DRUG: DepakoteER ER

GENERIC: Divalproex Sodium

DOSAGE: TABLET, EXTENDED RELEASE

ADMINSTRATION: ORAL

NDC: 70518-3754-0

COLOR: white

SHAPE: OVAL

SCORE: No score

SIZE: 17 mm

IMPRINT: HF

PACKAGING: 30 in 1 BLISTER PACK

ACTIVE INGREDIENT(S):

• DIVALPROEX SODIUM 250mg in 1

INACTIVE INGREDIENT(S):

• TITANIUM DIOXIDE
• SILICON DIOXIDE
• POTASSIUM SORBATE
• PROPYLENE GLYCOL
• FD&C BLUE NO. 1
• CELLULOSE, MICROCRYSTALLINE
• TRIACETIN
• LACTOSE, UNSPECIFIED FORM
• HYPROMELLOSE, UNSPECIFIED
• POLYETHYLENE GLYCOL, UNSPECIFIED

WARNING: LIFE THREATENING ADVERSE REACTIONS

1****INDICATIONS AND USAGE

1.1****Mania

Depakote ER is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features. A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The efficacy of Depakote ER is based in part on studies of Depakote (divalproex sodium delayed release tablets) in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania [see Clinical Studies(14.1)].

The effectiveness of valproate for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote ER for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient.

1.2****Epilepsy

Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Depakote ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older with multiple seizure types that include absence seizures.

Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present.

1.3****Migraine

Depakote ER is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote ER is useful in the acute treatment of migraine headaches.

1.4****Important Limitations

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, 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 [see Warnings and Precautions(5.2,5.3,5.4), Use in Specific Populations(8.1), and Patient Counseling Information(17)].

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

4****CONTRAINDICATIONS

• Depakote ER should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions(5.1)].

• Depakote ER is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (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)].

• Depakote ER is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions(5.12)].

• Depakote ER is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions(5.6)].

• For use in prophylaxis of migraine headaches: Depakote ER is 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)].

6****ADVERSE REACTIONS

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.

Information on pediatric adverse reactions is presented in section 8.

6.1****Mania

The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of Depakote ER in the treatment of manic episodes associated with bipolar disorder.

Table 3summarizes those adverse reactions reported for patients in these trials where the incidence rate in the Depakote ER-treated group was greater than 5% and greater than the placebo incidence.

The following additional adverse reactions were reported by greater than 1% of the Depakote ER-treated patients in controlled clinical trials:

Body as a Whole:Back Pain, Chills, Chills and Fever, Drug Level Increased, Flu Syndrome, Infection, Infection Fungal, Neck Rigidity.

Cardiovascular System:Arrhythmia, Hypertension, Hypotension, Postural Hypotension.

Digestive System:Constipation, Dry Mouth, Dysphagia, Fecal Incontinence, Flatulence, Gastroenteritis, Glossitis, Gum Hemorrhage, Mouth Ulceration.

Hemic and Lymphatic System:Anemia, Bleeding Time Increased, Ecchymosis, Leucopenia.

Metabolic and Nutritional Disorders:Hypoproteinemia, Peripheral Edema.

Musculoskeletal System:Arthrosis, Myalgia.

Nervous System:Abnormal Gait, Agitation, Catatonic Reaction, Dysarthria, Hallucinations, Hypertonia, Hypokinesia, Psychosis, Reflexes Increased, Sleep Disorder, Tardive Dyskinesia, Tremor.

Respiratory System:Hiccup, Rhinitis.

Skin and Appendages:Discoid Lupus Erythematosus, Erythema Nodosum, Furunculosis, Maculopapular Rash, Pruritus, Rash, Seborrhea, Sweating, Vesiculobullous Rash.

Special Senses:Conjunctivitis, Dry Eyes, Eye Disorder, Eye Pain, Photophobia, Taste Perversion.

Urogenital System:Cystitis, Urinary Tract Infection, Menstrual Disorder, Vaginitis.

6.2****Epilepsy

Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, Depakote was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the Depakote-treated patients (6%), compared to 1% of placebo-treated patients.

Table 4lists treatment-emergent adverse reactions which were reported by ≥ 5% of Depakote-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of Depakote and other antiepilepsy drugs.

Table 5 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of Depakote monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during the first portion of the trial, it is not possible, in many cases, to determine whether the following adverse reactions can be ascribed to Depakote alone, or the combination of valproate and other antiepilepsy drugs.

