Divalproex sodium capsule, coated pellets

Warning: life threatening adverse reactions

WARNING: LIFE THREATENING ADVERSE REACTIONS

See full prescribing information for complete boxed warning.

  • Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk. Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter ( 5.1)
  • Fetal Risk, particularly neural tube defects other major malformations, and decreased IQ ( 5.2, 5.3, 5.4)
  • Pancreatitis, including fatal hemorrhagic cases ( 5.5)

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Hepatotoxicity

General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. 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. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ( 5.1)].

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 delayed-release capsules (sprinkle) are used in this patient group, they 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.

Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase (POLG) gene (e.g. Alpers Huttenlocher Syndrome). Divalproex sodium delayed-release capsules (Sprinkle) are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications ( 4)]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium delayed-release capsules (sprinkle) should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium delayed-release capsules (sprinkle) for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions ( 5.1)].

Fetal Risk

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in uteroexposure.

Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4)].Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.

Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see Warnings and Precautions ( 5.2, 5.3, 5.4)] .

A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information ( 17)] .

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 ( 5.5)] .

Recent major changes

Boxed Warning, Fetal Risk 2/2019

Indications and Usage, Important Limitations ( 1.2) 2/2019

Contraindications ( 4) 2/2019

Warnings and Precautions, Use in Women of Childbearing Potential ( 5.4) 2/2019

1 indications and usage

Divalproex sodium delayed-release capsules (sprinkle) are an anti-epileptic drug indicated for:

  • 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 dosage and administration

  • Divalproex sodium delayed-release capsules (sprinkle) may be swallowed whole or the contents may be sprinkled on soft food. The drug/food mixture should be swallowed immediately (avoid chewing) ( 2.2)
  • Safety of doses above 60 mg/kg/day is not established ( 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 ( 2.1)
  • 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 ( 2.1)

3 dosage forms and strengths

Capsules: 125 mg ( 3)

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Divalproex sodium delayed-release capsules, USP (sprinkle) are for oral administration.

Divalproex sodium delayed-release capsules, USP (sprinkle) contain specially coated particles of divalproex sodium equivalent to 125 mg of valproic acid in a hard gelatin capsule.

4 contraindications

  • Hepatic disease or significant hepatic dysfunction ( 4, 5.1)
  • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase (POLG) ( 4, 5.1)
  • Suspected POLG-related disorder in children under two years of age ( 4, 5.1)
  • Known hypersensitivity to the drug ( 4, 5.12)
  • Urea cycle disorders ( 4, 5.6)
  • Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4, 8.1)

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  • Divalproex sodium delayed-release capsules (sprinkle) should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1)].
  • Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions ( 5.1)] .
  • Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions ( 5.12)].
  • Divalproex sodium delayed-release capsules (sprinkle) are contraindicated in patients with known urea cycle disorders [see Warnings and Precautions ( 5.6)].
  • For use in prophylaxis of migraine headaches: Divalproex sodium delayed-release capsules, USP (sprinkle) are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Warnings and Precautions ( 5.2, 5.3, 5.4) and Use in Specific Populations ( 8.1)].

5 warnings and precautions

  • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1)
  • Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure; should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable ( 5.2, 5.3, 5.4)
  • Pancreatitis; divalproex sodium delayed-release capsules (sprinkle) should ordinarily be discontinued ( 5.5)
  • Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium delayed-release capsules (sprinkle) increase the risk of suicidal thoughts or behavior ( 5.7)
  • Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests ( 5.8)
  • 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 ( 5.6, 5.9, 5.10)
  • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate ( 5.11)
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue divalproex sodium sprinkle capsules ( 5.12)
  • Somnolence in the elderly can occur. Divalproex sodium delayed-release capsules (sprinkle) dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.14)

6 adverse reactions

Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspnea, dyspepsia, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, thrombocytopenia, somnolence, vomiting, tremor, weight gain, weight loss, peripheral edema, pharyngitis, rhinitis, thinking abnormal, tinnitus ( 6.1)

  • The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4).

