DIVALPROEX SODIUM description, usages, side effects, indications, overdosage, supplying and lots more!

DIVALPROEX SODIUM

WOCKHARDT USA LLC

  • Description
  • Clinical Pharmacology
  • Indications & Usage
  • Contraindications
  • Warnings
  • Precautions
  • Side Effects
  • Overdosage
  • Dosage & Administration
  • How Supplied
  • Patient Counseling Information
  • Supplemental Patient Material
  • Boxed Warning
  • Patient Package Insert
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

BOXED WARNING

WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete boxed warning.

  • Hepatotoxicity, including fatalities, usually during first 6 months of treatment. Children under the age of two years are at considerably higher risk of fatal hepatotoxicity. Monitor patients closely, and perform liver function tests prior to therapy and at frequent intervals thereafter (5.1)
  • Teratogenicity, including neural tube defects (5.2)
  • Pancreatitis, including fatal hemorrhagic cases (5.3)

RECENT MAJOR CHANGES

Warnings and Precautions (5.5, 5.9, 5.11, 5.13, 5.14, 5.15) 3/2008
Pediatric Use (8.4) 3/2008

INDICATIONS AND USAGE

Divalproex sodium extended-release tablets are indicated for:

  • Acute treatment of manic or mixed episodes associated with bipolar disorder, with or without psychotic features (1.1)
  • Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures (1.2)
  • Prophylaxis of migraine headaches (1.3)

DOSAGE AND ADMINISTRATION

  • Divalproex sodium extended-release tablets are intended for once-a-day oral administration. Divalproex sodium extended-release tablets should be swallowed whole and should not be crushed or chewed.
  • 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 1000 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 hypersensitivity to the drug (4, 5.10)
  • Urea cycle disorders (4, 5.4)

WARNINGS AND PRECAUTIONS

  • Hepatotoxicity; monitor liver function tests (5.1)
  • Teratogenic effects; weigh divalproex sodium extended-release tablets benefits of use during pregnancy against risk to the fetus (5.2)
  • Pancreatitis; Divalproex sodium extended-release tablets should ordinarily be discontinued (5.3)
  • Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium extended-release tablets, increase the risk of suicidal thoughts or behavior (5.5)
  • Thrombocytopenia; monitor platelet counts and coagulation tests (5.6)
  • 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 (5.4, 5.7, 5.8)
  • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate (5.9)
  • Multi-organ hypersensitivity reaction; discontinue divalproex sodium extended-release tablets (5.10)
  • 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 (5.12)

Side Effects

  • Most common adverse reactions (reported >5%) reported in adult studies are nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, ambylopia/blurred, ataxia, nystagmus, emotional lability, thinking abnormal, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus (6.1, 6.2, 6.3, 6.4).
  • Most common, drug-related adverse reactions (reported >5% and twice the rate of placebo) reported in the controlled pediatric mania study are nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.

To report SUSPECTED ADVERSE REACTIONS, contact Wockhardt USA LLC., at 1-800-346-6854 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

DRUG INTERACTIONS

  • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dose adjustment is indicated whenever enzyme inducing or inhibiting drugs are introduced or withdrawn (7.1)
  • Aspirin, carbapenem antibiotics: Monitoring of valproate concentrations are recommended (7.1)
  • Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement (7.2)
  • Dosage adjustment of amitryptyline/nortryptyline, warfarin, and zidovudine may be necessary if used concomitantly with divalproex sodium extended-release tablets (7.2)
  • Topiramate: Hyperammonemia and encephalopathy (5.8, 7.3)

USE IN SPECIFIC POPULATIONS

  • Pregnancy: Divalproex sodium extended-release tablets can cause congenital malformations including neural tube defects (5.2, 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 (5.12, 8.5)

FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

BOXED WARNING

WARNING: LIFE THREATENING ADVERSE REACTIONS
Hepatotoxicity
Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid and its derivatives. 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.

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. Liver function tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions (5.1)].