The following additional adverse reactions were reported by greater than 1% but less than 5% of the 358 patients treated with valproate in the controlled trials of complex partial seizures:

Body as a Whole:Back pain, chest pain, malaise.

Cardiovascular System:Tachycardia, hypertension, palpitation.

Digestive System:Increased appetite, flatulence, hematemesis, eructation, pancreatitis, periodontal abscess.

Hemic and Lymphatic System:Petechia.

Metabolic and Nutritional Disorders:SGOT increased, SGPT increased.

Musculoskeletal System:Myalgia, twitching, arthralgia, leg cramps, myasthenia.

Nervous System:Anxiety, confusion, abnormal gait, paresthesia, hypertonia, incoordination, abnormal dreams, personality disorder.

Respiratory System:Sinusitis, cough increased, pneumonia, epistaxis.

Skin and Appendages:Rash, pruritus, dry skin.

Special Senses:Taste perversion, abnormal vision, deafness, otitis media.

Urogenital System:Urinary incontinence, vaginitis, dysmenorrhea, amenorrhea, urinary frequency.

6.3****Migraine

Based on two placebo-controlled clinical trials and their long term extension, valproate was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Of the 202 patients exposed to valproate in the placebo-controlled trials, 17% discontinued for intolerance. This is compared to a rate of 5% for the 81 placebo patients. Including the long term extension study, the adverse reactions reported as the primary reason for discontinuation by ≥ 1% of 248 valproate-treated patients were alopecia (6%), nausea and/or vomiting (5%), weight gain (2%), tremor (2%), somnolence (1%), elevated SGOT and/or SGPT (1%), and depression (1%).

Table 6includes those adverse reactions reported for patients in the placebo- controlled trial where the incidence rate in the Depakote ER-treated group was greater than 5% and was greater than that for placebo patients.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of Depakote ER-treated patients and with a greater incidence than placebo in the placebo-controlled clinical trial for migraine prophylaxis:

Body as a Whole:Accidental injury, viral infection.

Digestive System:Increased appetite, tooth disorder.

Metabolic and Nutritional Disorders:Edema, weight gain.

Nervous System:Abnormal gait, dizziness, hypertonia, insomnia, nervousness, tremor, vertigo.

Respiratory System:Pharyngitis, rhinitis.

Skin and Appendages:Rash.

Special Senses:Tinnitus.

Table 7includes those adverse reactions reported for patients in the placebo- controlled trials where the incidence rate in the valproate-treated group was greater than 5% and was greater than that for placebo patients.

The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 202 valproate-treated patients in the controlled clinical trials:

Body as a Whole:Chest pain.

Cardiovascular System:Vasodilatation.

Digestive System:Constipation, dry mouth, flatulence, and stomatitis.

Hemic and Lymphatic System:Ecchymosis.

Metabolic and Nutritional Disorders:Peripheral edema.

Musculoskeletal System:Leg cramps.

Nervous System:Abnormal dreams, confusion, paresthesia, speech disorder, and thinking abnormalities.

Respiratory System:Dyspnea, and sinusitis.

Skin and Appendages:Pruritus.

Urogenital System:Metrorrhagia.

6.4****Postmarketing Experience

The following adverse reactions have been identified during post approval use of Depakote. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Dermatologic:Hair texture changes, hair color changes, photosensitivity, erythema multiforme, toxic epidermal necrolysis, nail and nail bed disorders, and Stevens-Johnson syndrome.

Psychiatric:Emotional upset, psychosis, aggression, psychomotor hyperactivity, hostility, disturbance in attention, learning disorder, and behavioral deterioration.

Neurologic:Paradoxical convulsion, parkinsonism

There have been several reports of acute or subacute cognitive decline and behavioral changes (apathy or irritability) with cerebral pseudoatrophy on imaging associated with valproate therapy; both the cognitive/behavioral changes and cerebral pseudoatrophy reversed partially or fully after valproate discontinuation.

There have been reports of acute or subacute encephalopathy in the absence of elevated ammonia levels, elevated valproate levels, or neuroimaging changes. The encephalopathy reversed partially or fully after valproate discontinuation.

Musculoskeletal:Fractures, decreased bone mineral density, osteopenia, osteoporosis, and weakness.

Hematologic:Relative lymphocytosis, macrocytosis, leukopenia, anemia including macrocytic with or without folate deficiency, bone marrow suppression, pancytopenia, aplastic anemia, agranulocytosis, and acute intermittent porphyria.

