDivalproex Sodium Extended-release Tablets (N = 76)Placebo (N = 74)

Safety Study-Open-Label Mania Safety Data

Adverse Reactions (6.16.26.3)

Safety Studies-Epilepsy (Open-Label)


Safety Studies-Migraine (Controlled and Open-Label)


Prior Safety Experience
Boxed WarningWarnings and Precautions (5.1)




Nonclinical Developmental Toxicology


8.5 Geriatric Use


Warnings and Precautions (5.12)Dosage and Administration (2.4)

Clinical Pharmacology (12.3)

8.6 Effect of Disease

Liver Disease
Boxed WarningContraindications (4)Warnings and Precautions (5)Clinical Pharmacology (12.3)

OVERDOSAGE

10 OVERDOSAGE

DIVALPROEX SODIUM EXTENDED RELEASE DESCRIPTION

CLINICAL PHARMACOLOGY

12 CLINICAL PHARMACOLOGY

12.1 Mechanism of Action


12.2 Pharmacodynamics


Epilepsy


Mania
Dosage and Administration (2.1)

12.3 Pharmacokinetics

Absorption/Bioavailability



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


Table 9 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 PopulationRegimensRelativeBioavailablility

Distribution

Protein Binding
Drug Interactions (7)

CNS Distribution


Metabolism


Elimination



Special Populations

Effect of Age

Pediatric


Elderly
Dosage and Administration (2.4)

Effect of Sex


Effect of Race


Effect of Disease

Liver Disease
Boxed WarningContraindications (4)Warnings and Precautions (5.1)

Renal Disease

NONCLINICAL TOXICOLOGY

13 NONCLINICAL TOXICOLOGY

13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis


Mutagenesis


Fertility

CLINICAL STUDIES

14 CLINICAL STUDIES

14.1 Mania



14.2 Epilepsy




**









**






14.3 Migraine

HOW SUPPLIED

16 HOW SUPPLIED/STORAGE AND HANDLING

INFORMATION FOR PATIENTS

17 PATIENT COUNSELING INFORMATION
FDA-Approved Patient Labeling (17.8)

17.1 Hepatotoxicity
Warnings and Precautions (5.1)

17.2 Pancreatitis
Warnings and Precautions (5.3)

17.3 Teratogenicity/Usage in Pregnancy
Use in Specific Populations (8.1)
Use in Specific Populations (8.1)

17.4 Suicidal Thinking and Behavior
Warnings and Precautions (5.5)

17.5 Hyperammonemia
Warnings and Precautions (5.75.8)

17.6 CNS Depression


17.7 Multi-Organ Hypersensitivity Reaction
Warnings and Precautions (5.10)

17.8 FDA-Approved Patient Labeling

• ?You should take your medicine exactly as prescribed by your doctor to get the most benefit from your medicine and reduce the risk of side effects.

• ?If you have taken more than the prescribed dose, contact your hospital emergency room or local poison center immediately.

• ?Your medicine was prescribed for your particular condition. Do not use it for another condition or give the drug to others.

• ?Facts About Birth Defects

PACKAGE LABEL.PRINCIPAL DISPLAY PANEL SECTION

Divalproex Sodium Extended Release Divalproex Sodium Extended Release TABLET, EXTENDED RELEASE Product Information Product Type Human prescription drug label Item Code (Source) NDC:49349-226(NDC:0378-0473) Route of Administration ORAL DEA Schedule Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength Divalproex sodium valproic acid 500 mg Inactive Ingredients Ingredient Name Strength AMMONIA SILICON DIOXIDE DIBUTYL SEBACATE ETHYLCELLULOSES HYPROMELLOSES OLEIC ACID POLYDEXTROSE polyethylene glycol cellulose, microcrystalline titanium dioxide triacetin Product Characteristics Color Size Imprint Code Shape white 21 mm M;473 OVAL Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:49349-226-02 30 in 1 BLISTER PACK Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date ANDA ANDA077567 2011-05-06