To report SUSPECTED ADVERSE REACTIONS, contact Zydus Pharmaceuticals (USA) Inc. at 1-877-993-8779 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

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The following serious adverse reactions are described below and elsewhere in the labeling:

  • Hepatic failure [see Warnings and Precautions ( 5.1)]
  • Birth defects [see Warnings and Precautions ( 5.2)]
  • Decreased IQ following in uteroexposure [see Warnings and Precautions ( 5.3)]
  • Pancreatitis [see Warnings and Precautions ( 5.5)]
  • Hyperammonemic encephalopathy [see Warnings and Precautions ( 5.6, 5.9, 5.10)]
  • Suicidal behavior and ideation [see Warnings and Precautions ( 5.7)]
  • Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.8)]
  • Hypothermia [see Warnings and Precautions ( 5.11)]
  • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.12)]
  • Somnolence in the elderly [see Warnings and Precautions ( 5.14)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

7 drug interactions

  • Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, 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 dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1)
  • Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: Monitoring of valproate concentrations is recommended ( 7.1)
  • Coadministration 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)
  • Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2)
  • Dosage adjustment of amitriptyline/nortriptyline, propofol, warfarin, and zidovudine may be necessary if used concomitantly with divalproex sodium delayed-release capsules (sprinkle) ( 7.2)
  • Topiramate: Hyperammonemia and encephalopathy ( 5.10, 7.3)

8 use in specific populations

  • Pregnancy: Divalproex sodium delayed-release capsules (sprinkle) can cause congenital malformations including neural tube defects, decreased IQ, and neurodevelopmental disorders ( 5.2, 5.3, 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 ( 5.14, 8.5)

8.1 pregnancy

Pregnancy Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium delayed-release capsules (sprinkle), during pregnancy. Encourage women who are taking divalproex sodium delayed-release capsules (sprinkle) during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.

Risk Summary

For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4)].

For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions ( 5.2, 5.3)]. Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions ( 5.2) and Data (Human)].

Epidemiological studies have indicated that children exposed to valproate in uterohave lower IQ scores and a higher risk of neurodevelopmental disorders compared to children exposed to either another AED in uteroor to no AEDs in utero [see Warnings and Precautions ( 5.3) and Data (Human)].

An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see Data (Human)].

In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data (Animal)].

There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy.

Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.1, 5.8)].

Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate.

Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate is reduced by folic acid supplementation. Dietary folic acid supplementation both prior to conception and during pregnancy should be routinely recommended for patients using valproate [see Warnings and Precautions ( 5.2, 5.4)].

All pregnancies have a background risk of birth defect, loss, or other adverse outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively.

Clinical Considerations

Disease-associated maternal and/or embryo/fetal risk

To prevent major seizures, women with epilepsy should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Even minor seizures may pose some hazard to the developing embryo or fetus [see Warnings and Precautions (5.4)]. However, discontinuation of the drug may be considered prior to and during pregnancy in individual cases if the seizure disorder severity and frequency do not pose a serious threat to the patient.

Maternal adverse reactions

Pregnant women taking valproate may develop clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.8)]. If valproate is used in pregnancy, the clotting parameters should be monitored carefully in the mother. If abnormal in the mother, then these parameters should also be monitored in the neonate.

Patients taking valproate may develop hepatic failure [see Boxed Warning and Warnings and Precautions ( 5.1)]. Fatal cases of hepatic failure in infants exposed to valproate in uterohave also been reported following maternal use of valproate during pregnancy.

Hypoglycemia has been reported in neonates whose mothers have taken valproate during pregnancy.

Data

Human

Neural tube defects and other structural abnormalities

There is an extensive body of evidence demonstrating that exposure to valproate in uteroincreases the risk of neural tube defects and other structural abnormalities. Based on published data from the CDC's National Birth Defects Prevention Network, the risk of spina bifida in the general population is about 0.06 to 0.07% (6 to 7 in 10,000 births) compared to the risk following in uterovalproate exposure estimated to be approximately 1 to 2% (100 to 200 in 10,000 births).

The NAAED Pregnancy Registry has reported a major malformation rate of 9-11% in the offspring of women exposed to an average of 1,000 mg/day of valproate monotherapy during pregnancy. These data show an up to a five-fold increased risk for any major malformation following valproate exposure in uterocompared to the risk following exposure in uteroto other AEDs taken as monotherapy. The major congenital malformations included cases of neural tube defects, cardiovascular malformations, craniofacial defects (e.g., oral clefts, craniosynostosis), hypospadias, limb malformations (e.g., clubfoot, polydactyly), and other malformations of varying severity involving other body systems [see Warnings and Precautions ( 5.2)].

