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

DIVALPROEX SODIUM

Wockhardt Limited

Divalproex Sodium Delayed-Release Tablets, USP Rx only

FULL PRESCRIBING INFORMATION: CONTENTS*




FULL PRESCRIBING INFORMATION

BOX WARNING:


HEPATOTOXICITY:




TERATOGENICITY:


A PATIENT INFORMATION LEAFLET DESCRIBING THE TERATOGENIC POTENTIAL OF VALPROATE IS AVAILABLE FOR PATIENTS.

PANCREATITIS:
WARNINGS and PRECAUTIONS.

DESCRIPTION


DESCRIPTION

Divalproex sodium occurs as a white powder with a characteristic odor.

Divalproex sodium delayed-release tablets, USP are for oral administration. Divalproex sodium delayed-release tablets are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid.

Inactive Ingredients
Divalproex sodium delayed-release tablets: silicon dioxide, silicified microcrystalline cellulose, pregelatinized starch, povidone, croscarmellose sodium, glyceryl behenate, talc, hypromellose, polysorbate, simethicone emulsion, methacrylic acid copolymer, polyvinyl alcohol, titanium dioxide, polyethylene glycol, triethyl citrate, sodium bicarbonate, sodium lauryl sulfate.

CLINICAL PHARMACOLOGY


Pharmacodynamics

Pharmacokinetics




maxmaxmaxmax



DOSAGE AND ADMINISTRATION


Protein Binding
PRECAUTIONS - Drug Interactions

CNS Distribution








2222




Effect of Age







DOSAGE AND ADMINISTRATION

Effect of Gender
2

Effect of Race


Effect of Disease



BOXED WARNING, CONTRAINDICATIONS,WARNINGS









Epilepsy


Mania
DOSAGE AND ADMINISTRATION

Clinical Trials

Mania




Study 1
YMRS Total Score

1.   Mean score at baseline

2.   Change from baseline to Week 3 (LOCF)

3.   Difference in change from baseline to Week 3 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo

Group Baseline1 BL to Wk 32 Difference3
Placebo 28.8 + 0.2
Divalproex Sodium Delayed-Release Tablets 28.5 - 9.5 9.7
BPRS-A Total Score
Group Baseline1 BL to Wk 32 Difference3
Placebo 76.2 + 1.8
Divalproex Sodium Delayed-Release Tablets 76.4 -17.0 18.8
GAS Score
Group Baseline1 BL to Wk 32 Difference3
Placebo 31.8 0.0
Divalproex Sodium Delayed-Release Tablets 30.3 + 18.1 18.1



Study 2
MRS Total Score

1.   Mean score at baseline

2.   Change from baseline to Day 21 (LOCF)

3.   Difference in change from baseline to Day 21 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo and lithium and placebo

Group Baseline1 BL to Day 212 Difference3
Placebo 38.9 - 4.4
Lithium 37.9 -10.5 6.1
Divalproex Sodium Delayed-Release Tablets 38.1 - 9.5 5.1
MSS Total Score
Group Baseline1 BL to Day 212 Difference3
Placebo 18.9 - 2.5
Lithium 18.5 - 6.2 3.7
Divalproex Sodium Delayed-Release Tablets 18.9 - 6.0 3.5
BIS Total Score
Group Baseline1 BL to Day 212 Difference3
Placebo 16.4 - 1.4
Lithium 16.0 - 3.8 2.4
Divalproex Sodium Delayed-Release Tablets 15.7 - 3.2 1.8




Figure 1. Percentage of Patients Achieving ≥ 30% Reduction in Symptom Score From Baseline
Clinical Trials

Migraine

















Figure 2. Mean 4-week Migraine Rates
Migraine

1
2

Epilepsy




Adjunctive Therapy Study Median Incidence of CPS per 8 Weeks
Add-on
Treatment
Number
of Patients
Baseline
Incidence
Experimental
Incidence

*Reduction from baseline statistically significantly greater for divalproex sodium delayed-release tablets than placebo at p ≤ 0.05 level.

