Divalproex Sodium 500 mg Tablet, Delayed Release, 100-count
Other active recalls for Divalproex Sodium (different manufacturers) — 1 · tap to view
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Mood Stabilizer class.
Where does this data come from?
🏭 Manufacturer & labeler
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🩺 Clinical
- 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.
Where does this data come from?
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 5138Q19F1X
Ammonia is a colorless gas made from nitrogen and hydrogen. It's used in medicines as a pH buffer to maintain the correct acidity level and help keep the product stable.
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UNII 8PJ61P6TS3
Butyl alcohol is a clear liquid organic solvent derived from petroleum or natural sources. In medicines, it helps dissolve active ingredients and serves as a solvent in liquid formulations and some topical products.
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UNII M28OL1HH48
Croscarmellose sodium is a plant-based substance derived from cellulose. It acts as a disintegrant, helping tablets and capsules break down quickly in the digestive system so the medicine can be absorbed.
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UNII UF064M00AF
Diethyl phthalate is a clear, colorless liquid made from phthalic acid. It's used in medicines as a plasticizer to make tablet coatings flexible and as a solvent to help dissolve and distribute active ingredients evenly throughout the product.
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UNII L06K8R7DQK
A synthetic blue dye approved by the FDA for use in medications and foods. It serves as a colorant to make pills and liquids visually distinct and easier to identify.
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UNII WZB9127XOA
A synthetic red dye used to color medications and make them easier to identify. It serves as a colorant in tablets, capsules, and liquid formulations.
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UNII XM0M87F357
A dark iron oxide compound that gives medicines their black or dark color. It's used as a colorant in tablets and capsules to help identify the product and make it visually distinctive.
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UNII 36SFW2JZ0W
Hypromellose 2910 is a plant-based thickening agent derived from cellulose. In medicines, it forms a protective coating on tablets or capsules and controls how quickly the drug dissolves and releases into your body.
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UNII ND2M416302
Isopropyl alcohol is a clear liquid solvent derived from petroleum. In medicines, it dissolves active ingredients and other components, helps the product flow smoothly, and aids in sterilization during manufacturing.
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UNII 1DI56QDM62
A natural fatty substance from soybeans that helps mix oil and water-based ingredients together. It acts as an emulsifier and lubricant in medicines to improve texture and help the product break down properly in your body.
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UNII 2165RE0K14
A plant-based thickener made from cellulose that helps control how quickly the medicine dissolves and releases its active ingredient. It also binds ingredients together and improves the tablet's texture and handling during manufacturing.
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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 OP1R32D61U
Microcrystalline cellulose is a purified form of cellulose, a natural fiber from plant sources. It acts as a binder and filler in tablets and capsules, helping hold ingredients together and give the medicine its shape and size.
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UNII G2M7P15E5P
Polyethylene glycol 3350 is a synthetic polymer used as a solvent, humectant, and thickening agent in medicines. It helps dissolve other ingredients, retain moisture in the product, and achieve the desired consistency.
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UNII 532B59J990
Polyvinyl alcohol is a synthetic polymer made from plant-derived materials. It's used as a binder to hold ingredients together, a film-former in coatings, and a thickener in liquid formulations.
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UNII U725QWY32X
Povidone K30 is a synthetic polymer made from petroleum. It acts as a binder to hold tablet ingredients together and as a disintegrant to help the tablet break apart in the stomach so the medicine can be absorbed.
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UNII 6DC9Q167V3
Propylene glycol is a clear liquid derived from petroleum or vegetable sources. It acts as a solvent, humectant, and preservative in medicines, helping dissolve active ingredients and maintain product stability.
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UNII 46N107B71O
Shellac is a natural resin secreted by the lac beetle. It's used as a coating on tablets and capsules to control how quickly the medicine dissolves and to improve appearance and stability.
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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 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 XHX3C3X673
Triacetin is a clear, oily liquid made from glycerin and acetic acid. It works as a plasticizer and solvent in medicines, helping soften coatings and improve how liquids mix together in formulations.
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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.
23 inactive ingredients listed in the exact product block matched to this NDC.
Where does this data come from?
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
Are inactive ingredients the same for every manufacturer?
