Divalproex Sodium 250 mg Tablet, Delayed Release, 90-count
Other active recalls for Divalproex Sodium (different manufacturers) — 1 · tap to view
🆔 Identity & classification
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🏷️ RxNorm drug class
This medicine belongs to the Mood Stabilizer class.
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🏭 Manufacturer & labeler
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🩺 Clinical
Valproic acid is used to treat certain types of seizures. Valproic acid is also used to treat mania (episodes of frenzied, abnormally excited mood) in people with bipolar disorder (manic-depressive disorder; a disease that causes episodes of depression, episodes of mania, and other abnormal moods). It is also used to prevent migraine headaches, but not to relieve headaches that have already begun. Valproic acid is in a class of medications called anticonvulsants. It works by increasing the amount of a certain natural substance in the brain.
Read the full MedlinePlus article ↗- Divalproex is used for three main things: controlling certain types of seizures (epilepsy), treating acute manic or mixed episodes in bipolar disorder, and preventing migraines. Wh...
- What exactly is divalproex used for — my doctor prescribed it but I'm not totally sure why.
- That depends on your specific form. If you're taking the extended-release tablet, you take it once a day and should swallow it whole — don't crush or chew it. The delayed-release t...
- How should I take it — does it matter when during the day or whether I eat first?
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Divalproex Sodium — tap one for details:
Divalproex Sodium may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.
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Ask a licensed pharmacist directly — free, answered by our team.
💊 What it looks like
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🧪 Inactive Ingredients / Excipients
Inactive ingredients, also called excipients, are components of the drug product other than the active ingredient. They may include fillers, dyes, coatings, preservatives, flavors, or other formulation ingredients.
💡 Tap an ingredient (hover on desktop) to see what it is and why it’s used.
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UNII H77VEI93A8
A synthetic yellow dye used to color medications. It helps identify the drug and make it visually distinctive, with no effect on how the medicine works.
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UNII 1K09F3G675
Ferric oxide red is an inorganic iron compound used as a colorant in medicines. It gives tablets, capsules, or other dosage forms a red or reddish tint for identification and appearance.
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UNII NX76LV5T8J
A synthetic plastic polymer made from methacrylic acid and ethyl acrylate. It's used as a coating or binder to control how and where the medicine dissolves in your digestive system.
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UNII FZ989GH94E
Povidone is a synthetic polymer made from a plastic-like material. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in your stomach so the medicine can be absorbed.
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UNII ETJ7Z6XBU4
Silicon dioxide is a naturally occurring mineral used as a glidant and anti-caking agent. It helps powder ingredients flow smoothly and prevents clumping during manufacturing and storage.
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UNII 8MDF5V39QO
A white powder form of baking soda that acts as a buffer and pH regulator in medicines. It helps maintain the right acid-base balance and may aid tablet disintegration.
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UNII 368GB5141J
A detergent and foaming agent derived from coconut or palm oil. In medications, it helps break down and mix oil and water-based ingredients, aids in tablet disintegration, and improves how the drug dissolves and spreads in the mouth or digestive system.
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UNII O8232NY3SJ
A plant-based carbohydrate derived from corn kernels. It acts as a filler to add bulk, a binder to hold ingredients together, and a disintegrant to help the tablet break apart in your stomach for absorption.
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UNII 7SEV7J4R1U
A powder made from a naturally occurring mineral. In medicines, talc works as a glidant and anti-caking agent, helping tablets and capsules flow smoothly during manufacturing and preventing clumping.
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UNII 15FIX9V2JP
Titanium dioxide is a bright white mineral powder commonly used as a colorant and opacifying agent. It makes pills and tablets white or lighter in color and helps make coatings non-transparent.
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UNII 8Z96QXD6UM
Triethyl citrate is a clear liquid derived from citric acid. It acts as a plasticizer and solvent in tablet coatings and film formulations, helping the coating remain flexible and adhere properly to the medicine.
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UNII CHI530446X
Vanillin is a natural or synthetic aromatic compound that gives vanilla flavor. It's used in medicines as a flavoring agent to mask bitter tastes and improve how the medicine tastes.
