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Divalproex Sodium 500 mg Tablet, Delayed Release, 100-count — NDC 68180-0267-01 package photo
Label image from the product's FDA listing (DailyMed) — may show a different pack size or an older label revision.

Divalproex Sodium 500 mg Tablet, Delayed Release, 100-count — NDC 68180-267-01 (Billing 68180-0267-01)

by Lupin Pharmaceuticals, Inc. · 100 TABLET, DELAYED RELEASE in 1 BOTTLE

This is a package of 100 tablets of Divalproex Sodium 500 mg Tablet, Delayed Release from Lupin Pharmaceuticals, Inc., no longer marketed (first marketed Jul 2008), no longer in the FDA NDC Directory. It is the main listing for this product, which comes in 4 package sizes.

NDC 68180-0267-01
🏷️ FDA NDC (as labeled) 68180-267-01 billing pads the product segment with a zero
This package
Contains100-count Pack sizes4 compare ↓
Main listing for product 68180-267 · Also comes in: 10 tablets 68180-267-11 500 tablets 68180-267-02 1000 tablets 68180-267-03
Rx only Generic Discontinued Non-controlled ⚠ Discontinued by firm ⇄ Compare with another NDC
🗂️ FDA directory synced Oct 1, 2026 · this listing last changed Jul 24, 2026 · sources: openFDA · FDA label (DailyMed) · FDA Orange & Purple Book · First Databank · CMS NADAC, ASP, Medicare & Medicaid · RxNorm
📋 All sources & update times →

This page is curated, coded, and maintained by

Compiled from public FDA, CMS, DailyMed, NADAC, and related drug data sources. Editorial policy

⚠️
Other active recalls for Divalproex Sodium (different manufacturers) — 1 · tap to view
These affect other manufacturers’ products for the same ingredient — not necessarily the exact NDC on this page.
Class II · Jun 26, 2026 — Presence of Foreign Tablets/Capsules (Bionpharma Inc.) · FDA recall D-0742-2026
Each entry is an official FDA enforcement report — look up any recall number in the FDA recall database ↗
⚠️
Excluded from the active FDA NDC Directory. The labeler reported this product as discontinued, so it is excluded from the active NDC Directory. A label may still appear on DailyMed, but the NDC is no longer in the current FDA NDC Directory. Search the FDA NDC Directory ↗

Identity & classification

Regulatory identifiers FDA, NLM and CMS codes for this package

FDA NDC (as labeled) 68180-267-01
Product NDC 68180-267
11-digit billing NDC 68180026701
NCPDP billing unit EA — each (per item)
RxCUI 1099625, 1099678, 1099870
UNII 644VL95AO6
UPC 0368180267010
Application # ANDA078790
SPL Set ID 33798a7c-c5a9-49a5-be5d-1312910ef468
Established class (EPC) Anti-epileptic Agent; Mood Stabilizer
Physiologic effect Decreased Central Nervous System Disorganized Electrical Activity
DEA schedule Non-controlled
Marketing category ANDA
Marketing status Discontinued
FDA listing status Discontinued by firm
Marketing start 2008-07-29
Route ORAL
Dosage form TABLET, DELAYED RELEASE
Substance DIVALPROEX SODIUM

Drug-database identifiers Medi-Span GPI and First Databank GCN / HICL / AHFS classification

GCN Seq No 004540
GCN 17291
HICL code 001884
Ingredient (HICL) Divalproex Sodium
HIC1 code H
Therapeutic class — broad (HIC1) Nervous System (Except Autonomic)
HIC2 code H4
Therapeutic class — intermediate (HIC2) Anticonvulsants
HIC3 code H4B
Therapeutic class — specific (HIC3) Anticonvulsants
AHFS code 28:12.28.00
AHFS class Gaba-Mediated Anticonvulsants
FDB label name DIVALPROEX SOD DR 500 MG TAB
FDB brand name Divalproex Sodium
Legend status F — Federal legend — prescription drug or device
Quick answers
  • GSN (GCN sequence number): 004540
  • GCN: 17291
  • HICL (First Databank): 001884
  • AHFS class code: 28:12.28.00
  • RxCUI (RxNorm): 1099625
Why two NDCs? The FDA registers this code as 68180-267-01 — a 5-3-2 layout, and that's what's printed on the package and shown on DailyMed. For insurance claims, every NDC is standardized to a uniform 11-digit 5-4-2 format by adding a zero to the product segment → 68180-0267-01. Same drug, same package — only the format differs.
Where does this data come from?
Identifiers from the FDA openFDA NDC Directory and Structured Product Labeling; RxCUI from RxNorm (NLM); GPI from Medi-Span; GCN / HIC / AHFS / legend from First Databank.