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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 ea | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.161 | $16.05 / 100 tablets |
| Medicaid paysCMS SDUD · 12 mo | $0.2524 | $25.24 / 100 tablets |
| Medicare drug plans payPart D · Q2 2026 | $0.1520 | $15.20 / 100 tablets |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Divalproex Sodium 500 mg 00832-7124-01 | Upsher-Smith | 1 tablet | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mg 00904-6861-61 | Major | 1 tablet | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mg 29300-0140-01 | Unichem | 100 tablets | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mgthis 57237-0048-01 | Rising | 100 tablets | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mg 60687-0879-61 | American | 1 tablet | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mg 68001-0474-00 | BluePoint | 100 tablets | $0.161 | AB | Availability likely | — |
| Divalproex Sodium 500 mg 68084-0782-61 | American | 1 tablet | $0.164 | AB | Discontinued | +2% |
| Depakote 500 mg 00074-7327-13 | AbbVie | 100 tablets | $7.453 | AB | Availability likely | +4543% |
| divalproex sodium 500 mg 00615-8588-39 | NCS | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 500 mg 55111-0531-01 | Dr.Reddy's | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 55154-2336-00 | Cardinal | 1 tablet | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 55154-4679-00 | Cardinal | 1 tablet | — | AB | Discontinued | — |
| Divalproex Sodium 500 mg 55154-5633-00 | Cardinal | 1 tablet | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 60760-0798-60 | St. | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 61919-0249-60 | DirectRx | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 62756-0798-08 | Sun | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 63187-0743-30 | Proficient | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 63629-4278-01 | Bryant | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 65862-0403-01 | Aurobindo | 100 tablets | — | AB | FDA listed | — |
| divalproex sodium 500 mg 67046-1647-03 | Coupler | 30 tablets | — | AB | FDA listed | — |
| divalproex sodium 500 mg 69452-0435-13 | Bionpharma | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 70518-1558-00 | REMEDYREPACK | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 70518-2357-00 | REMEDYREPACK | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 70518-2626-00 | REMEDYREPACK | 1 tablet | — | AB | Discontinued | — |
| Divalproex Sodium 500 mg 70518-2674-02 | REMEDYREPACK | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 70518-4575-00 | REMEDYREPACK | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 71335-2124-01 | Bryant | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 71335-2158-01 | Bryant | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 71335-2344-01 | Bryant | 60 tablets | — | AB | FDA listed | — |
| divalproex sodium 500 mg 71335-2782-01 | Bryant | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 71610-0032-53 | Aphena | 60 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 72789-0354-01 | PD-Rx | 100 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 87441-0028-01 | Unit | 30 tablets | — | AB | FDA listed | — |
| Divalproex Sodium 500 mg 68180-0267-01 | Lupin | 100 tablets | — | — | Discontinued | — |
Where does this data come from?
⏳ 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?
🗺️ Medicaid utilization & spend
💊 Medicaid utilization by pack size
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
🔬 Reported adverse events (FAERS)
Top reported reactions
Age at onset
Reporter sex
Serious outcomes
Where does this data come from?
📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 57237-0048-01 You're viewing this | 100 TABLET, DELAYED RELEASE in 1 BOTTLE (57237-048-01) | $0.1605 / ea | $16.05 | 2014-10-24 | Active |
| 57237-0048-05 | 500 TABLET, DELAYED RELEASE in 1 BOTTLE (57237-048-05) | $0.1605 / ea | $80.27 | 2014-10-24 | Active |
You're viewing the smallest of 2 pack sizes for this product.
This pack has the lowest per-ea cost of the 2 priced pack sizes ($0.1605 NADAC).
This pack accounts for about 41% of this product's recent Medicaid fills; most go to the 500 tablets pack. See all packs ↓
Pack size FAQ
What quantity is in NDC 57237-0048-01?
What is the difference between NDC 57237-0048-01 and NDC 57237-0048-05?
What NDC number is used to bill for this package of Divalproex Sodium 500 mg Tablet, Delayed Release?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: LIFE THREATENING ADVERSE REACTIONS 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 and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see Contraindications (4) ] .
Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see Warnings and Precautions (5.2 , 5.3, 5.4) ] .
A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information (17) ] . Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death.
Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Divalproex sodium is 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 delayed-release tablets are a valproate and are 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, 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, divalproex sodium delayed-release tablets are contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications (4) ].
⏱️ 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 1,000 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, optimal cli…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Divalproex sodium delayed-release tablets, USP are supplied as: 125 mg is pink-red colored, oval shaped enteric-coated tablets, imprinted with “D 84” on one side with black edible ink and plain on other side. 250 mg is peach colored, oval shaped enteric-coated tablets, imprinted with “D 85”on one side with black edible ink and plain on other side. 500 mg is pink colored, oval shaped enteric-coated tablets, imprinted with “D 86” on one side with black edible ink and plain on other side.