12 inactive ingredients listed in the exact product block matched to this NDC.
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ingredient classCode="IACT" elements from the exact product block matched by this NDC. Label-section narrative from DailyMed / the openFDA label index is shown separately when available.Inactive ingredient FAQ
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💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per each | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | Not in the retail survey — common for institutional, discontinued, or low-volume packs. | |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $0.1520 | $13.68 / 90 tablets |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Divalproex Sodium 250 mg 00832-7123-01 | Upsher-Smith | 1 tablet | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 00904-6860-61 | Major | 1 tablet | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 29300-0139-01 | Unichem | 100 tablets | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 57237-0047-01 | Rising | 100 tablets | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 60687-0868-01 | American | 1 tablet | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 68001-0473-00 | BluePoint | 100 tablets | $0.085 | AB | Availability likely | — |
| Divalproex Sodium 250 mg 68084-0776-01 | American | 1 tablet | $0.086 | AB | Discontinued | — |
| Depakote 250 mg 00074-7326-13 | AbbVie | 100 tablets | $4.049 | AB | Availability likely | — |
| divalproex sodium 250 mg 00615-8587-39 | NCS | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 17856-0797-01 | ATLANTIC | 1 tablet | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 50090-1123-00 | A-S | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 50090-2007-00 | A-S | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 50090-7763-00 | A-S | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 51655-0365-52 | Northwind | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 55111-0530-01 | Dr.Reddy's | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 55154-4154-00 | Cardinal | 1 tablet | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 55154-7145-00 | Cardinal | 1 tablet | — | AB | Discontinued | — |
| Divalproex Sodium 250 mg 60760-0698-60 | St. | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 62756-0797-08 | Sun | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 63187-0742-30 | Proficient | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 65862-0402-01 | Aurobindo | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 67046-1571-03 | Coupler | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 68071-3553-06 | NuCare | 60 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 68788-4079-03 | Preferred | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 68788-8609-03 | Preferred | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 69452-0434-13 | Bionpharma | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 70518-3055-00 | REMEDYREPACK | 30 tablets | — | AB | Discontinued | — |
| Divalproex Sodium 250 mg 70518-3431-00 | REMEDYREPACK | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 71335-0008-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 71335-2277-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 71335-2783-01 | Bryant | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 71335-2862-01 | Bryant | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 71335-2885-01 | Bryant | 500 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mgthis 71610-0031-60 | Aphena | 90 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 72162-2316-01 | Bryant | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 72162-2460-01 | Bryant | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium D/R 250 mg 72189-0636-60 | Direct_Rx | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 72789-0353-01 | PD-Rx | 100 tablets | — | AB | FDA listed | — |
| divalproex sodium 250 mg 82804-0233-30 | Proficient | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 87441-0027-01 | Unit | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 250 mg 68180-0266-01 | Lupin | 100 tablets | — | — | Discontinued | — |
| divalproex sodium 250 mg 67046-1683-03 | Coupler | 30 tablets | — | AB | FDA listed | — |
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⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
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📦 Packaging — all sizes for this product
| Package NDC | Description | Marketing start | Status |
|---|---|---|---|
| 71610-0031-60 You're viewing this | 90 TABLET, DELAYED RELEASE in 1 BOTTLE (71610-031-60) | 2018-01-19 | Active |
🧭 About this NDC listing & data coverage
What data is (and isn’t) available for this NDC — tap to expand
| NDC identity (package / product / labeler codes) | ✓ Available |
| Labeler | ✓ Available |
| Product & package description | ✓ Available |
| Marketing category & status | ✓ Available |
| Active ingredient / dosage form / route | ✓ Available |
| FDA label (SPL via DailyMed) | ✓ Available |
| Package photos | ✓ Available |
| Inactive ingredients (structured) | ✓ Available |
| NADAC pharmacy acquisition price (CMS) | — Not published for this NDC CMS publishes NADAC only for NDCs reported in its retail-pharmacy survey. |
| Orange Book / therapeutic-equivalence data | ✓ Available |
| HCPCS J-code billing crosswalk | — Not published for this NDC Most self-administered / retail products have no J-code — that is normal. |
| Medicaid utilization (CMS SDUD) | — Not published for this NDC CMS reports utilization only for NDCs with Medicaid claims above its privacy threshold. |
Questions about this listing
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📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: LIFE THREATENING ADVERSE REACTIONS WARNINGS: 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 ) 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 tablets 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.