Effect on IQ and neurodevelopmental effects

Published epidemiological studies have indicated that children exposed to valproate in uterohave lower IQ scores than children exposed to either another AED in uteroor to no AEDs in utero. The largest of these studies 1is a prospective cohort study conducted in the United States and United Kingdom that found that children with prenatal exposure to valproate (n=62) had lower IQ scores at age 6 (97 [95% C.I. 94-101]) than children with prenatal exposure to the other anti-epileptic drug monotherapy treatments evaluated: lamotrigine (108 [95% C.I. 105110]), carbamazepine (105 [95% C.I. 102108]) and phenytoin (108 [95% C.I. 104112]). It is not known when during pregnancy cognitive effects in valproate-exposed children occur. Because the women in this study were exposed to AEDs throughout pregnancy, whether the risk for decreased IQ was related to a particular time period during pregnancy could not be assessed [see Warnings and Precautions ( 5.3)].

Although the available studies have methodological limitations, the weight of the evidence supports a causal association between valproate exposure in uteroand subsequent adverse effects on neurodevelopment, including increases in autism spectrum disorders. An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7-4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6%-7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5%-1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in uterovalproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive.

Other

There are published case reports of fatal hepatic failure in offspring of women who used valproate during pregnancy.

Animal

In developmental toxicity studies conducted in mice, rats, rabbits, and monkeys, increased rates of fetal structural abnormalities, intrauterine growth retardation, and embryo-fetal death occurred following administration of valproate to pregnant animals during organogenesis at clinically relevant doses (calculated on a body surface area [mg/m 2] basis). Valproate induced malformations of multiple organ systems, including skeletal, cardiac, and urogenital defects. In mice, in addition to other malformations, fetal neural tube defects have been reported following valproate administration during critical periods of organogenesis, and the teratogenic response correlated with peak maternal drug levels. Behavioral abnormalities (including cognitive, locomotor, and social interaction deficits) and brain histopathological changes have also been reported in mice and rat offspring exposed prenatally to clinically relevant doses of valproate.

8.3 females and males of reproductive potential

Contraception

Women of childbearing potential should use effective contraception while taking valproate [see Boxed Warning, Warnings and Precautions ( 5.4), Drug Interactions ( 7), and Use in Specific Populations ( 8.1)]. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications ( 4)].

Infertility

There have been reports of male infertility coincident with valproate therapy [see Adverse Reactions ( 6.2)].

In animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see Nonclinical Toxicology ( 13.1)].

8.4 pediatric use

Experience has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning, Warning and Precautions ( 5.1)]. When divalproex sodium delayed-release capsules (sprinkle) 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. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

Pediatric Clinical Trials

Divalproex sodium was studied in seven pediatric clinical trials.

Two of the pediatric studies were double blinded placebo-controlled trials to evaluate the efficacy of divalproex sodium extended-release tablets for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium extended-release tablets) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium extended-release tablets). Efficacy was not established for either the treatment of migraine or the treatment of mania. The most common drug-related adverse reactions (reported > 5% and twice the rate of placebo) reported in the controlled pediatric mania study were nausea, upper abdominal pain, somnolence, increased ammonia, gastritis and rash.

The remaining five trials were long term safety studies. Two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of mania (292 patients aged 10 to 17 years). Two twelve-month pediatric studies were conducted to evaluate the long-term safety of divalproex sodium extended-release tablets for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of divalproex sodium delayed-release capsules (sprinkle) in the indication of partial seizures (169 patients aged 3 to 10 years).

In these seven clinical trials, the safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions ( 6)].

Juvenile Animal Toxicology

In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum recommended human dose on a mg/m 2basis.

8.5 geriatric use

No patients above the age of 65 years were enrolled in double blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions ( 5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration ( 2.2)].

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years) [see Clinical Pharmacology ( 12.3)].

10 overdosage

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Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported; however patients have recovered from valproate levels as high as 2120 mcg/mL.

In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug. The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output.

Naloxone has been reported to reverse the CNS depressant effects of valproate over dosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

11 description

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Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:

Structured product formula for Divalproex

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

Each divalproex sodium delayed-release capsules, USP (sprinkle) intended for oral administration contains divalproex sodium equivalent to 125 mg of valproic acid. In addition, each capsule contains the following inactive ingredients: colloidal silicon dioxide, FD &C blue # 1, gelatin, hypromellose, methacrylic acid copolymer dispersion, microcrystalline cellulose spheres, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. Each capsule is printed with black pharmaceutical ink which contains: ammonia solution, butyl alcohol, dehydrated alcohol, ferrosoferric oxide, isopropyl alcohol, propylene glycol, potassium hydroxide, purified water and shellac.