Tablets: 125 mg, 250 mg and 500 mg (3)
⛔ Contraindications ▾
4 CONTRAINDICATIONS Divalproex sodium delayed-release tablets are contraindicated in patients: with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1) ] . 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) ]. with known hypersensitivity to divalproex sodium, sodium valproate, or valproic acid.
Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema [see Warnings and Precautions (5.12 , 5.13 , 5.14) ] . with known urea cycle disorders [see Warnings and Precautions (5.6) ] . being treated for prophylaxis of migraine headaches who are pregnant or 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) ] . 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 divalproex sodium, sodium valproate, or valproic acid ( 4 , 5.12 , 5.13 , 5.14 ) Urea cycle disorders ( 4 , 5.6) Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure: Should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable (5.2, 5.3, 5.4) Pancreatitis: Divalproex sodium delayed-release 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 occur in patients using concomitant topiramate (5.11) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity Reactions, serious dermatologic reactions, and angioedema: Discontinue divalproex sodium delayed-release tablets unless an alternate etiology is established ( 4 , 5.12 , 5.13 , 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 of valproate therapy.
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 cases of liver failure in patients with these syndromes have been identified in children and adolescents. POLG-relate…
🤒 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 and Neurodevelopmental Disorders 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) ] Serious Dermatologic Reactions [see Warnings and Precautions (5.13) ] Angioedema [see Warnings and Precautions (5.14) ] Somnolence in the Elderly [see Warnings and Precautions (5.16) ] 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 ≥15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness, headache, infection, insomnia, nausea, somnolence, thrombocytopenia, tremor, vomiting ( 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 Rising Pharma Holdings, Inc. at 1-844-874-7464 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 delayed-release tablets 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 delayed-release tablets, and lithium carbonate.
A total of 4%, 8% and 11% of patients discontinued therapy due to intolerance in the placebo, divalproex sodium delayed-release tablets, 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 delayed-release tablets-treated group was greater than 5% and greater than the placebo incidence, or where the incidence in the divalproex sodium delayed-release tablets-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 delayed-release tablets compared to placebo. Table 2. Adverse Reactions Reported by > 5% of Divalproex Sodium Delayed-Release Tablets-Treated Patients During Placebo-Controlled Trials of Acute Mania 1 Adverse Reaction Divalproex Sodium Delayed-Release Tablets (n = 89) % Placebo (n = 97) % 1 The following adverse reactions occurred at an equal or greater incidence for placebo than for divalproex sodium delayed-release tablets: back pain, headache, constipation, diarrhea, tremor, and pharyngitis.
Nausea 22 15 Somnolence 19 12 Dizziness 12 4 Vomiting 12 3 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 delayed-release tablets-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, palpitati…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn (7.1) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives, methotrexate: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration 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) Cannabidiol: ALT and/or AST elevation ( 7.4 )
7.1Effects of Co-Administered 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 co-administration 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 co-administered. 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 is 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 (5.15) ] .
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 freq…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: Divalproex sodium delayed-release tablets can cause congenital malformations including neural tube defects, decreased IQ, and neurodevelopmental disorders ( 5.2 , 5.3 , 8.1 ) Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence ( 5.16 , 8.5 )
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium delayed-release tablets, during pregnancy. Encourage women who are taking divalproex sodium delayed-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications (4)] . For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions (5.2 , 5.3)] .
Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations).
This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. In utero exposure 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) and Data] . Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID, defined as an IQ < 70), and attention deficit/hyperactivity disorder (ADHD), compared to children exposed to either another AED in utero or to no AEDs in utero [see Warnings and Precautions (5.3) and Data] .
In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data] . 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 wom…
🤰 Pregnancy ▾
8.1Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium delayed-release tablets, during pregnancy. Encourage women who are taking divalproex sodium delayed-release tablets during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself.
Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications (4)] . For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions (5.2 , 5.3)] .
Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations).
This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. In utero exposure 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) and Data] . Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID, defined as an IQ < 70), and attention deficit/hyperactivity disorder (ADHD), compared to children exposed to either another AED in utero or to no AEDs in utero [see Warnings and Precautions (5.3) and Data] .
In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data] . 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…
🧒 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 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.
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 ER for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on divalproex sodium ER) and migraine (304 patients aged 12 to 17 years, 231 of whom were on divalproex sodium 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 divalproex sodium 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 divalproex sodium ER 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 (5.16) ] .
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.
Co-administration 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 disea…
🧬 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: Divalproex Sodium Delayed-Release Tablets USP, 125 mg are pink-red colored, oval shaped enteric-coated tablets, imprinted with “D 84” on one side with black edible ink and plain on other side. Bottles of 100 NDC 57237-106-01 Bottles of 500 NDC 57237-106-05 Divalproex Sodium Delayed-Release Tablets USP, 250 mg are peach colored, oval shaped enteric-coated tablets, imprinted with “D 85”on one side with black edible ink and plain on other side.