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 γ (POLG) gene (e.g. Alpers-Huttenlocher Syndrome).
Divalproex sodium delayed-release tablets 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 tablets 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 tablets 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 following in utero exposure.
Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see Contraindications (4) ]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.
This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Women should use effective contraception while using valproate [see Warnings and Precautions (5.2 , 5.3 , 5.4) ] . A Medication Guide describing the risks of valproate is av…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Divalproex Sodium Delayed-Release Tablets are an anti-epileptic drug indicated for: Treatment of manic episodes associated with bipolar disorder ( 1.1 ) 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 ) Prophylaxis of migraine headaches ( 1.3 )
1.1Mania Divalproex sodium is a valproate and is indicated for the treatment of the manic episodes associated with bipolar disorder. 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.
The efficacy of divalproex sodium delayed-release tablets was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania [see Clinical Studies (14.1) ] . The safety and effectiveness of divalproex sodium delayed-release tablets 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 divalproex sodium delayed-release tablets for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.
1.2Epilepsy Divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium delayed-release tablets are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs.
Complex absence is the term used when other signs are also present.
1.3Migraine Divalproex sodium delayed-release tablets are indicated for prophylaxis of migraine headaches. There is no evidence that divalproex sodium delayed-release tablets are useful in the acute treatment of migraine headaches.
1.4Important Limitations Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition [see Warnings and Precautions (5.2 , 5.3 , 5.4) , Use in Specific Populations (8.1) , and Patient Counseling Information (17) ] . Divalproex sodium delayed-release tablets are contraindicated for prophylaxis of migraine headaches in women who are pregnant.
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Divalproex sodium delayed-release tablets are intended for oral administration. Divalproex sodium delayed-release tablets should be swallowed whole and should not be crushed or chewed. Patients should be informed to take divalproex sodium delayed-release tablets every day as prescribed.
If a dose is missed it should be taken as soon as possible, unless it is almost time for the next dose. If a dose is skipped, the patient should not double the next dose. Divalproex sodium delayed-release tablets are administered orally in divided doses.
Divalproex sodium delayed-release tablets should be swallowed whole and should not be crushed or chewed ( 2.1 , 2.2 ). Mania: Initial dose is 750 mg daily, increasing as rapidly as possible to achieve therapeutic response or desired plasma level ( 2.1 ). The maximum recommended dosage is 60 mg/kg/day ( 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 ( 2.2 ). The maximum recommended dosage is 60 mg/kg/day ( 2.1 , 2.2 ). 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 ( 2.2 ).
The maximum recommended dosage is 60 mg/kg/day ( 2.1 , 2.2 ). Migraine: The recommended starting dose is 250 mg twice daily, thereafter increasing to a maximum of 1000 mg/day as needed ( 2.3 ).
2.1Mania Divalproex sodium delayed-release tablets are administered orally. The recommended initial dose is 750 mg daily in divided doses. The dose should be increased as rapidly as possible to achieve the lowest therapeutic dose which produces the desired clinical effect or the desired range of plasma concentrations.
In placebo-controlled clinical trials of acute mania, patients were dosed to a clinical response with a trough plasma concentration between 50 and 125 mcg/mL. Maximum concentrations were generally achieved within 14 days. The maximum recommended dosage is 60 mg/kg/day.
There is no body of evidence available from controlled trials to guide a clinician in the longer term management of a patient who improves during divalproex sodium delayed-release tablets treatment of an acute manic episode. While it is generally agreed that pharmacological treatment beyond an acute response in mania is desirable, both for maintenance of the initial response and for prevention of new manic episodes, there are no data to support the benefits of divalproex sodium delayed-release tablets in such longer-term treatment.