The Product meets USP Dissolution Test 4.

12 clinical pharmacology

12.1 mechanism of action

Divalproex sodium dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its therapeutic effects have not been established. It has been suggested that its activity in epilepsy is related to increased brain concentrations of gamma-aminobutyric acid (GABA).

12.2 pharmacodynamics

The relationship between plasma concentration and clinical response is not well documented. One contributing factor is the nonlinear, concentration dependent protein binding of valproate which affects the clearance of the drug. Thus, monitoring of total serum valproate may not provide a reliable index of the bioactive valproate species.

For example, because the plasma protein binding of valproate is concentration dependent, the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Higher than expected free fractions occur in the elderly, in hyperlipidemic patients, and in patients with hepatic and renal diseases.

Epilepsy

The therapeutic range in epilepsy is commonly considered to be 50 to 100 mcg/mL of total valproate, although some patients may be controlled with lower or higher plasma concentrations.

12.3 pharmacokinetics

Absorption/Bioavailability

Although the rate of valproate ion absorption may vary with the formulation administered (liquid, solid, or sprinkle), conditions of use (e.g., fasting or postprandial) and the method of administration (e.g., whether the contents of the capsule are sprinkled on food or the capsule is taken intact), these differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy.

However, it is possible that differences among the various valproate products in T maxand C maxcould be important upon initiation of treatment. For example, in single dose studies, the effect of feeding had a greater influence on the rate of absorption of the tablet (increase in T maxfrom 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in T maxfrom 3.3 to 4.8 hours).

While the absorption rate from the G.I. tract and fluctuation in valproate plasma concentrations vary with dosing regimen and formulation, the efficacy of valproate as an anticonvulsant in chronic use is unlikely to be affected. Experience employing dosing regimens from once-a-day to four-times-a-day, as well as studies in primate epilepsy models involving constant rate infusion, indicate that total daily systemic bioavailability (extent of absorption) is the primary determinant of seizure control and that differences in the ratios of plasma peak to trough concentrations between valproate formulations are inconsequential from a practical clinical standpoint.

Coadministration of oral valproate products with food and substitution among the various divalproex sodium formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration ( 2.1)] .

Distribution

Protein Binding

The plasma protein binding of valproate is concentration dependent and the free fraction increases from approximately 10% at 40 mcg/mL to 18.5% at 130 mcg/mL. Protein binding of valproate is reduced in the elderly, in patients with chronic hepatic diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions ( 7)for more detailed information on the pharmacokinetic interactions of valproate with other drugs].

CNS Distribution

Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

Metabolism

Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial -oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine.

The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding. The kinetics of unbound drug are linear.

Elimination

Mean plasma clearance and volume of distribution for total valproate are 0.56 L/hr/1.73 m 2and 11 L/1.73 m 2, respectively. Mean plasma clearance and volume of distribution for free valproate are 4.6 L/hr/1.73 m 2and 92 L/1.73 m 2. Mean terminal half-life for valproate monotherapy ranged from 9 to 16 hours following oral dosing regimens of 250 to 1,000 mg.

The estimates cited apply primarily to patients who are not taking drugs that affect hepatic metabolizing enzyme systems. For example, patients taking enzyme-inducing antiepileptic drugs (carbamazepine, phenytoin, and phenobarbital) will clear valproate more rapidly. Because of these changes in valproate clearance, monitoring of antiepileptic concentrations should be intensified whenever concomitant antiepileptics are introduced or withdrawn.

Special Populations

Effect of Age

Children

Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

Elderly

The capacity of elderly patients (age range: 68 to 89 years) to eliminate valproate has been shown to be reduced compared to younger adults (age range: 22 to 26 years). Intrinsic clearance is reduced by 39%; the free fraction is increased by 44%. Accordingly, the initial dosage should be reduced in the elderly [see Dosage and Administration ( 2.2)].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and females (4.80.17 and 4.70.07 L/hr per 1.73 m 2, respectively).

Effect of Race

The effects of race on the kinetics of valproate have not been studied.

