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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 | DIVALPROEX SODIUM [WOCKHARDT LIMITED] | BioPortfolio

11:54 EST 27th January 2019 | BioPortfolio

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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.

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)].

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
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
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%
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
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%
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%
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%

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:

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

Enter section text here

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.

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
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

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 20-25C (68-77F) [see USP Controlled Room Temperature

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)].

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)].

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)].

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.

Manufacturer

WOCKHARDT LIMITED

Active Ingredients

Source

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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-...

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