RxNorm drug class

This medicine belongs to the Mood Stabilizer class.

Pharmacologic class Mood Stabilizer, Anti-epileptic Agent
Drug family (ATC) Fatty acid derivatives
Where does this data come from?
Therapeutic classes from RxNorm RxClass (U.S. National Library of Medicine) — Established Pharmacologic Class (FDA), ATC drug family (WHO) and mechanism of action, matched by this product’s RxCUI.

Clinical

Label name DIVALPROEX SOD DR 500 MG TAB Ingredient Divalproex Sodium
📖 What it is MedlinePlus · NLM

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 ↗
📗 Our plain-language guide HelloPharmacist
  • It treats seizures, manic episodes of bipolar disorder, and prevents migraines. Which uses apply depends on the product. Capsules are only for seizures. Ask me to check which one y...
  • Swallow tablets whole and never crush or chew them. Extended-release tablets are once a day. Capsules can be swallowed whole or sprinkled on soft food and swallowed right away. Tak...
  • For delayed-release tablets, take it as soon as you remember unless it is almost time for the next dose. Do not double up. Ask your prescriber if you take another form.
  • Nausea, stomach upset, sleepiness, dizziness, tremor, headache and hair loss are common. Call your doctor if they bother you a lot. Call right away for severe stomach pain, vomitin...
📖 Read our full Divalproex guide →
1
Nutrient depletion considerations

Divalproex Sodium may be associated with lower levels of 1 nutrient — worth a chat with your pharmacist, not a cause for alarm.

🧪 Full Divalproex Sodium nutrient depletion report →
An association is not a deficiency. Educational only — don't start or stop anything without professional guidance.
Where does this data come from?
Plain-language summary from MedlinePlus (U.S. National Library of Medicine); supplement & herbal interactions and nutrient depletion data from the Natural Medicines database; our full guide is HelloPharmacist editorial content.

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 systemPer eachPer 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 · quarterly No Part D plan price is available for this NDC in our data.
ℹ️
No price is published for this exact package yet. CMS surveys NADAC per package size, so a different pack of the same drug often has one.
Try another pack size: 10 tablets 500 tablets 1000 tablets
Where does this data come from?
NADAC (National Average Drug Acquisition Cost) is the CMS weekly pharmacy-acquisition-cost survey — what pharmacies pay. ASP (Average Sales Price) is the CMS Medicare Part B drug-payment file, published quarterly. Medicaid pays is computed by us from CMS State Drug Utilization Data (total reimbursed ÷ units, trailing 12 months) — gross of rebates and inclusive of dispensing fees, so it reflects what Medicaid paid, not an acquisition cost. Medicare drug plans pay is the median negotiated point-of-sale unit cost across plans listing this NDC in the CMS quarterly Prescription Drug Plan pricing files, before rebates. The VA pays is the federal contract price (FSS, and the statutory Big 4 ceiling where listed) from the VA National Acquisition Center pharmaceutical price file. All are free public government data; each measures a different payer, so the figures are not directly comparable.

Packaging — all sizes for this product

Package NDCDescription Marketing startMarketing endStatus
68180-0267-01 You're viewing this Main listing 100 TABLET, DELAYED RELEASE in 1 BOTTLE 2008-07-29 — Discontinued by firm
68180-0267-02 68180-267-02 500 TABLET, DELAYED RELEASE in 1 BOTTLE 2008-07-29 — Discontinued by firm
68180-0267-03 68180-267-03 1000 TABLET, DELAYED RELEASE in 1 BOTTLE 2008-07-29 — Active
68180-0267-11 68180-267-11 10 TABLET, DELAYED RELEASE in 1 BLISTER PACK 2008-07-29 — Active

You're viewing one of 4 pack sizes for this product.