Effect of Disease

Liver Disease

Liver disease impairs the capacity to eliminate valproate. In one study, the clearance of free valproate was decreased by 50% in 7 patients with cirrhosis and by 16% in 4 patients with acute hepatitis, compared with 6 healthy subjects. In that study, the half-life of valproate was increased from 12 to 18 hours. Liver disease is also associated with decreased albumin concentrations and larger unbound fractions (2 to 2.6 fold increase) of valproate. Accordingly, monitoring of total concentrations may be misleading since free concentrations may be substantially elevated in patients with hepatic disease whereas total concentrations may appear to be normal [see Boxed Warning, Contraindications ( 4), Warnings and Precautions ( 5.1) ].

Renal Disease

A slight reduction (27%) in the unbound clearance of valproate has been reported in patients with renal failure (creatinine clearance < 10 mL/minute); however, hemodialysis typically reduces valproate concentrations by about 20%. Therefore, no dosage adjustment appears to be necessary in patients with renal failure. Protein binding in these patients is substantially reduced; thus, monitoring total concentrations may be misleading.

13 nonclinical toxicology

13.1 carcinogenesis, mutagenesis, and impairment of fertility

Carcinogenesis

Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m 2basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. The significance of these findings for humans is unknown.

Mutagenesis

Valproate was not mutagenic in an in vitrobacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivocytogenetic study in rats. Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate; this association was not observed in another study conducted in adults.

Impairment of Fertility

In chronic toxicity studies in juvenile and adult rats and dogs, administration of valproate resulted in testicular atrophy and reduced spermatogenesis at oral doses of 400 mg/kg/day or greater in rats (approximately equal to or greater than the maximum recommended human dose (MRHD) on a mg/m 2basis) and 150 mg/kg/day or greater in dogs (approximately equal to or greater than the MRHD on a mg/m 2basis). Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m 2basis) for 60 days.

14 clinical studies

15 references

1. Meador KJ, Baker GA, Browning N, et al. Fetal antiepileptic drug exposure and cognitive outcomes at age 6 years (NEAD study): a prospective observational study. Lancet Neurology 2013; 12 (3):244-252.

16 how supplied/storage and handling

Spl unclassified section

Divalproex sodium delayed-release capsules, USP (sprinkle) equivalent to 125 mg of valproic acid are white to off-white free flowing pellets filled in size '0' hard gelatin capsules with blue colored cap printed with "ZA66" in black ink and white body printed with "125mg" in black ink and are supplied as follows:

NDC 68382-106-01 in bottle of 100 capsules

NDC 68382-106-10 in bottle of 1,000 capsules

NDC 68382-106-77 in unit dose blister carton of 100 (10 x 10) Unit dose capsules

Storage:

Store at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].

Dispense in a tight, light-resistant container.

17 patient counseling information

Spl unclassified section

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

Hepatotoxicity

Warn patients and guardians 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)].

Pancreatitis

Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions ( 5.5)].

Birth Defects and Decreased IQ

Inform pregnant women and women of childbearing potential (including girls beginning the onset of puberty) that use of valproate during pregnancy increases the risk of birth defects, decreased IQ, and neurodevelopmental disorders in children who were exposed in utero. Advise women to use effective contraception while taking valproate. When appropriate, counsel these patients about alternative therapeutic options. This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headache [see Contraindications (4)]. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions ( 5.2, 5.3, 5.4) and Use in Specific Populations ( 8.1)].

Pregnancy Registry

Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant.

Encourage women who are taking divalproex sodium delayed-release capsules (sprinkle) to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 or visit the website, http://www.aedpregnancyregistry.org/ [see Use in Specific Populations ( 8.1)].

Suicidal Thinking and Behavior

Counsel patients, their caregivers, and families that AEDs, including divalproex sodium delayed-release capsules (sprinkle), may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm. Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [see Warnings and Precautions ( 5.7)].

Hyperammonemia

Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to notify the prescriber if any of these symptoms occur [see Warnings and Precautions ( 5.9, 5.10)].

CNS Depression

Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.

Multiorgan Hypersensitivity Reactions

Instruct patients 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 ( 5.12)].

Medication Residue in the Stool

Instruct patients to notify their healthcare provider if they notice a medication residue in the stool [see Warnings and Precautions ( 5.18)].

Administration Guide

Divalproex sodium delayed-release capsules (sprinkle)

Divalproex sodium delayed-release capsules (sprinkle) may be swallowed whole or the capsule contents may be sprinkled onto soft food such as applesauce or pudding.