Teratogenicity
Valproate can produce teratogenic effects such as neural tube defects (e.g., spina bifida). Accordingly, the use of divalproex sodium extended-release tablets in women of childbearing potential requires that the benefits of its use be weighed against the risk of injury to the fetus. This is especially important when the treatment of a spontaneously reversible condition not ordinarily associated with permanent injury or risk of death (e.g., migraine) is contemplated [see Warnings and Precautions (5.2)].

An information sheet describing the teratogenic potential of valproate is available for patients [see Patient Counseling Information (17.8)].

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 (5.3)].

RECENT MAJOR CHANGES

1INDICATIONS AND USAGE

1.1Mania






1.2Epilepsy

Divalproex sodium extended-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium extended-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.
Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

1.3Migraine

Divalproex sodium extended-release tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium extended-release tablets are useful in the acute treatment of migraine headaches. Because it may be a hazard to the fetus, divalproex sodium extended-release tablets should be considered for women of childbearing potential only after this risk has been thoroughly discussed with the patient and weighed against the potential benefits of treatment [see Warnings and Precautions (5.2), Patient Counseling Information (17.3)].

2DOSAGE AND ADMINISTRATION

2.1Mania




2.2Epilepsy




















2.3Migraine


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



Table 1: Dose Conversion
Divalproex Sodium Delayed-Release Tablets Total Daily Dose (mg)
Divalproex Sodium Extended-Release Tablets (mg)
500*-625
750
750*-875
1000
1000*-1125
1250
1250-1375
1500
1500-1625
1750
1750
2000
1875-2000
2250
1225-2250
2500
2375
2750
2500-2750
3000
2875
3250
3000-3125 3500

min

2.5General Dosing Advice




>>



3DOSAGE FORMS AND STRENGTHS










4CONTRAINDICATIONS

  • Divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)].
  • Divalproex sodium extended-release tablets are contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.10)].
  • Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.4)].

5WARNINGS AND PRECAUTIONS

5.1Hepatotoxicity





5.2Teratogenicity/Usage in Pregnancy




5.3Pancreatitis

5.4Urea Cycle Disorders

5.5Suicidal Behavior and Ideation









Table 2. Risk by Indication for Antiepileptic Drugs in the Pooled Analysis
Indication
Placebo Patients with Events
Per 1000 Patients
Drug Patients with Events
Per 1000 Patients
Relative Risk: Incidence of Events
in Drug Patients/Incidence in
Placebo Patients

Risk Difference: Additional Drug Patients  with Events
Per 1000 Patients

Epilepsy
1.0
3.4
3.5
2.4
Psychiatric
5.7
8.5
1.5
2.9
Other
1.0
1.8
1.9
0.9
Total
2.4
4.3
1.8
1.9





5.6Thrombocytopenia

9

5.7Hyperammonemia




5.8Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use

5.9Hypothermia

00

5.10Multi-Organ Hypersensitivity Reactions

5.11Interaction with Carbapenem Antibiotics

5.12Somnolence in the Elderly

5.13Monitoring: Drug Plasma Concentration


5.14Effect on Ketone and Thyroid function Tests


5.15Effect on HIV and CMV Viruses Replication


6ADVERSE REACTIONS


6.1Mania




Table 3: Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release Tablets-Treated Patients During Placebo-Controlled Trials of Acute Mania1
Adverse Event
Divalproex Sodium Extended-Release Tablets (n=338)
Placebo (n=263)
Somnolence
26%
14%
Dyspepsia
23% 11%
Nausea
19% 13%
Vomiting
13% 5%
Diarrhea
12% 8%
Dizziness
12% 7%
Pain
11% 10%
Abdominal Pain
10% 5%
Accidental injury
6% 5%
Asthenia
6% 5%
Pharyngitis
6% 5%
1















6.2 Epilepsy




Table 4: Adverse reactions Reported by > 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures
Body System/Event
Divalproex Sodium Delayed-Release
Tablets (%)
(n=77)
Placebo (%)
(n=70)
Body as a Whole