Pack size FAQ

What quantity is in this package?
This is a 100-count package — 100 tablet, delayed release in 1 bottle.
How does this package differ from NDC 68180-0267-11?
Both are Divalproex Sodium 500 mg Tablet, Delayed Release — the drug itself is identical. This page's package is the 100-count one, while NDC 68180-0267-11 is the 10 tablets package.
What NDC number is used to bill for this package of Divalproex Sodium 500 mg Tablet, Delayed Release?
Use the 11-digit billing form listed in the identifiers section of this page. Pharmacy and medical claims use the 11-digit form; the FDA label may print a shorter form of the same code.

Therapeutic equivalents

ProductLabelerPackNADAC/unitTEStatusPrice 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 mg 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 —
Depakote 500 mg 00074-7327-13 AbbVie 100 tablets $7.456 AB Availability likely —
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 mgthis 68180-0267-01 Lupin 100 tablets — — Discontinued —
About this product: this is a generic version of the medicine. FDA equivalence ratings are shown when available, and other versions are listed above, least expensive first.
Where does this data come from?
Equivalents are other NDCs of the same ingredient, form and route from the openFDA NDC Directory, ranked least-expensive-first by NADAC. Therapeutic-equivalence (AB) ratings come from the FDA Orange Book; biologics use the FDA Purple Book for biosimilar & interchangeable status.

Availability & generic status

🏛️
2008
On the market since
Jul 2008
📍
2026
Currently FDA-listed
18 years listed
🔓
·
Generic on the market
this product is a generic
✅This is a generic drug

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?
Patents and exclusivity from the FDA Orange Book (small-molecule drugs), refreshed from public FDA data. Generic launch timing is an estimate, not a guarantee.

What it looks like

Color Pink
ShapeOval
ImprintL007
Size19 mm
ScoringNot scored
One label can cover several strengths, so colors may be combined — always confirm a loose pill against the dispensed prescription label or a pharmacist.
Where does this data come from?
Physical description (imprint, shape, color, scoring, coating) from this product’s FDA Structured Product Labeling (SPL), mirrored from DailyMed / openFDA.

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.

  • 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.
  • UNII 2S42T2808B
    A synthetic red dye used as a colorant to give the medicine its red color. It helps make pills or liquids visually distinct and easier to identify.
  • 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.
  • UNII EX438O2MRT
    Ferric oxide yellow is a naturally occurring iron compound used as a colorant in medications. It gives tablets, capsules, and other forms a yellow or golden hue for identification and appearance.
  • 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.
  • UNII RFW2ET671P
    Hydroxypropyl cellulose is a plant-derived thickening agent made from cellulose. It acts as a binder to hold tablet ingredients together and as a film-former to coat tablets or control how fast the medicine releases.
  • 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.
  • UNII 87Y6436BKR
    Hypromellose phthalate is a plant-derived polymer that forms a protective coating around pills and capsules. It dissolves in the intestines rather than the stomach, helping deliver the medicine to the right place for absorption.
  • UNII 3NXW29V3WO
    Hypromellose is a plant-based thickener made from cellulose. It's used in medicines as a binder to hold ingredients together, a coating for tablets, and a thickener for liquids.
  • UNII 70097M6I30
    Magnesium stearate is a salt made from magnesium and stearic acid, a fatty substance. It's used in tablets and capsules as a lubricant and glidant to help ingredients flow smoothly during manufacturing and prevent sticking.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.

17 inactive ingredients listed in the exact product block matched to this NDC.