Endocrine:Irregular menses, secondary amenorrhea, hyperandrogenism, hirsutism, elevated testosterone level, breast enlargement, galactorrhea, parotid gland swelling, polycystic ovary disease, decreased carnitine concentrations, hyponatremia, hyperglycinemia, and inappropriate ADH secretion.

There have been rare reports of Fanconi's syndrome occurring chiefly in children.

Metabolism and nutrition:Weight gain.

Reproductive:Aspermia, azoospermia, decreased sperm count, decreased spermatozoa motility, male infertility, and abnormal spermatozoa morphology.

Genitourinary:Enuresis, urinary tract infection, and tubulointerstitial nephritis.

Special Senses:Hearing loss.

Other:Allergic reaction, anaphylaxis, developmental delay, bone pain, bradycardia, and cutaneous vasculitis.

8****USE IN SPECIFIC POPULATIONS

8.1****Pregnancy

Pregnancy Exposure Registry

There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Depakote ER, during pregnancy. Encourage women who are taking Depakote ER 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 [seeBoxed Warningand 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. In uteroexposure to valproate may also result in hearing impairment or hearing loss. 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)andData (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)andData (Human)].

An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [seeData (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 [seeData (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. 105–110]), carbamazepine (105 [95% C.I. 102–108]) and phenytoin (108 [95% C.I. 104–112]). 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 and attention deficit/hyperactivity disorder (ADHD). 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. Another observational study found that children who were exposed to valproate in uterohad an increased risk of ADHD (adjusted HR 1.48; 95% CI, 1.09-2.00) compared with the unexposed children. Because these studies were observational in nature, conclusions regarding a causal association between in uterovalproate exposure and an increased risk of autism spectrum disorder and ADHD 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.

8.2****Lactation

Risk Summary

Valproate is excreted in human milk. Data in the published literature describe the presence of valproate in human milk (range: 0.4 mcg/mL to 3.9 mcg/mL), corresponding to 1% to 10% of maternal serum levels. Valproate serum concentrations collected from breastfed infants aged 3 days postnatal to 12 weeks following delivery ranged from 0.7 mcg/mL to 4 mcg/mL, which were 1% to 6% of maternal serum valproate levels. A published study in children up to six years of age did not report adverse developmental or cognitive effects following exposure to valproate via breast milk [seeData (Human)].

There are no data to assess the effects of Depakote on milk production or excretion.

Clinical Considerations

The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for Depakote and any potential adverse effects on the breastfed infant from Depakote or from the underlying maternal condition.

Monitor the breastfed infant for signs of liver damage including jaundice and unusual bruising or bleeding. There have been reports of hepatic failure and clotting abnormalities in offspring of women who used valproate during pregnancy [see Use in Specific Populations(8.1)].

Data

Human

In a published study, breast milk and maternal blood samples were obtained from 11 epilepsy patients taking valproate at doses ranging from 300 mg/day to 2,400 mg/day on postnatal days 3 to 6. In 4 patients who were taking valproate only, breast milk contained an average valproate concentration of 1.8 mcg/mL (range: 1.1 mcg/mL to 2.2 mcg/mL), which corresponded to 4.8% of the maternal plasma concentration (range: 2.7% to 7.4%). Across all patients (7 of whom were taking other AEDs concomitantly), similar results were obtained for breast milk concentration (1.8 mcg/mL, range: 0.4 mcg/mL to 3.9 mcg/mL) and maternal plasma ratio (5.1%, range: 1.3% to 9.6%).

A published study of 6 breastfeeding mother-infant pairs measured serum valproate levels during maternal treatment for bipolar disorder (750 mg/day or 1,000 mg/day). None of the mothers received valproate during pregnancy, and infants were aged from 4 weeks to 19 weeks at the time of evaluation. Infant serum levels ranged from 0.7 mcg/mL to 1.5 mcg/mL. With maternal serum valproate levels near or within the therapeutic range, infant exposure was 0.9% to 2.3% of maternal levels. Similarly, in 2 published case reports with maternal doses of 500 mg/day or 750 mg/day during breastfeeding of infants aged 3 months and 1 month, infant exposure was 1.5% and 6% that of the mother, respectively.

A prospective observational multicenter study evaluated the long-term neurodevelopmental effects of AED use on children. Pregnant women receiving monotherapy for epilepsy were enrolled with assessments of their children at ages 3 years and 6 years. Mothers continued AED therapy during the breastfeeding period. Adjusted IQs measured at 3 years for breastfed and non- breastfed children were 93 (n=11) and 90 (n=24), respectively. At 6 years, the scores for breastfed and non-breastfed children were 106 (n=11) and 94 (n=25), respectively (p=0.04). For other cognitive domains evaluated at 6 years, no adverse cognitive effects of continued exposure to an AED (including valproate) via breast milk were observed.