  Headache
31
21
  Asthenia
27
7
  Fever
6
4
Gastrointestinal System

  Nausea
48
14
  Vomiting
27
7
  Abdominal pain
23
6
  Diarrhea
13
6
  Anorexia
12
0
  Dyspepsia
8
4
  Constipation
5
1
Nervous System

  Somnolence
27
11
  Tremor
25
6
  Dizziness
25
13
  Diplopia
16
9
  Amblyopia/Blurred Vision
12
9
  Ataxia
8
1
  Nystagmus 8
1
  Emotional Lability 6
4
  Thinking Abnormal
6
0
  Amnesia
5
1
Respiratory System

  Flu Syndrome
12 9
  Infection
12
6
  Bronchitis
5
1
  Rhinitis
5
4
Other

  Alopecia
6
1
  Weight Loss
6
0


Table 5: Adverse reactions Reported by > 5% of Patients in the High Dose Group in the Controlled Trial of Valproate Monotherapy for Complex Partial Seizures1
Body System/Events High Dose (%)
(n=131)
Low Dose (%)
(n=134)
Body as a Whole

  Asthenia
21
10
Digestive System

  Nausea
34
26
  Diarrhea
23
19
  Vomiting
23
15
  Abdominal pain
12
9
  Anorexia
11
4
  Dyspepsia
11
10
Hemic/Lymphatic System

  Thrombocytopenia
24
1
  Ecchymosis
5
4
Metabolic/Nutritional

  Weight Gain
9
4
  Peripheral Edema
8
3
Nervous System

  Tremor
57
19
  Somnolence
30
18
  Dizziness
18
13
  Insomnia
15
9
  Nervousnes
11
7
  Amnesia
7
4
  Nystagmus
7
1
  Depression
5
4
Respiratory System

  Infection
20
13
  Pharynigits
8
2
  Dyspnea
5
1
Skin and Appendages

  Alopecia 24
13
Special Senses

  Amblyopia/Blurred Vision
8
4
  Tinnitus
7
1
1



















6.3Migraine





Table 6: Adverse Reactions Reported by > 5% of Divalproex Sodium Extended- Release Tablet-Treated Patients During the Migraine Placebo-controlled Trial with a Greater Incidence than Patients Taking Placebo1
Body System Event
Divalproex Sodium Extended- Release
(n=122)
Placebo
(n=115)
Gastrointestinal System

  Nausea
15%
9%
  Dyspepsia
7% 4%
  Diarrhea
7% 3%
  Vomiting
7% 2%
  Abdominal pain
7% 5%
Nervous System

  Somnolence
7% 2%
Other

  Infection
15% 14%
1












Table 7: Adverse Reactions Reported by > 5% of Valproate-Treated Patients During Migraine Placebo Controlled Trials with a Greater Incidence than Patients Taking Placebo1
Body System
Reaction
Divalproex Sodium Delayed-Release Tablets
(n=202)
Placebo
(n=81)
Gastrointestinal System

  Nausea
31%
10%
  Dyspepsia
13% 9%
  Diarrhea
12% 7%
  Vomiting
11% 1%
  Abdominal pain
9% 4%
  Increased appetite
6% 4%
Nervous System

  Asthenia
20% 9%
  Somnolence
17% 5%
  Dizziness
12% 6%
  Tremor
9% 0%
Other

  Weight gain
8% 2%
  Back pain
8% 6%
  Alopecia
7% 1%
1










6.4Other Patient Populations






























































7DRUG INTERACTIONS

7.1Effects of Co-Administered Drugs on Valproate Clearance Valproate Clearance
































7.2Effects of Valproate on Other Drugs

























































7.3Topiramate

Concomitant administration of topiramate with valproic acid 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 (5.7, 5.9)].