Divalproex Sodium Delayed-Release Tablets 75 16.0 8.9*
Placebo 69 14.5 11.5


Figure 3.
Migraine


Monotherapy Study Median Incidence of CPS per 8 Weeks
Treatment Number of
Patients
Baseline
Incidence
Randomized
Phase Incidence

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

High dose Divalproex Sodium Delayed-Release Tablets 131 13.2 10.7*
Low dose Divalproex Sodium Delayed-Release Tablets 134 14.2 13.8


Figure 4.

Migraine

INDICATIONS AND USAGE

Mania


Clinical TrialsCLINICAL PHARMACOLOGY



Epilepsy




Migraine

WARNINGS - Usage In Pregnancy, PRECAUTIONS - Information for Patients

WARNINGS

CONTRAINDICATIONS





WARNINGS

WARNINGS


Hepatotoxicity

Hepatic failure resulting in fatalities has occurred in patients receiving valproic acid. 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. 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 divalproex sodium delayed-release tablets 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. 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 delayed-release tablet is 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 this age group, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

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.

Pancreatitis

BOXED WARNING

Urea Cycle Disorders (UCD)

CONTRAINDICATIONSPRECAUTIONS

Usage In Pregnancy

VALPROATE CAN PRODUCE TERATOGENIC EFFECTS. DATA SUGGEST THAT THERE IS AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS ASSOCIATED WITH THE USE OF VALPROATE BY WOMEN WITH SEIZURE DISORDERS DURING PREGNANCY WHEN COMPARED TO THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO DO NOT USE ANTIEPILEPTIC DRUGS DURING PREGNANCY, THE INCIDENCE IN WOMEN WITH SEIZURE DISORDERS WHO USE OTHER ANTIEPILEPTIC DRUGS, AND THE BACKGROUND INCIDENCE FOR THE GENERAL POPULATION. THEREFORE, VALPROATE SHOULD BE CONSIDERED FOR WOMEN OF CHILDBEARING POTENTIAL ONLY AFTER THE RISKS HAVE BEEN THOROUGHLY DISCUSSED WITH THE PATIENT AND WEIGHED AGAINST THE POTENTIAL BENEFITS OF TREATMENT.

THERE ARE MULTIPLE REPORTS IN THE CLINICAL LITERATURE THAT INDICATE THE USE OF ANTIEPILEPTIC DRUGS DURING PREGNANCY RESULTS IN AN INCREASED INCIDENCE OF CONGENITAL MALFORMATIONS IN OFFSPRING. ANTIEPILEPTIC DRUGS, INCLUDING VALPROATE, SHOULD BE ADMINISTERED TO WOMEN OF CHILDBEARING POTENTIAL ONLY IF THEY ARE CLEARLY SHOWN TO BE ESSENTIAL IN THE MANAGEMENT OF THEIR MEDICAL CONDITION.

Antiepileptic drugs should not be discontinued abruptly 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. In individual cases where the severity and frequency of the seizure disorder are such that the removal of medication does not pose a serious threat to the patient, discontinuation of the drug may be considered prior to and during pregnancy, although it cannot be said with any confidence that even minor seizures do not pose some hazard to the developing embryo or fetus.

Human Data
Congenital Malformations
The North American Antiepileptic Drug Pregnancy Registry reported 16 cases of congenital malformations among the offspring of 149 women with epilepsy who were exposed to valproic acid monotherapy during the first trimester of pregnancy at doses of approximately 1,000 mg per day, for a prevalence rate of 10.7% (95% CI 6.3% to 16.9%). Three of the 149 offspring (2%) had neural tube defects and 6 of the 149 (4%) had less severe malformations. Among epileptic women who were exposed to other antiepileptic drug monotherapies during pregnancy (1,048 patients) the malformation rate was 2.9% (95% CI 2.0% to 4.1%). There was a 4-fold increase in congenital malformations among infants with valproic acid-exposed mothers compared with those treated with other antiepileptic monotherapies as a group (Odds Ratio 4.0; 95% CI 2.1 to 7.4). This increased risk does not reflect a comparison versus any specific antiepileptic drug, but the risk versus the heterogeneous group of all other antiepileptic drug monotherapies combined. The increased teratogenic risk from valproic acid in women with epilepsy is expected to be reflected in an increased risk in other indications (e.g., migraine or bipolar disorder).