Although there are no efficacy data that specifically address longer-term antimanic treatment with divalproex sodium delayed-release tablets, the safety of divalproex sodium delayed-release tablets in long-term use is supported by data from record reviews involving approximately 360 patients treated with divalproex sodium delayed-release tablets for greater than 3 months.
2.2Epilepsy Divalproex sodium delayed-release tablets are administered orally. Divalproex sodium delayed-release tablets are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the divalproex sodium delayed-release tablets dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions (7.2) ] .
Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Divalproex sodium delayed-release tablets have not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day.
The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily,…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Divalproex Sodium Delayed-Release Tablets, USP are supplied as: 125 mg (as valproic acid) rose-colored tablets 250 mg (as valproic acid) peach-colored tablets 500 mg (as valproic acid) light pink-colored tablets Tablets: 125 mg, 250 mg and 500 mg ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Divalproex sodium delayed-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1) ] . Divalproex sodium delayed-release tablets are 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) ] .
Divalproex sodium delayed-release tablets are contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12) ] . Divalproex sodium delayed-release tablets are contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6) ] . Divalproex sodium delayed-release tablets are contraindicated for use in prophylaxis of migraine headaches in pregnant women [see Warnings and Precautions (5.3) and Use in Specific Populations (8.1) ] .
Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (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 ) Pregnant patients treated for prophylaxis of migraine headaches ( 4 , 8.1 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 ) Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy or bipolar disorder if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential ( 5.2 , 5.3 , 5.4 ) Pancreatitis; divalproex sodium delayed-release tablets should ordinarily be discontinued ( 5.5 ) Suicidal behavior or ideation; Antiepileptic drugs, including divalproex sodium delayed-release tablets, 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 delayed-release tablets ( 5.12 ) Somnolence in the elderly can occur. Divalproex sodium delayed-release tablets dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.14 )
5.1Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. 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.
However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk.
See below, " Patients with Known or Suspected Mitochondrial Disease ." Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium delayed-release tablets 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.
In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Divalproex sodium delayed-release tablets 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) ] . Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes.
Most of the reported case…
🤒 Adverse Reactions ▾
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 utero exposure [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.
Most common adverse reactions (reported >5%) reported in patients are abdominal pain, accidental injury, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss ( 6.1 , 6.2 , 6.3 ).
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 Upsher-Smith Laboratories, Inc. at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Mania The incidence of treatment-emergent events has been ascertained based on combined data from two three week placebo-controlled clinical trials of divalproex sodium in the treatment of manic episodes associated with bipolar disorder. The adverse reactions were usually mild or moderate in intensity, but sometimes were serious enough to interrupt treatment. In clinical trials, the rates of premature termination due to intolerance were not statistically different between placebo, divalproex sodium, and lithium carbonate.
A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium, and lithium carbonate groups, respectively. Table 2 summarizes those adverse reactions reported for patients in these trials where the incidence rate in the divalproex sodium-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium-treated group was statistically significantly greater than the placebo group. Vomiting was the only reaction that was reported by significantly (p ≤ 0.05) more patients receiving divalproex sodium compared to placebo.
Table 2. Adverse Reactions Reported by > 5% of Divalproex Sodium-Treated Patients During Placebo-Controlled Trials of Acute Mania The following adverse reactions occurred at an equal or greater incidence for placebo than for divalproex sodium: back pain, headache, constipation, diarrhea, tremor, and pharyngitis. Adverse Reaction Divalproex Sodium (n = 89) Placebo (n = 97) Nausea 22% 15% Somnolence 19% 12% Dizziness 12% 4% Vomiting 12% 3% Accidental Injury 11% 5% Asthenia 10% 7% Abdominal pain 9% 8% Dyspepsia 9% 8% Rash 6% 3% The following additional adverse reactions were reported by greater than 1% but not more than 5% of the 89 divalproex sodium-treated patients in controlled clinical trials: Body as a Whole: Chest pain, chills, chills and fever, fever, neck pain, neck rigidity.