Bottles of 100 NDC 57237-047-01 Bottles of 500 NDC 57237-047-05 Divalproex Sodium Delayed-Release Tablets USP, 500 mg are pink colored, oval shaped enteric-coated tablets, imprinted with “D 86” on one side with black edible ink and plain on other side. Bottles of 100 NDC 57237-048-01 Bottles of 500 NDC 57237-048-05 Recommended Storage 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].
📋 Description ▾
11 DESCRIPTION Divalproex sodium is a stable co-ordination compound comprised of sodium valproate and valproic acid in a 1:1 molar relationship. Chemically it is designated as sodium hydrogen bis(2-propylpentanoate). Divalproex sodium has the following structure: Divalproex sodium USP occurs as a white crystalline 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 USP equivalent to 125 mg, 250 mg, or 500 mg of valproic acid. Inactive Ingredients Divalproex sodium delayed-release tablets, USP: silicon dioxide, microcrystalline cellulose, croscarmellose sodium, povidone (Kollidon 30), hydroxypropyl cellulose low substituted, talc, methacrylic acid and ethyl acrylate copolymer dispersion, and diethyl phthalate.
In addition, 125 mg tablets are coated with opadry clear 04K59023 and opadry II complete film coating system 86G540000 pink. Opadry clear 04K59023 contains hypromellose and triacetin, opadry II complete film coating system 86G540000 pink contains polyvinyl alcohol, talc, titanium dioxide, macrogol/PEG 3350, FD&C Red #40, lecithin (soya), and vanillin. 250 mg tablets are coated with opadry clear 04K59023 and opadry II 86G53866 orange.
Opadry clear 04K59023 contains hypromellose and triacetin, opadry II 86G53866 orange contains polyvinyl alcohol, talc, titanium dioxide, macrogol/PEG 3350, lecithin (soya), vanillin, FD&C Yellow #6, and iron oxide yellow. 500 mg tablets are coated with opadry clear 04K59023 and opadry II 86G84795 pink. Opadry clear 04K59023 contains hypromellose and triacetin, opadry II 86G84795 pink contains polyvinyl alcohol, talc, titanium dioxide, macrogol/PEG 3350, lecithin (soya), FD&C Red #40, vanillin, and FD&C Blue #2.
The tablets are printed with opacode black S-1-17823 containing shellac glaze in ethanol, isopropyl alcohol, iron oxide black, N-butyl alcohol, propylene glycol, and ammonium hydroxide. 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, Decreased IQ, and Neurodevelopmental Disorders 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 [see Warnings and Precautions (5.2 , 5.3 , 5.4 ) and Use in Specific Populations (8.1) ] . 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) ] . Pregnancy Registry Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage women who are taking divalproex sodium delayed-release tablets to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant.
This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 or visit the website, http://www.aedpregnancyregistry.org/ [see Use in Specific Populations (8.1) ] . Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including divalproex sodium delayed-release 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.
Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/ Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related. Advise patients to report such reactions to a healthcare provider immediately [see Warnings and Precautions (5.12) ] . Serious Dermatologic Reactions Advise patients of the early signs and symptoms of severe cutaneous adverse reactions and to report any occurrence immediately to a healthcare provider [see Warnings and Precautions (5.13) ] .
Angioedema Advise patients to discontinue divalproex sodium delayed-release tablets and seek immediate medical care if they develop signs or symptoms of angioedema, such as facial, perioral, or upper airway swelling [see Warnings and Precautions (5.14) ] . Medication Residue in the Stool Instruct patients to notify their healthcare provider if…
💬 Medication Guide ▾
Dispense with Medication Guide available at: https://risingpharma.com/Medguides/DivalproexSodiumDRTabletsMG.pdf MEDICATION GUIDE Divalproex Sodium (dye val' proe ex soe' dee um) Delayed-Release Tablets, USP What is the most important information I should know about divalproex sodium delayed-release tablets? Do not stop divalproex sodium delayed-release tablets without first talking to a healthcare provider. Stopping divalproex sodium delayed-release tablets 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). 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 and 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 divalproex sodium delayed-release tablets. 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 (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 divalproex sodium delayed-release tablets 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 divalproex sodium delayed-release tablets to prevent migraine headaches.
All women of childbearing age (including girls from the start of puberty) should talk to their healthcare provider about using other possible treatments instead of divalproex sodium delayed-release 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 (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.…