Serving suggestions

Divalproex sodium delayed-release capsules (sprinkle) provide the medicine that your healthcare provider has prescribed. The sprinkles are flavorless. Soft foods such as applesauce or pudding are best to use for mixing and taking divalproex sodium delayed-release capsules (sprinkle).

Divalproex sprinkle capsule

Make sure this medicine is taken exactly as your healthcare provider prescribed it. If you have any questions, please contact your healthcare provider or pharmacist. Keep all of your healthcare provider's appointments as scheduled. Make sure that divalproex sodium delayed-release capsules (sprinkle) and all other medicines are kept out of the reach of children.

Note:

You may see the specially coated particles of divalproex sodium delayed-release capsules (sprinkle) in stool. If you do, you should inform your healthcare provider.

Ask your healthcare provider or pharmacist about possible side effects with divalproex sodium delayed-release capsules (sprinkle).

Store divalproex sodium delayed-release capsules (sprinkle) at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].

Spl unclassified section

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 03/19

Spl medguide section

MEDICATION GUIDE

Divalproex Sodium

(dye val PRO ex sew dee uhm)

Delayed-release Capsules, USP (Sprinkle)

Read this Medication Guide before you start taking divalproex sodium delayed-release capsules (sprinkle) and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.

What is the most important information I should know about divalproex sodium delayed-release capsules (sprinkle)?

Do not stop taking divalproex sodium delayed-release capsules (sprinkle) without first talking to your healthcare provider.

Stopping divalproex sodium delayed-release capsules (sprinkle) suddenly can cause serious problems.

Divalproex sodium delayed-release capsules (sprinkle) can cause serious side effects, including:

  1. Serious liver damage that can cause death, especially in children younger than 2 years old.

The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment.

Call your healthcare provider right away if you get any of the following symptoms:

  • nausea or vomiting that does not go away
  • loss of appetite
  • pain on the right side of your stomach (abdomen)
  • dark urine
  • swelling of your face
  • yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

2 Divalproex sodium delayed-release capsules (sprinkle) may harm your unborn baby.

  • If you take divalproex sodium delayed-release capsules (sprinkle) during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy. These defects can begin in the first month, even before you know you are pregnant. Other birth defects that affect the structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom of the penis can also happen.
  • Birth defects may occur even in children born to women who are not taking any medicines and do not have other risk factors.
  • Taking folic acid supplements before getting pregnant and during early pregnancy can lower the chance of having a baby with a neural tube defect.
  • If you take divalproex sodium delayed-release capsules (sprinkle) during pregnancy for any medical condition, your child is at risk for having lower IQ.
  • There may be other medicines to treat your condition that have a lower chance of causing birth defects, decreased IQ, or other disorders in your child.
  • Women who are pregnant must not take divalproex sodium delayed-release capsules (sprinkle) to prevent migraine headaches.
  • All women of childbearing age (including girls from the start of puberty) should talk to their healthcare provider about using other possible treatments instead of divalproex sodium delayed-release capsules (sprinkle). If the decision is made to use divalproex sodium delayed-release capsules (sprinkle), you should use effective birth control (contraception).
  • Tell your healthcare provider right away if you become pregnant while taking divalproex sodium delayed-release capsules (sprinkle). You and your healthcare provider should decide if you will continue to take divalproex sodium delayed-release capsules (sprinkle) while you are pregnant.
  • Pregnancy Registry: If you become pregnant while taking divalproex sodium delayed-release capsules (sprinkle), talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling toll-free 1-888-233-2334 or by visiting the website, http://www.aedpregnancyregistry.org/. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

3 Inflammation of your pancreas that can cause death.

Call your healthcare provider right away if you have any of these symptoms:

  • severe stomach pain that you may also feel in your back
  • nausea or vomiting that does not go away

4 Like other antiepileptic drugs, divalproex sodium delayed-release capsules (sprinkle) may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

  • thoughts about suicide or dying
  • attempts to commit suicide
  • new or worse depression
  • new or worse anxiety
  • feeling agitated or restless
  • panic attacks
  • trouble sleeping (insomnia)
  • new or worse irritability
  • acting aggressive, being angry, or violent
  • acting on dangerous impulses
  • an extreme increase in activity and talking (mania)
  • other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

  • Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
  • Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop divalproex sodium delayed-release capsules (sprinkle) without first talking to a healthcare provider.Stopping divalproex sodium delayed-release capsules (sprinkle) suddenly can cause serious problems. Stopping a seizure medicine suddenly in a patient who has epilepsy can cause seizures that will not stop (status epilepticus).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What are divalproex sodium delayed-release capsules (sprinkle)?