THE STRONGEST ASSOCIATION OF MATERNAL VALPROATE USAGE WITH CONGENITAL MALFORMATIONS IS WITH NEURAL TUBE DEFECTS (AS DISCUSSED UNDER THE NEXT SUBHEADING). HOWEVER, OTHER CONGENITAL ANOMALIES (E.G. CRANIOFACIAL DEFECTS, CARDIOVASCULAR MALFORMATIONS AND ANOMALIES INVOLVING VARIOUS BODY SYSTEMS), COMPATIBLE AND INCOMPATIBLE WITH LIFE, HAVE BEEN REPORTED. SUFFICIENT DATA TO DETERMINE THE INCIDENCE OF THESE CONGENITAL ANOMALIES IS NOT AVAILABLE.

Neural Tube Defects

THE INCIDENCE OF NEURAL TUBE DEFECTS IN THE FETUS IS INCREASED IN MOTHERS RECEIVING VALPROATE DURING THE FIRST TRIMESTER OF PREGNANCY. THE CENTERS FOR DISEASE CONTROL (CDC) HAS ESTIMATED THE RISK OF VALPROIC ACID EXPOSED WOMEN HAVING CHILDREN WITH SPINA BIFIDA TO BE APPROXIMATELY 1 TO 2%. THE AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG) ESTIMATES THE GENERAL POPULATION RISK FOR CONGENITAL NEURAL TUBE DEFECTS AS 0.14% TO 0.2%.

Tests to detect neural tube and other defects using current accepted procedures should be considered a part of routine prenatal care in pregnant women receiving valproate.

Evidence suggests that pregnant women who receive folic acid supplementation may be at decreased risk for congenital neural tube defects in their offspring compared to pregnant women not receiving folic acid. Whether the risk of neural tube defects in the offspring of women receiving valproate specifically is reduced by folic acid supplementation is unknown. DIETARY FOLIC ACID SUPPLEMENTATION BOTH PRIOR TO AND DURING PREGNANCY SHOULD BE ROUTINELY RECOMMENDED TO PATIENTS CONTEMPLATING PREGNANCY.

Other Adverse Pregnancy Effects
PATIENTS TAKING VALPROATE MAY DEVELOP CLOTTING ABNORMALITIES (SEE PRECAUTIONS - GENERAL AND WARNINGS). A PATIENT WHO HAD LOW FIBRINOGEN WHEN TAKING MULTIPLE ANTICONVULSANTS INCLUDING VALPROATE GAVE BIRTH TO AN INFANT WITH AFIBRINOGENEMIA WHO SUBSEQUENTLY DIED OF HEMORRHAGE. IF VALPROATE IS USED IN PREGNANCY, THE CLOTTING PARAMETERS SHOULD BE MONITORED CAREFULLY.

PATIENTS TAKING VALPROATE MAY DEVELOP HEPATIC FAILURE (SEE WARNINGS - HEPATOTOXICITY AND BOX WARNING). FATAL HEPATIC FAILURES, IN A NEWBORN AND IN AN INFANT, HAVE BEEN REPORTED FOLLOWING THE MATERNAL USE OF VALPROATE DURING PREGNANCY.