8.3****Females and Males of Reproductive Potential

Contraception

Women of childbearing potential should use effective contraception while taking valproate [seeBoxed 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(6.4)].

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 [seeBoxed Warningand Warnings and Precautions (5.1)]. When Depakote ER 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 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

Depakote was studied in seven pediatric clinical trials.

Two of the pediatric studies were double-blinded placebo-controlled trials to evaluate the efficacy of Depakote ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER). 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 six-month pediatric studies were conducted to evaluate the long-term safety of Depakote ER 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 Depakote ER for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules in the indication of partial seizures (169 patients aged 3 to 10 years).

In these seven clinical trials, the safety and tolerability of Depakote 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(2.5)].

There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.

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)].

8.6****Effect of Disease

Liver Disease

Liver disease impairs the capacity to eliminate valproate [seeBoxed Warning, Contraindications(4), Warnings and Precautions(5.1), and Clinical Pharmacology(12.3)].

11****DESCRIPTION

Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship and formed during the partial neutralization of valproic acid with 0.5 equivalent of sodium hydroxide. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure:

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

Depakote ER 250 and 500 mg tablets are for oral administration. Depakote ER tablets contain divalproex sodium in a once-a-day extended-release formulation equivalent to 250 and 500 mg of valproic acid.

Inactive Ingredients

Depakote ER 250 and 500 mg tablets: FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin.

In addition, 500 mg tablets contain iron oxide and polydextrose.

Meets USP Dissolution Test 2.

14****CLINICAL STUDIES

14.1****Mania

The effectiveness of Depakote ER for the treatment of acute mania is based in part on studies establishing the effectiveness of Depakote (divalproex sodium delayed release tablets) for this indication. Depakote ER’s effectiveness was confirmed in one randomized, double-blind, placebo-controlled, parallel group, 3-week, multicenter study. The study was designed to evaluate the safety and efficacy of Depakote ER in the treatment of bipolar I disorder, manic or mixed type, in adults. Adult male and female patients who had a current DSM-IV TR primary diagnosis of bipolar I disorder, manic or mixed type, and who were hospitalized for acute mania, were enrolled into this study. Depakote ER was initiated at a dose of 25 mg/kg/day given once daily, increased by 500 mg/day on Day 3, then adjusted to achieve plasma valproate concentrations in the range of 85-125 mcg/mL. Mean daily Depakote ER doses for observed cases were 2,362 mg (range: 500-4,000), 2,874 mg (range: 1,500-4,500), 2,993 mg (range: 1,500-4,500), 3,181 mg (range: 1,500-5,000), and 3,353 mg (range: 1,500-5,500) at Days 1, 5, 10, 15, and 21, respectively. Mean valproate concentrations were 96.5 mcg/mL, 102.1 mcg/mL, 98.5 mcg/mL, 89.5 mcg/mL at Days 5, 10, 15 and 21, respectively. Patients were assessed on the Mania Rating Scale (MRS; score ranges from 0-52).

Depakote ER was significantly more effective than placebo in reduction of the MRS total score.

14.2****Epilepsy

The efficacy of valproate in reducing the incidence of complex partial seizures (CPS) that occur in isolation or in association with other seizure types was established in two controlled trials.

In one, multi-clinic, placebo controlled study employing an add-on design (adjunctive therapy), 144 patients who continued to suffer eight or more CPS per 8 weeks during an 8 week period of monotherapy with doses of either carbamazepine or phenytoin sufficient to assure plasma concentrations within the "therapeutic range" were randomized to receive, in addition to their original antiepilepsy drug (AED), either Depakote or placebo. Randomized patients were to be followed for a total of 16 weeks. The following table presents the findings.

Figure 1 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the adjunctive therapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for an effective treatment is shifted to the left of the curve for placebo. This figure shows that the proportion of patients achieving any particular level of improvement was consistently higher for valproate than for placebo. For example, 45% of patients treated with valproate had a ≥ 50% reduction in complex partial seizure rate compared to 23% of patients treated with placebo.