8USE IN SPECIFIC POPULATIONS

8.1Pregnancy





















22
22



8.3Nursing Mothers

8.4Pediatric Use


Mania





Migraine Prophylaxis




Epilepsy


Pediatric Safety


Safety Studies-Mania





Table 8: Common, Drug-Related Adverse Reactions reported by > 5% of Divalproex Sodium Extended-Release Tablet-Treated Patients during Placebo Controlled Trials for Pediatric Acute Mania
Adverse reaction- prefered term
Divalproex sodium Extended-Release Tablets
(n=76)
Placebo
(n=74)
Nausea
                                                    9%
        1%
Upper abdominal Pain
                                                    8%
        1%
Somnolence
                                                    7%
        1%
Increased Ammonia
                                                    5%
        0%
Gastritis
                                                    5%
         0%
Rash
                                                    5%
         1%


Safety Study-Open Label Mania Safety Data



Safety Study-Epilepsy (open label)


Safety Studies-Migraine (controlled and open label)


Prior Safety Experience





Nonclinical Developmental Toxicology


8.5Geriatric Use





8.6Effect of Disease

Liver Disease


10OVERDOSAGE



11DESCRIPTION


Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. 

Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:
11DESCRIPTION








12CLINICAL PHARMACOLOGY


12.1Mechanism of Action



12.2Pharmacodynamics







12.3Pharmacokinetics

Absorption/Bioavailability


max


maxmin
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
Population

Regimens
   Relative Bioavailability

Divalproex Sodium Extended-Release Tablets
vs.
Divalproex Sodium Delayed-Release Tablets

AUC24
Cmax
Cmin
Healthy Volunteers (N=35)
1000 and 1500 mgDivalproex sodium extended-release
 tablets vs
 875 and 1250 mg Divalproex sodium delayed-release
 tablets

1.059
0.882
1.173
Patients with epilepsy on concomitant
enzyme-inducing antiepilepsy drugs
(N = 64)
1000 and 5000 mgDivalproex sodium extended-release
 tablets vs
 875 and 4250 mg Divalproex sodium delayed-release
 tablets
1.008
0.899
1.022



Distribution






Metabolism




Elimination
22
22


Special Populations







2











13NONCLINICAL TOXICOLOGY

Enter section text here

13.1Carcinogenesis, Mutagenesis, Impairment of Fertility

Carcinogenesis


Mutagenesis


Fertility


CLINICAL STUDIES


14.1Mania

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 tablets 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 was initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the range of 85-125 mcg/mL. Mean daily divalproex sodium delayed-release tablets doses for observed cases were 2362 mg (range: 500-4000), 2874 mg (range: 1500-4500), 2993 mg (range: 1500-4500), 3181 mg (range: 1500-5000), and 3353 mg (range: 1500-5500) 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 0-52).

Divalproex sodium extended-release tablets was significantly more effective than placebo in reduction of the MRS total score.

14.2Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials. In one, multiclinic, placebo controlled study employing an add-on design, (adjunctive therapy) 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the “therapeutic range” were randomized to receive, in addition to their original antiepilepsy drug (AED), either divalproex sodium delayed-release tablets or placebo. Randomized patients were to be followed for a total of 16 weeks. The following Table presents the findings.

Table 10: Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add on
Treatment

Number of
Patients
Baseline
Incidence
Experimental
Incidence

Divalproex sodium delayed-release tablets
              75
            16.0
                 8.9*
Placebo
             69
             14.5
                11.5



14.2Epilepsy


Table 11: Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment
Number of Patients   
Baseline
Incidence
Randomized Phase
Incidence
High dose Valproate
                               131
             13.2
                            10.7*
Low dose Valproate
                               134
             14.2
                            13.8




14.2Epilepsy


14.3Migraine








14.3Migraine

16HOW SUPPLIED/STORAGE AND HANDLING

Divalproex sodium extended-release 250 mg tablets are available as white, oval shaped film coated biconvex beveled edge tablets, debossed with W on one side and 724 on other side. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 250 mg of valproic acid in the following packaging sizes:
Bottles of 30          (NDC 64679-724-01)
Bottles of 100        (NDC 64679-724-02)
Bottles of 500        (NDC 64679-724-03)
Unit Dose Pack
 of 100 (10 x 10)     (NDC 64679-724-04)