Animal Data
Animal studies have demonstrated valproate-induced teratogenicity. Increased frequencies of malformations, as well as intrauterine growth retardation and death, have been observed in mice, rats, rabbits, and monkeys following prenatal exposure to valproate. Malformations of the skeletal system are the most common structural abnormalities produced in experimental animals, but neural tube closure defects have been seen in mice exposed to maternal plasma valproate concentrations exceeding approximately 230 mcg/mL (2.3 times the upper limit of the human therapeutic range) during susceptible periods of embryonic development. Administration of an oral dose of 200 mg/kg/day or greater (50% of the maximum human daily dose or greater on a mg/ m2 basis) to pregnant rats during organogenesis produced malformations (skeletal, cardiac, and urogenital) and growth retardation in the offspring. These doses resulted in peak maternal plasma valproate levels of approximately 340 mcg/mL or greater (3.4 times the upper limit of the human therapeutic range or greater). Behavioral deficits have been reported in the offspring of rats given a dose of 200 mg/kg/day throughout most of pregnancy. An oral dose of 350 mg/kg/day (approximately 2 times the maximum human daily dose on a mg/ m2 basis) produced skeletal and visceral malformations in rabbits exposed during organogenesis. Skeletal malformations, growth retardation, and death were observed in rhesus monkeys following administration of an oral dose of 200 mg/kg/day (equal to the maximum human daily dose on a mg/ m2 basis) during organogenesis. This dose resulted in peak maternal plasma valproate levels of approximately 280 mcg/mL (2.8 times the upper limit of the human therapeutic range).

Suicidal Behavior and Ideation
Antiepileptic drugs, (AEDs), including divalproex sodium delayed-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 1 shows absolute and relative risk by indication for all evaluated AEDs.

Table 1. 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

Anyone considering prescribing divalproex sodium delayed-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.

Interaction with Carbapenem Antibiotics
Carbapenem antibiotics (ertapenem, imipenem, meropenem) may reduce serum valproic acid concentrations to subtherapeutic levels, resulting in loss of seizure control. 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 Drug Interactions).

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 events. 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).

Thrombocytopenia
The frequency of adverse effects (particularly elevated liver enzymes and thrombocytopenia (see PRECAUTIONS) may be dose-related. In a clinical trial of divalproex sodium delayed-release tablets 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 109/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.

PRECAUTIONS


Hepatic Dysfunction

BOXED WARNING, CONTRAINDICATIONS WARNINGS.

Pancreatitis

BOXED WARNING WARNINGS.

Hypothermia

Drug Interactions - Topiramate

Hyperammonemia

PRECAUTIONS, HypothermiaCONTRAINDICATIONSWARNINGS - Urea Cycle Disorders (UCD) PRECAUTIONS - HyperammonemiaEncephalopathy Associated with Concomitant Topiramate Use

CONTRAINDICATIONSWARNINGS - Urea Cycle DisordersPRECAUTIONS - Hyperammonemia

Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate Use
PRECAUTIONS - HypothermiaCONTRAINDICATIONSWARNINGS - Urea Cycle DisordersPRECAUTIONS - Hyperammonemia

General

WARNINGS9

PRECAUTIONS-Drug Interactions







in vitroin vitro

Multi-organ Hypersensitivity Reaction

Information for Patients

Pancreatitis


Hyperammonemia
PRECAUTIONS - Hyperammonemia

CNS Depression


Birth Defects
Patient Information Leaflet

PRECAUTIONS - Pregnancy

Suicidal Thinking and Behavior
WARNINGS

Multi-organ Hypersensitivity Reaction
PRECAUTIONS-Multi-organ Hypersensitivity Reaction

Drug Interactions












Aspirin


Felbamate


Carbapenem Antibiotics
WARNINGS

Rifampin




Antacids


Chlorpromazine


Haloperidol


Cimetidine and Ranitidine










Amitriptyline/Nortriptyline


Carbamazepine/carbamazepine-10,11-Epoxide


Clonazepam


Diazepam


Ethosuximide


Lamotrigine


Phenobarbital






Phenytoin




Tolbutamide


Topiramate
CONTRAINDICATIONS WARNINGS - Urea Cycle Disorders PRECAUTIONS - Hyperammonemia Hyperammonemia and Encephalopathy Associated with Concomitant Topiramate UsePRECAUTIONS -  HypothermiaHyperammonemia

Warfarin
in vitro

Zidovudine




Acetaminophen


Clozapine


Lithium


Lorazepam


Oral Contraceptive Steroids



Carcinogenesis, Mutagenesis, Impairment of Fertility


2


in vitro in vivo


222

Pregnancy

WARNINGS.