Divalproex sodium come in different dosage forms with different usages.

Divalproex sodium delayed-release capsules (sprinkle) are prescription medicines used alone or with other medicines to treat:

  • complex partial seizures in adults and children 10 years of age and older
  • simple and complex absence seizures, with or without other seizure types

Who should not take divalproex sodium delayed-release capsules (sprinkle)?

Do not take divalproex sodium delayed-release capsules (sprinkle) if you:

  • have liver problems
  • have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers-Huttenlocher syndrome)
  • are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in divalproex sodium delayed-release capsules (sprinkle). See the end of this leaflet for a complete list of ingredients in divalproex sodium delayed-release capsules (sprinkle).
  • have a genetic problem called urea cycle disorder
  • are taking it to prevent migraine headaches and are either pregnant or may become pregnant because you are not using effective birth control (contraception)

What should I tell my healthcare provider before taking divalproex sodium delayed-release capsules (sprinkle)?

Before you take divalproex sodium delayed-release capsules (sprinkle), tell your healthcare provider if you:

  • have a genetic liver problem caused by a mitochondrial disorder (e.g. Alpers- Huttenlocher syndrome)
  • drink alcohol
  • are pregnant or breastfeeding. Divalproex sodium can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take divalproex sodium delayed-release capsules (sprinkle).
  • have or have had depression, mood problems, or suicidal thoughts or behavior
  • have any other medical conditions

Tell your healthcare provider about all the medicines you take,including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.

Taking divalproex sodium delayed-release capsules (sprinkle) with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take divalproex sodium delayed-release capsules (sprinkle)?

  • Take divalproex sodium delayed-release capsules (sprinkle) exactly as your healthcare provider tells you. Your healthcare provider will tell you how much divalproex sodium delayed-release capsules (sprinkle) to take and when to take it.
  • Your healthcare provider may change your dose.
  • Do not change your dose of divalproex sodium delayed-release capsules (sprinkle) without talking to your healthcare provider.
  • Do not stop taking divalproex sodium delayed-release capsules (sprinkle) without first talking to your healthcare provider. Stopping divalproex sodium delayed-release capsules (sprinkle) suddenly can cause serious problems.
  • Divalproex sodium delayed-release capsules (sprinkle) may be swallowed whole, or they may be opened and the contents may be sprinkled on a small amount of soft food, such as applesauce or pudding. See the Administration Guide at the end of this Medication Guide for detailed instructions on how to use divalproex sodium delayed-release capsules (sprinkle).
  • If you take too much divalproex sodium delayed-release capsules (sprinkle), call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking divalproex sodium delayed-release capsules (sprinkle)?

  • Divalproex sodium delayed-release capsules (sprinkle) can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking divalproex sodium delayed-release capsules (sprinkle), until you talk with your doctor. Taking divalproex sodium delayed-release capsules (sprinkle) with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
  • Do not drive a car or operate dangerous machinery until you know how divalproex sodium delayed-release capsules (sprinkle) affects you. Divalproex sodium delayed-release capsules (sprinkle) can slow your thinking and motor skills.

What are the possible side effects of divalproex sodium delayed-release capsules (sprinkle)?

  • See "What is the most important information I should know about divalproex sodium delayed-release capsules (sprinkle)?"

Divalproex sodium delayed-release capsules (sprinkle) can cause serious side effects including:

  • Bleeding problems:red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose.
  • High ammonia levels in your blood:feeling tired, vomiting, changes in mental status.
  • Low body temperature (hypothermia):drop in your body temperature to less than 950F, feeling tired, confusion, coma.
  • Allergic (hypersensitivity) reactions:fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing.
  • Drowsiness or sleepiness in the elderly.This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of divalproex sodium delayed-release capsules (sprinkle).

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of divalproex sodium delayed-release capsules (sprinkle) include:

  • nausea
  • headache
  • sleepiness
  • vomiting
  • weakness
  • tremor
  • dizziness
  • stomach pain
  • blurry vision
  • double vision
  • diarrhea
  • increased appetite
  • weight gain
  • hair loss
  • loss of appetite
  • problems with walking or coordination

These are not all of the possible side effects of divalproex sodium delayed-release capsules (sprinkle). For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store divalproex sodium delayed-release capsules (sprinkle)?