The second study assessed the capacity of valproate to reduce the incidence of CPS when administered as the sole AED. The study compared the incidence of CPS among patients randomized to either a high or low dose treatment arm. Patients qualified for entry into the randomized comparison phase of this study only if

1. they continued to experience 2 or more CPS per 4 weeks during an 8 to 12 week long period of monotherapy with adequate doses of an AED (i.e., phenytoin, carbamazepine, phenobarbital, or primidone) and 2) they made a successful transition over a two week interval to valproate. Patients entering the randomized phase were then brought to their assigned target dose, gradually tapered off their concomitant AED and followed for an interval as long as 22 weeks. Less than 50% of the patients randomized, however, completed the study. In patients converted to Depakote monotherapy, the mean total valproate concentrations during monotherapy were 71 and 123 mcg/mL in the low dose and high dose groups, respectively.

The following table presents the findings for all patients randomized who had at least one post-randomization assessment.

Figure 2 presents the proportion of patients (X axis) whose percentage reduction from baseline in complex partial seizure rates was at least as great as that indicated on the Y axis in the monotherapy study. A positive percent reduction indicates an improvement (i.e., a decrease in seizure frequency), while a negative percent reduction indicates worsening. Thus, in a display of this type, the curve for a more effective treatment is shifted to the left of the curve for a less effective treatment. This figure shows that the proportion of patients achieving any particular level of reduction was consistently higher for high dose valproate than for low dose valproate. For example, when switching from carbamazepine, phenytoin, phenobarbital or primidone monotherapy to high dose valproate monotherapy, 63% of patients experienced no change or a reduction in complex partial seizure rates compared to 54% of patients receiving low dose valproate.

Information on pediatric studies is presented in section 8.

14.3****Migraine

The results of a multicenter, randomized, double-blind, placebo-controlled, parallel-group clinical trial demonstrated the effectiveness of Depakote ER in the prophylactic treatment of migraine headache. This trial recruited patients with a history of migraine headaches with or without aura occurring on average twice or more a month for the preceding three months. Patients with cluster or chronic daily headaches were excluded. Women of childbearing potential were allowed in the trial if they were deemed to be practicing an effective method of contraception.

Patients who experienced ≥ 2 migraine headaches in the 4-week baseline period were randomized in a 1:1 ratio to Depakote ER or placebo and treated for 12 weeks. Patients initiated treatment on 500 mg once daily for one week, and were then increased to 1,000 mg once daily with an option to permanently decrease the dose back to 500 mg once daily during the second week of treatment if intolerance occurred. Ninety-eight of 114 Depakote ER-treated patients (86%) and 100 of 110 placebo-treated patients (91%) treated at least two weeks maintained the 1,000 mg once daily dose for the duration of their treatment periods. Treatment outcome was assessed on the basis of reduction in 4-week migraine headache rate in the treatment period compared to the baseline period.

Patients (50 male, 187 female) ranging in age from 16 to 69 were treated with Depakote ER (N=122) or placebo (N=115). Four patients were below the age of 18 and 3 were above the age of 65. Two hundred and two patients (101 in each treatment group) completed the treatment period. The mean reduction in 4-week migraine headache rate was 1.2 from a baseline mean of 4.4 in the Depakote ER group, versus 0.6 from a baseline mean of 4.2 in the placebo group. The treatment difference was statistically significant (see Figure 3).

3****DOSAGE FORMS AND STRENGTHS

Depakote ER 250 mg contains divalproex sodium equivalent to 250 mg of valproic acid in each tablet and is available as:

• White ovaloid tablets with the “a” logo and the code HF
• White ovaloid tablets with the code HF

10****OVERDOSAGE

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 2,120 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 overdosage. Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.

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.

Mania

In placebo-controlled clinical trials of acute mania, patients were dosed to clinical response with trough plasma concentrations between 85 and 125 mcg/mL [see Dosage and Administration(2.1)].

12.3****Pharmacokinetics

Absorption/Bioavailability

The absolute bioavailability of Depakote ER tablets administered as a single dose after a meal was approximately 90% relative to intravenous infusion.

When given in equal total daily doses, the bioavailability of Depakote ER is less than that of Depakote (divalproex sodium delayed-release tablets). In five multiple-dose studies in healthy subjects (N=82) and in subjects with epilepsy (N=86), when administered under fasting and nonfasting conditions, Depakote ER given once daily produced an average bioavailability of 89% relative to an equal total daily dose of Depakote given BID, TID, or QID. The median time to maximum plasma valproate concentrations (C max) after Depakote ER administration ranged from 4 to 17 hours. After multiple once-daily dosing of Depakote ER, the peak-to-trough fluctuation in plasma valproate concentrations was 10-20% lower than that of regular Depakote given BID, TID, or QID.