Nursing Mothers

Pediatric Use

BOXED WARNING









22

Geriatric Use



WARNINGS-Somnolence in the ElderlyDOSAGE AND ADMINISTRATION

ADVERSE REACTIONS


Mania




Table 2. Adverse Events Reported by > 5% of Divalproex Sodium Delayed-Release Tablets - Treated Patients During Placebo-Controlled Trials of Acute Mania1
Adverse Event Divalproex Sodium Delayed-Release Tablets
(n = 89)
Placebo
(n = 97)

1.  The following adverse events occurred at an equal or greater incidence for placebo than for divalproex sodium delayed-release tablets: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.

Nausea 22% 15%
Somnolence 19% 12%
Dizziness 12% 4%
Vomiting 12% 3%
Asthenia 10% 7%
Abdominal pain 9% 8%
Dyspepsia 9% 8%
Rash 6% 3%











































Migraine




Table 3. Adverse Events Reported by > 5% of Divalproex Sodium Delayed-Release Tablets-Treated Patients During Migraine Placebo-Controlled Trials with a Greater Incidence Than Patients Taking Placebo1
Body System Event Divalproex Sodium Delayed-Release Tablets
(N = 202)
Placebo
(N = 81)

1.   The following adverse events occurred in at least 5% of divalproex sodium delayed-release tablets - treated patients and at an equal or greater incidence for placebo than for divalproex sodium delayed-release tablets: flu syndrome and pharyngitis.

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%














































Epilepsy



Table 4. Adverse Events Reported by ≥ 5% of Patients Treated with Divalproex Sodium Delayed-Release Tablets 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 Events Reported by ≥ 5% of Patients in the High Dose Group in the Controlled Trial of Divalproex Sodium Delayed-Release Tablets Monotherapy for Complex Partial Seizures1
Body System/Event High Dose (%)
(n = 131)
Low Dose (%)
(n = 134)

1.   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.

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
     Nervousness 11 7
     Amnesia 7 4
     Nystagmus 7 1
     Depression 5 4
Respiratory System
     Infection 20 13
     Pharyngitis 8 2
     Dyspnea 5 1
Skin and Appendages
     Alopecia 24 13
Special Senses
     Amblyopia/Blurred Vision 8 4
     Tinnitus 7 1














































Other Patient Populations






WARNINGS - Urea Cycle DisordersPRECAUTIONS





PRECAUTIONS - Drug Interactions









PRECAUTIONS - GeneralDrug Interactions


WARNINGS


PRECAUTIONS




WARNINGS


PRECAUTIONS















OVERDOSAGE






DOSAGE AND ADMINISTRATION


Mania




Epilepsy
PRECAUTIONS - Drug Interactions





Monotherapy (Initial Therapy)





Conversion to Monotherapy


Adjunctive Therapy


CLINICAL STUDIESDrug InteractionsPRECAUTIONS - Drug Interactions




CLINICAL PHARMACOLOGY

PRECAUTIONS





Migraine


General Dosing Advice

WARNINGS


PRECAUTIONS


HOW SUPPLIED



















Recommended storage






Patient Information Leaflet


Important Information for Women Who Could Become Pregnant About the Use of Divalproex Sodium Delayed-Release Tablets.


Information For Women Who Could Become Pregnant



Before using any of these medications, women who can become pregnant should consider the fact that these medications have been associated with birth defects, in particular, with spina bifida and other defects related to failure of the spinal canal to close normally. Approximately 1 to 2% of children born to women with epilepsy taking divalproex sodium delayed-release tablets in the first 12 weeks of pregnancy had these defects (based on data from the Centers for Disease Control, a U.S. agency based in Atlanta). The incidence in the general population is 0.1 to 0.2%.

These medications have also been associated with other birth defects such as defects of the heart, the bones, and other parts of the body. Information suggests that birth defects may be more likely to occur with these medications than some other drugs that treat your medical condition.