Cardiovascular System: Hypertension, hypotension, palpitations, postural hypotension, tachycardia,…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, primidone, phenobarbital, 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 dose adjustment is indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: Monitoring of valproate concentrations are 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 tablets ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 )
7.1Effects of Coadministered Drugs on Valproate Clearance Drugs that affect the level of expression of hepatic enzymes, particularly those that elevate levels of glucuronosyltransferases (such as ritonavir), may increase the clearance of valproate. For example, phenytoin, carbamazepine, and phenobarbital (or primidone) can double the clearance of valproate. Thus, patients on monotherapy will generally have longer half-lives and higher concentrations than patients receiving polytherapy with antiepilepsy drugs.
In contrast, drugs that are inhibitors of cytochrome P450 isozymes, e.g., antidepressants, may be expected to have little effect on valproate clearance because cytochrome P450 microsomal mediated oxidation is a relatively minor secondary metabolic pathway compared to glucuronidation and beta-oxidation. Because of these changes in valproate clearance, monitoring of valproate and concomitant drug concentrations should be increased whenever enzyme inducing drugs are introduced or withdrawn. The following list provides information about the potential for an influence of several commonly prescribed medications on valproate pharmacokinetics.
The list is not exhaustive nor could it be, since new interactions are continuously being reported. Drugs for which a potentially important interaction has been observed Aspirin A study involving the coadministration of aspirin at antipyretic doses (11 to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone.
The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be coadministered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control.
The mechanism of this interaction in not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions (5.13) ] .
Estrogen-Containing Hormonal Contraceptives Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentr…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: Divalproex sodium delayed-release tablets can cause congenital malformations including neural tube defects and decreased IQ. ( 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 )
8.1Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2 , 5.3) ] . Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4) ] . Pregnancy Registry To collect information on the effects of in utero exposure to divalproex sodium delayed-release tablets, physicians should encourage pregnant patients taking divalproex sodium delayed-release tablets to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure.
Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). 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 (5.3) ] .
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3) ] . An observational study has suggested that exposure to valproate products during pregnancy may increase 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 to 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% to 7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5% to 1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1 to 2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.
Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childb…
🤰 Pregnancy ▾
8.1Pregnancy Pregnancy Category D for epilepsy and for manic episodes associated with bipolar disorder [see Warnings and Precautions (5.2 , 5.3) ] . Pregnancy Category X for prophylaxis of migraine headaches [see Contraindications (4) ] . Pregnancy Registry To collect information on the effects of in utero exposure to divalproex sodium delayed-release tablets, physicians should encourage pregnant patients taking divalproex sodium delayed-release tablets to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry.
This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure.
Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). 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 (5.3) ] .
Several published epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see Warnings and Precautions (5.3) ] . An observational study has suggested that exposure to valproate products during pregnancy may increase 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 to 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% to 7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5% to 1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits.
Clinical Considerations Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1 to 2%, compared to an estimated general population risk for spina bifida of about 0.06 to 0.07% (6 to 7 in 10,000 births). Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy.
Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Valproate is contraindicated during pregnancy in women being treated for prophylaxis of migraine headaches.
Valproate should not be used to treat women with epilepsy or bipolar disorder who are…
🧒 Pediatric Use ▾
8.4Pediatric 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 and Warnings and Precautions (5.1) ] . When valproate 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 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 six-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 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 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 2 basis.
🧓 Geriatric Use ▾
8.5Geriatric 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 (2.4) ] . There is insufficient information available to discern the safety and effectiveness of valproate for the prophylaxis of migraines in patients over 65.
🆘 Overdosage ▾
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.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism 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).
12.2Pharmacodynamics 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 cannot 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 50 and 125 mcg/mL [see Dosage and Administration (2.1) ] .