Conversion from Depakote to Depakote ER

When Depakote ER is given in doses 8 to 20% higher than the total daily dose of Depakote, the two formulations are bioequivalent. In two randomized, crossover studies, multiple daily doses of Depakote were compared to 8 to 20% higher once-daily doses of Depakote ER. In these two studies, Depakote ER and Depakote regimens were equivalent with respect to area under the curve (AUC; a measure of the extent of bioavailability). Additionally, valproate C maxwas lower, and C minwas either higher or not different, for Depakote ER relative to Depakote regimens (see Table 8).

Concomitant antiepilepsy drugs (topiramate, phenobarbital, carbamazepine, phenytoin, and lamotrigine were evaluated) that induce the cytochrome P450 isozyme system did not significantly alter valproate bioavailability when converting between Depakote and Depakote ER.

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(7.2)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, 30-50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose. Usually, less than 15-20% 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.

SpecificPopulations

Effect of Age

Pediatric

The valproate pharmacokinetic profile following administration of Depakote ER was characterized in a multiple-dose, non-fasting, open label, multi-center study in children and adolescents. Depakote ER once daily doses ranged from 250-1,750 mg. Once daily administration of Depakote ER in pediatric patients (10-17 years) produced plasma VPA concentration-time profiles similar to those that have been observed in 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(2.4)].

Effect of Sex

There are no differences in the body surface area adjusted unbound clearance between males and females (4.8±0.17 and 4.7±0.07 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 [seeBoxed Warning, Contraindications(4), and 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.

Drug Interaction Studieswith No Interaction or Likely Clinically Unimportant Interaction

Antacids

A study involving the co-administration of valproate 500 mg with commonly administered antacids (Maalox, Trisogel, and Titralac - 160 mEq doses) did not reveal any effect on the extent of absorption of valproate.

Chlorpromazine

A study involving the administration of 100 to 300 mg/day of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

Haloperidol

A study involving the administration of 6 to 10 mg/day of haloperidol to schizophrenic patients already receiving valproate (200 mg BID) revealed no significant changes in valproate trough plasma levels.

Cimetidine and Ranitidine

Cimetidine and ranitidine do not affect the clearance of valproate.

Acetaminophen

Valproate had no effect on any of the pharmacokinetic parameters of acetaminophen when it was concurrently administered to three epileptic patients.

Clozapine

In psychotic patients (n=11), no interaction was observed when valproate was co-administered with clozapine.

Lithium

Co-administration of valproate (500 mg BID) and lithium carbonate (300 mg TID) to normal male volunteers (n=16) had no effect on the steady-state kinetics of lithium.

Lorazepam

Concomitant administration of valproate (500 mg BID) and lorazepam (1 mg BID) in normal male volunteers (n=9) was accompanied by a 17% decrease in the plasma clearance of lorazepam.

Olanzapine

No dose adjustment for olanzapine is necessary when olanzapine is administered concomitantly with valproate. Co-administration of valproate (500 mg BID) and olanzapine (5 mg) to healthy adults (n=10) caused 15% reduction in C maxand 35% reduction in AUC of olanzapine.

Oral Contraceptive Steroids

Administration of a single-dose of ethinyloestradiol (50 mcg)/levonorgestrel (250 mcg) to 6 women on valproate (200 mg BID) therapy for 2 months did not reveal any pharmacokinetic interaction.

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.

Depakote ER 250 mg is available as white ovaloid tablets containing divalproex sodium equivalent to 250 mg of valproic acid in each tablet in the following package sizes:

NDC: 70518-3754-00

PACKAGING: 30 in 1 BLISTER PACK

Recommended Storage: Store tablets at 25°C (77°F); excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Repackaged and Distributed By:

Remedy Repack, Inc.

625 Kolter Dr. Suite #4 Indiana, PA 1-724-465-8762

MEDICATION GUIDE

DEPAKOTE ER(dep-a-kOte)
(divalproex sodium)
Extended-Release Tablets, for oral use

DEPAKOTE(dep-a-kOte)
(divalproex sodium)
Delayed-Release Tablets, for oral use

DEPAKOTE****Sprinkle Capsules (dep-a-kOte)
(divalproex sodium delayed release capsules)
for oral use

What is the most important information I should know aboutDEPAKOTE?

**Do not stop Depakote without first talking toahealthcare provider.**Stopping Depakote 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).