Information For Women Who Are Planning to Get Pregnant
  • Women taking any of these medications who are planning to get pregnant should discuss the treatment options with their doctor.
Information For Women Who Become Pregnant
  • If you become pregnant while taking any of these medications you should contact your doctor immediately.
Other Important Information
  • Your medication should be taken exactly as it is prescribed by your doctor to get the most benefit from your medication and reduce the risk of side effects.
  • If you have taken more than the prescribed dose of your medication, contact your hospital emergency room or local poison center immediately.
  • Your medication was prescribed for your particular condition. Do not use it for another condition or give the drug to others.
Facts About Birth Defects




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DIVALPROEX SODIUM

DIVALPROEX SODIUM TABLET, DELAYED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:55648-973
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

Ingredient Name Basis of Strength Strength
Divalproex sodium valproic acid 125 mg

Inactive Ingredients

Ingredient Name Strength
SILICON DIOXIDE
cellulose, microcrystalline
STARCH, CORN
povidone
CROSCARMELLOSE SODIUM
GLYCERYL BEHENATE
talc
HYPROMELLOSES
polyethylene glycol
POLYVINYL ALCOHOL
polysorbate 80
METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A
TRIETHYL CITRATE
SODIUM BICARBONATE
SODIUM LAURYL SULFATE
DIMETHICONE
titanium dioxide

Product Characteristics

Color Size Imprint Code Shape
white (White) 9 mm 973 ROUND

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:55648-973-01 100 in 1 BOTTLE
2 NDC:55648-973-03 30 in 1 BOTTLE
3 NDC:55648-973-02 500 in 1 BOTTLE
4 10 in 1 BLISTER PACK
5 NDC:55648-973-04 100 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077296 2008-07-31


DIVALPROEX SODIUM

DIVALPROEX SODIUM TABLET, DELAYED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:55648-974
Route of Administration ORAL DEA Schedule

Active Ingredient/Active Moiety

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

Inactive Ingredients

Ingredient Name Strength
SILICON DIOXIDE
cellulose, microcrystalline
STARCH, CORN
povidone
CROSCARMELLOSE SODIUM
GLYCERYL BEHENATE
talc
HYPROMELLOSES
polyethylene glycol
POLYVINYL ALCOHOL
polysorbate 80
METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A
TRIETHYL CITRATE
SODIUM BICARBONATE
SODIUM LAURYL SULFATE
DIMETHICONE
titanium dioxide

Product Characteristics

Color Size Imprint Code Shape
white (White) 16 mm W974 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:55648-974-01 100 in 1 BOTTLE
2 NDC:55648-974-02 500 in 1 BOTTLE
3 NDC:55648-974-03 30 in 1 BOTTLE
4 10 in 1 BLISTER PACK
5 NDC:55648-974-04 100 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077296 2008-07-31


DIVALPROEX SODIUM

DIVALPROEX SODIUM TABLET, DELAYED RELEASE

Product Information

Product Type Human prescription drug label Item Code (Source) NDC:55648-975
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
SILICON DIOXIDE
cellulose, microcrystalline
STARCH, CORN
povidone
CROSCARMELLOSE SODIUM
GLYCERYL BEHENATE
talc
HYPROMELLOSES
polyethylene glycol
POLYVINYL ALCOHOL
polysorbate 80
METHACRYLIC ACID - ETHYL ACRYLATE COPOLYMER (1:1) TYPE A
TRIETHYL CITRATE
SODIUM BICARBONATE
SODIUM LAURYL SULFATE
DIMETHICONE
titanium dioxide

Product Characteristics

Color Size Imprint Code Shape
white (White) 19 mm W975 OVAL

Packaging

# Item Code Package Description Marketing Start Date Marketing End Date
1 NDC:55648-975-01 100 in 1 BOTTLE
2 NDC:55648-975-02 500 in 1 BOTTLE
3 NDC:55648-975-03 30 in 1 BOTTLE
4 10 in 1 BLISTER PACK
5 NDC:55648-975-04 100 in 1 CARTON

Marketing Information

Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date
ANDA ANDA077296 2008-07-31


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