12.3Pharmacokinetics Absorption/Bioavailability Equivalent oral doses of divalproex sodium products and valproic acid capsules deliver equivalent quantities of valproate ion systemically. 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 max and C max could 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 max from 4 to 8 hours) than on the absorption of the sprinkle capsules (increase in T max from 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. Whether or not rate of absorption influences the efficacy of valproate as an antimanic or antimigraine agent is unknown.
Coadministration of oral valproate products with food and substitution among the various divalproex sodium and valproic acid formulations should cause no clinical problems in the management of patients with epilepsy [see Dosage and Administration (2.2) ] . Nonetheless, any changes in dosage administration, or the addition or discontinuance of concomitant drugs should ordinarily be accompanied by close monitoring of clinical status and valproate plasma concentrations. 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 disease…
🧬 Mechanism of Action ▾
12.1Mechanism 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).
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Divalproex Sodium Delayed-Release Tablets, USP are supplied as 250 mg (as valproic acid) tablets for oral administration. The 250 mg (as valproic acid) tablets are peach-colored, enteric-coated, capsule-shaped, imprinted with "U-S 250". 250 mg (as valproic acid) tablets: NDC 71610-031-60 Bottles of 90 Store at 20° to 25°C (68° to 77°F).
Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container with a child-resistant closure.
📦 Storage and Handling ▾
Store at 20° to 25°C (68° to 77°F). Excursions permitted to 15° to 30°C (59° to 86°F). [See USP Controlled Room Temperature.] Dispense in a tight, light-resistant container with a child-resistant closure.
📋 Description ▾
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.
Divalproex Sodium Delayed-Release Tablets, USP are for oral administration. Divalproex Sodium Delayed-Release Tablets, USP are supplied in three dosage strengths containing divalproex sodium equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Divalproex Sodium Delayed-Release Tablets, USP contain the following inactive ingredients: methacrylic acid copolymer type C, povidone, pregelatinized corn starch, silicon dioxide, simethicone emulsion, sodium bicarbonate, sodium lauryl sulfate, talc, triethyl citrate, titanium dioxide, vanillin.
The tablets are imprinted using a pharmaceutical ink. In addition, individual tablets contain: 125 mg tablets: FD&C Red No. 40.
250 mg tablets: FD&C Yellow No. 6 and iron oxide red. 500 mg tablets: FD&C Red No.
40. Chemical Structure
💬 Information for Patients ▾
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 that use of valproate during pregnancy increases the risk of birth defects and decreased IQ in children who were exposed. Advise women to use effective contraception while using 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. 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) ] . 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 patients to enroll in the 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 [see Use in Specific Populations (8.1) ] .
Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including divalproex sodium delayed-release tablets, 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) ] .
💬 Medication Guide ▾
MEDICATION GUIDE DIVALPROEX (di∙val∙pro∙ex) SODIUM DELAYED-RELEASE TABLETS, USP Read this Medication Guide before you start taking Divalproex Sodium Delayed-Release Tablets 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 Tablets? Do not stop taking Divalproex Sodium Delayed-Release Tablets without first talking to your healthcare provider. Stopping Divalproex Sodium Delayed-Release Tablets suddenly can cause serious problems.
Divalproex Sodium Delayed-Release Tablets 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 Tablets may harm your unborn baby.
If you take Divalproex Sodium Delayed-Release Tablets 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 Tablets during pregnancy for any medical condition, your child is at risk for having a lower IQ. There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child. Women who are pregnant must not take Divalproex Sodium Delayed-Release Tablets to prevent migraine headaches.
All women of childbearing age should talk to their healthcare provider about using other possible treatments instead of Divalproex Sodium Delayed-Release Tablets. If the decision is made to use Divalproex Sodium Delayed-Release Tablets, you should use effective birth control (contraception). Tell your healthcare provider right away if you become pregnant while taking Divalproex Sodium Delayed-Release Tablets.
You and your healthcare provider should decide if you will continue to take Divalproex Sodium Delayed-Release Tablets while you are pregnant. Pregnancy Registry: If you become pregnant while taking Divalproex Sodium Delayed-Release Tablets, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334.
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 Tablets may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if…