Divalproex sodium extended-release 500 mg tablets are available as dark grey colored, oval shaped film coated biconvex tablets, debossed with W725 on one side and plain on other side. Each divalproex sodium extended-release tablet contains divalproex sodium equivalent to 500 mg of valproic acid in the following packaging sizes:
Bottles of 30          (NDC 64679-725-01)
Bottles of 100        (NDC 64679-725-02)
Bottles of 500        (NDC 64679-725-03)
Unit Dose Pack
of 100 (10x10)       (NDC 64679-725-04)

Recommended Storage
Store at 200-250C (680-770F) [see USP Controlled Room Temperature

17PATIENT COUNSELING INFORMATION

17.1Hepatotoxicity

Patients and guardians should be warned that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.1)].

17.2Pancreatitis

Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions (5.3)].

17.3Teratogenicity/Usage in Pregnancy





17.4Suicidal Thinking and Behavior

17.5Hyperammonemia



17.6CNS depression


17.7Multi-organ Hypersensitivity Reaction

Patients should be instructed 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 (5.10)].

17.8 FDA-Approved Patient Labeling

Important Information for Women Who Could Become Pregnant About the Use of divalproex sodium extended-release tablets.

Please read this leaflet carefully before you take any of this medication. This leaflet provides a summary of important information about taking this medication to women who could become pregnant. If you have any questions or concerns, or want more information about this medication, contact your doctor or pharmacist.

Information For Women Who Could Become Pregnant
You can only obtain this medication by prescription from your doctor. The decision to use this medicine should be made by you and your doctor based on your health needs and medical condition.
Before starting this medicine, you should know that using this medicine during pregnancy causes an increased chance of birth defects in your baby. These birth defects may include spina bifida and other defects where the spinal canal does not close normally. These defects usually occur in 1 to 2 out of every 1000 babies born in the United States. Studies show that for babies born to epileptic women who took valproate in the first 12 weeks of pregnancy, these defects occur in 1 to 2 out of every 100 babies.
Use of valproate during pregnancy also increases the chance of other birth defects such as of the heart, bones, and other parts of the body. Studies suggest that other medicines used to treat your condition may be less likely to cause these defects.

Information For Women Who Are Planning to Get Pregnant
Women using valproate who plan to get pregnant should discuss their treatment options with their doctor.

Information For Women Who Become Pregnant
If you become pregnant while taking valproate, you should contact your doctor immediately.

Other Important Information

  • 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
It is important to know that birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
This summary provides important information about the use of divalproex sodium extended-release tablets to women who could become pregnant. If you would like more information, ask your doctor or pharmacist to let you read the professional labeling and then discuss it with them. If you have any questions or concerns about taking this medication, you should discuss them with your doctor.

Manufactured by:
Wockhardt Limited,
Mumbai, India.

Distributed by:
Wockhardt USA LLC.
20 Waterview Blvd.
Parsippany, NJ 07054,
USA.


DIVALPROEX SODIUM

DIVALPROEX SODIUM TABLET, FILM COATED, EXTENDED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:64679-724
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Divalproex sodium valproic acid 250 mg

Product Characteristics

Color Size Imprint Code Shape
white (White) 15 mm W;724 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:64679-724-01 30 in 1 BOTTLE
2 NDC:64679-724-02 100 in 1 BOTTLE
3 NDC:64679-724-03 500 in 1 BOTTLE
4 10 in 1 BLISTER PACK
5 NDC:64679-724-04 10 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078705 2009-02-10


DIVALPROEX SODIUM

DIVALPROEX SODIUM TABLET, FILM COATED, EXTENDED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:64679-725
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Divalproex sodium valproic acid 500 mg

Product Characteristics

Color Size Imprint Code Shape
gray (Dark Gray) 19 mm W;725 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:64679-725-01 30 in 1 BOTTLE
2 NDC:64679-725-02 100 in 1 BOTTLE
3 NDC:64679-725-03 500 in 1 BOTTLE
4 10 in 1 BLISTER PACK
5 NDC:64679-725-04 10 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA078705 2009-08-04


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Be sure to consult your doctor before taking any medication!
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