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
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
| 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 |
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
| 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
5.7Hyperammonemia
5.8Hyperammonemia and Encephalopathy associated with Concomitant Topiramate Use
5.9Hypothermia
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
| 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% |
6.2 Epilepsy
| 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 |
| 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 |
6.3Migraine
| 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% |
| 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% |
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
8USE IN SPECIFIC POPULATIONS
8.1Pregnancy
8.3Nursing Mothers
8.4Pediatric Use
| Nausea | 9% | 1% |
| Upper abdominal Pain | 8% | 1% |
| Somnolence | 7% | 1% |
| Increased Ammonia | 5% | 0% |
| Gastritis | 5% | 0% |
| Rash | 5% | 1% |
8.5Geriatric Use
8.6Effect of 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:
12CLINICAL PHARMACOLOGY
12.1Mechanism of Action
12.2Pharmacodynamics
12.3Pharmacokinetics
| 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 |
13NONCLINICAL TOXICOLOGY
Enter section text here
13.1Carcinogenesis, Mutagenesis, Impairment of 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.
| Divalproex sodium delayed-release tablets | 75 | 16.0 | 8.9* |
| Placebo | 69 | 14.5 | 11.5 |
| High dose Valproate | 131 | 13.2 | 10.7* |
| Low dose Valproate | 134 | 14.2 | 13.8 |
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 Packof 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
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
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.
- 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.