Depakote can cause serious side effects, including:

1.**Serious liver damage that can cause death, especially in children younger than 2 years oldand patients with mitochondrial disorders.**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:

• feeling very weak, tired, or uncomfortable (malaise)
• swelling of your face
• not feeling hungry
• nausea or vomiting that does not go away
• diarrhea
• pain on the right side of your stomach (abdomen)
• dark urine
• yellowing of your skin or the whites of your eyes
• loss of seizure control in people with epilepsy

In some cases, liver damage may continue even though the medicine is stopped. Your healthcare provider will do blood tests to check your liver before and during treatment with DEPAKOTE.

2.Depakote may harm your unborn baby.

• If you take Depakote during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord (such as spina bifida or neural tube defects). 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. Decreased hearing or hearing loss 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 Depakote during pregnancy for any medical condition, your child is at risk for having lower IQ and may be at risk for developing autism or attention deficit/hyperactivity disorder.
• 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 Depakote 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 Depakote. If the decision is made to use Depakote, you should use effective birth control (contraception).
• Tell your healthcare provider right away if you become pregnant while taking Depakote. You and your healthcare provider should decide if you will continue to take Depakote while you are pregnant. *Pregnancy Registry: If you become pregnant while taking Depakote, talk to your healthcare provider about registering with the North American Antiepileptic Drug (NAAED) 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.**Swelling (Inflammation) and bleeding (hemorrhaging)**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
• not feeling hungry

4.Like other antiepileptic drugs, Depakote 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.

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.

WhatisDepakote?

Depakote ER tablets, Depakote delayed-release tablets, and Depakote Sprinkle Capsules 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 other medications to treat:

◦ patients with multiple seizure types that include absence seizures

Depakote ER tablets and Depakote delayed-release tablets are also used to prevent migraine headaches.

Depakote ER tablets are also used to treat acute manic or mixed episodes associated with bipolar disorder with or without psychotic features.

Depakote delayed-release tablets are also used to treat manic episodes associated with bipolar disorder.

Do not take Depakote if you:

• have liver problems.
• have or think you have a genetic liver problem caused by a mitochondrial disorder such as Alpers-Huttenlocher syndrome.
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in Depakote. See the end of this Medication Guide for a complete list of ingredients in Depakote.
• have a genetic problem called a 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).

Before taking Depakote, tell yourhealthcare provider about all of your medical conditions including if you:

• have or have had liver problems.
• have or think you have a genetic liver problem caused by a mitochondrial disorder such as Alpers-Huttenlocher syndrome.
• drink alcohol.
• have or have had depression, suicidal thoughts or behavior, unusual changes in mood, or thoughts about self-harm
• are male and plan to father a child. DEPAKOTE may cause fertility problems, which may affect your ability to father a child. Talk to your healthcare provider if this is a problem for you.
• are pregnant or may become pregnant. DEPAKOTE may harm your unborn baby. See “2. Depakote may harm your unborn baby” above for more information.
• are breastfeeding. Depakote can pass into breast milk and may harm your baby. Talk to your healthcare provider about the best way to feed your baby if you take Depakote.

**Tell your healthcare provider about all the medicines you take,**including prescription and over-the-counter medicines, vitamins, and herbal supplements.

DEPAKOTE may affect the way other medicines work, and other medicines may affect how DEPAKOTE works. Using DEPAKOTE with other medicines can cause serious side effects.Do notstart or stop other medicines without talking to your healthcare provider.

Especially tell your healthcare provider if you take:

• medicines that can affect how the liver breaks down other medicines (such as phenytoin, carbamazepine, felbamate, phenobarbital, primidone, rifampin)
• aspirin, carbapenem antibiotics, or estrogen-containing hormonal contraceptives
• methotrexate
• topiramate
• cannabidiol

You can ask your healthcare provider or pharmacist for a list of these medicines if you are not sure.

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 Depakote?

• Depakote comes in different dosage forms.
• Take Depakote exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Depakote to take and when to take it.
• Your healthcare provider may change your dose, if needed.
• Do not change your dose of Depakote without talking to your healthcare provider. *Do not stop taking Depakote without first talking to your healthcare provider. Stopping Depakote suddenly can cause serious problems.
• Swallow Depakote ER tablets or DEPAKOTE delayed-release tablets whole.Do notcrush or chew them. Tell your healthcare provider if you cannot swallow Depakote ER tablets or DEPAKOTE delayed-release tablets whole. You may need a different medicine.
• Depakote Sprinkle Capsules may be swallowed whole, or the capsule may be opened and the contents may be mixed into a small amount of soft food, such as applesauce or pudding.See****the Instructions for Usethat comes with this Medication Guide for detailed instructions on how to use Depakote Sprinkle Capsules.
• If you miss a dose of DEPAKOTE ER tablets or DEPAKOTE delayed-release tablets, take it as soon as you remember unless it’s almost time for your next dose. Take the next dose at your regular time.Do nottake 2 doses at the same time.
• If you take too much DEPAKOTE, call your healthcare provider or poison control center right away.