  • Store divalproex sodium delayed-release capsules (sprinkle) at 20 to 25C (68 to 77F) [See USP Controlled Room Temperature].

Keep divalproex sodium delayed-release capsules (sprinkle) and all medicines out of the reach of children.

General information about the safe and effective use of divalproex sodium delayed-release capsules (sprinkle)

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use divalproex sodium delayed-release capsules (sprinkle) for a condition for which it was not prescribed. Do not give divalproex sodium delayed-release capsules (sprinkle) to other people, even if they have the same symptoms that you have. It may harm them.

This Medication Guide summarizes the most important information about divalproex sodium delayed-release capsules (sprinkle). If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about divalproex sodium delayed-release capsules (sprinkle) that is written for health professionals.

Please address medical inquiries to, MedicalAffairs@zydususa.com or Tel.: 1-877-993-8779.

What are the ingredients in divalproex sodium delayed-release capsules (sprinkle)?

Active ingredient: divalproex sodium, USP

Inactive ingredients: colloidal silicon dioxide, FD &C blue # 1, gelatin, hypromellose, methacrylic acid copolymer dispersion, microcrystalline cellulose spheres, sodium lauryl sulfate, talc, titanium dioxide and triethyl citrate. Each capsule is printed with black pharmaceutical ink which contains: ammonia solution, butyl alcohol, dehydrated alcohol, ferrosoferric oxide, isopropyl alcohol, propylene glycol, potassium hydroxide, purified water and shellac.

This Medication Guide has been approved by the U.S. Food and Drug Administration.

The product's labeling may have been updated. For latest package insert, please visit

www.zydususa.com

Manufactured by:

Cadila Healthcare Ltd.

Ahmedabad, India

Distributed by:

Zydus Pharmaceuticals (USA) Inc.

Pennington, NJ 08534

Rev.: 03/19

Ingredients and appearance - Product information

Divalproex sodium capsule, coated pellets- Divalproex sodium

Product information

Product Type HUMAN PRESCRIPTION DRUG LABEL Item Code (Source) NDC: 68382-106
Route of Administration Oral

Active Ingredient/Active Moiety

Ingredient Name Strength
Divalproex sodium ( UNII: 644VL95AO6)( Valproic acid - UNII: 614OI1Z5WI ) 125 mgin 1

Inactive Ingredients

Ingredient Name Code
Alcohol ( UNII: 3K9958V90M)
Ammonia ( UNII: 5138Q19F1X)
Butyl alcohol ( UNII: 8PJ61P6TS3)
Cellulose, microcrystalline ( UNII: OP1R32D61U)
Fd&c blue no. 1 ( UNII: H3R47K3TBD)
Ferrosoferric oxide ( UNII: XM0M87F357)
Gelatin ( UNII: 2G86QN327L)
Hypromelloses ( UNII: 3NXW29V3WO)
Isopropyl alcohol ( UNII: ND2M416302)
Methacrylic acid ( UNII: 1CS02G8656)
Potassium hydroxide ( UNII: WZH3C48M4T)
Propylene glycol ( UNII: 6DC9Q167V3)
Shellac ( UNII: 46N107B71O)
Silicon dioxide ( UNII: ETJ7Z6XBU4)
Sodium lauryl sulfate ( UNII: 368GB5141J)
Talc ( UNII: 7SEV7J4R1U)
Titanium dioxide ( UNII: 15FIX9V2JP)
Triethyl citrate ( UNII: 8Z96QXD6UM)
Water ( UNII: 059QF0KO0R)

Product Characteristics

Color WHITE (WHITE) Shape CAPSULE (CAPSULE)
Size 22 mm Score 1
Imprint Code ZA66;125mg

Marketing Information

Marketing Category Application Number or Monograph Citation Territorial Authority Marketing Start Date
ANDA ANDA078919 USA

Labeler - Zydus Pharmaceuticals (USA) Inc.( 156861945)

Establishment

Name ID/FEI Business Operations
Zydus Pharmaceuticals (USA) Inc. 156861945 ANALYSIS( 68382-106), MANUFACTURE( 68382-106)

Package label.principal display panel

NDC 68382-106-01 in bottle of 100 Capsules

Divalproex sodium delayed-release capsules, USP (sprinkle)

R xonly

100 capsules

ZYDUS