What should I avoid while taking Depakote?

*Do notdrink alcohol while taking Depakote. Depakote and alcohol can affect each other causing side effects such as sleepiness and dizziness.

• Do not drive a car, operate dangerous machinery, or do dangerous activities until you know how Depakote affects you. Depakote can slow your thinking and motor skills and may affect your vision.

What are the possible side effects of Depakote?

**Call your healthcare provider right away if you have any of the symptoms listed below.**Your healthcare provider may do additional tests before and during your treatment with DEPAKOTE. Your healthcare provider may reduce your dose, temporarily stop, or permanently stop treatment if you have certain side effects.

Depakote can cause serious side effects including:

• See**“What is the most important information I should know about Depakote?”** b**leeding problems***.** Call your healthcare provider if you have any symptoms of bleeding, including:

*increased ammonia levels in your blood.High ammonia levels can seriously affect your mental activities, slow your alertness, make you feel tired, or cause vomiting (encephalopathy). This has happened when DEPAKOTE is taken alone or with a medicine called topiramate. Call your health care provider if you have any of these symptoms. *low body temperature (hypothermia)**.**A drop in your body temperature to less than 95°F can happen during treatment with DEPAKOTE. Call your healthcare provider if you have any of the following symptoms:

***severe multiorgan reactions.**Treatment with DEPAKOTE may cause severe multiorgan reactions that can be life-threatening or may lead to death. Stop taking DEPAKOTE, and contact your healthcare provider or get medical help right away if you develop any of these symptoms of a severe skin reaction:

*d**rowsiness or sleepiness in the elderly.**This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your healthcare provider if you are not able to eat or drink as you normally do. Your healthcare provider may start you at a lower dose of Depakote. ***medicine residue in your stool.**Tell your healthcare provider if you have or think you may have medicine residue in your stool.

The common side effects of DEPAKOTE include:

These are not all of the possible side effects ofDepakote.

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 Depakote?

• Store Depakote ER Tablets at room temperature between 68°F to 77°F (20°C to 25°C).
• Store Depakote delayed release tablets below 86°F (30°C).
• Store Depakote Sprinkle Capsules below 77°F (25°C).

Keep Depakote and all medicines out of the reach of children.

General information about the safe and effective use of Depakote

Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Depakote for a condition for which it was not prescribed. Do not give Depakote to other people, even if they have the same symptoms that you have. It may harm them.

You can ask your pharmacist or healthcare provider for information about Depakote that is written for health professionals.

What are the ingredients in Depakote?

Active ingredient: divalproex sodium

Inactive ingredients:

Depakote ER**t*ablets:FD&C Blue No. 1, hypromellose, lactose, microcrystalline cellulose, polyethylene glycol, potassium sorbate, propylene glycol, silicon dioxide, titanium dioxide, and triacetin. The 500 mg tablets also contain iron oxide and polydextrose. *Depakotedelayed-release t**ablets:**cellulosic polymers, diacetylated monoglycerides, povidone, pregelatinized starch (contains corn starch), silica gel, talc, titanium dioxide, and vanillin.
○ Individual tablets also contain:
125 mg tablets: FD&C Blue No. 1 and FD&C Red No. 40,
**250 mg tablets:**FD&C Yellow No. 6 and iron oxide,
**500 mg tablets:**D&C Red No. 30, FD&C Blue No. 2, and iron oxide.

***Depakote Sprinkle Capsules:**cellulosic polymers, D&C Red No. 28, FD&C Blue No. 1 gelatin, iron oxide, magnesium stearate, silica gel, titanium dioxide, and triethyl citrate.

For more information, go to www.rxabbvie.com or call 1-800-633-9110.

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

Repackaged By / Distributed By: RemedyRepack Inc.

625 Kolter Drive, Indiana, PA 15701

(724) 465-8762

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.

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.

17****PATIENT COUNSELING INFORMATION

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 Depakote ER 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 Depakote ER, 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)].

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