Where does this data come from?
Data sourced from official FDA Structured Product Labeling (SPL) via DailyMed — 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?
No. Inactive ingredients can differ by manufacturer, dosage form, strength, and package / product version.
Why might an inactive ingredient be missing?
Some SPLs do not provide a complete structured inactive-ingredient list, and older or unusual labels may only include the information in narrative text.
Can inactive ingredients matter?
Yes. They can matter for allergies, intolerances, dyes, gluten / lactose concerns, preservatives, and formulation differences — but confirm with a pharmacist or the manufacturer when it’s clinically important.

Manufacturer & labeler

LabelerLupin Pharmaceuticals, Inc.
Application holderLUPIN LTD
FDA applicationANDA078790 (ANDA)
Labeler code68180
First marketedJul 2008
Product typeHuman Prescription Drug
Portfolio404 products on file
The labeler markets the product; the application holder owns the FDA approval. They’re often the same company but can differ (e.g. a repackager or an authorized generic). A mailing address / phone appears here when the manufacturer includes it in the product’s FDA label (not all do).
Where does this data come from?
Labeler, application holder and registered establishment from the FDA openFDA NDC Directory and Drugs@FDA; address/contact from the product’s FDA label.

Full prescribing information FDA SPL

The complete FDA label for this product — the official prescribing information, verbatim, section by section. Very long sections are excerpted here and marked; the full text is on DailyMed (linked in the sources below). Jump with a chip, search within the label, or expand everything.
🚨 Boxed Warning 🎯 Indications and Usage ⏱️ Dosage and Administration 💊 Dosage Forms and Strengths ⛔ Contraindications ⚠️ Warnings and Cautions 🤒 Adverse Reactions 🔄 Drug Interactions 👥 Use in Specific Populations 🤰 Pregnancy 🧒 Pediatric Use 🧓 Geriatric Use 🆘 Overdosage 🧬 Clinical Pharmacology 🧬 Mechanism of Action 📦 How Supplied / Storage and Handling 📋 Description 💬 Information for Patients 💬 Medication Guide 🍼 Nursing Mothers 🧬 Pharmacokinetics 🧬 Pharmacodynamics 🔬 Clinical Studies 🧪 Nonclinical Toxicology 📚 References 📄 Recent Major Changes 📄 Package Label / Principal Display Panel
🚨 Boxed Warning ~3 min read ▾

WARNING: LIFE THREATENING ADVERSE REACTIONS WARNING: LIFE THREATENING ADVERSE REACTIONS See full prescribing information for complete boxed warning. Hepatotoxicity, including fatalities, usually during the first 6 months of treatment. Children under the age of two years and patients with mitochondrial disorders are at higher risk.

Monitor patients closely, and perform serum liver testing prior to therapy and at frequent intervals thereafter ( 5.1 ) Fetal Risk, particularly neural tube defects, other major malformations, and decreased IQ ( 5.2 , 5.3 , 5.4 ) Pancreatitis, including fatal hemorrhagic cases ( 5.5 ) 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 is 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 should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium 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… [Excerpted — this section continues on DailyMed.]

🎯 Indications and Usage ~2 min read ▾

1 INDICATIONS AND USAGE Divalproex sodium delayed-release tablet 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 tablet 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 tablet is 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 ~3 min read ▾

2 DOSAGE AND ADMINISTRATION 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 ).

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.

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… [Excerpted — this section continues on DailyMed.]

💊 Dosage Forms and Strengths 106 words ▾

3 DOSAGE FORMS AND STRENGTHS Tablets: 125 mg, 250 mg and 500 mg ( 3 ) Divalproex sodium delayed-release tablets, 125 mg are pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L005" (in black ink) on one side and plain on the other side. Divalproex sodium delayed-release tablets, 250 mg are pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L006" (in black ink) on one side and plain on the other side. Divalproex sodium delayed-release tablets, 500 mg are pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L007" (in black ink) on one side and plain on the other side.

⛔ Contraindications ~1 min read ▾

4 CONTRAINDICATIONS 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 ) 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 ) ] .

⚠️ Warnings and Cautions ~3 min read ▾

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 should ordinarily be discontinued ( 5.5 ) Suicidal behavior or ideation: Antiepileptic drugs, including divalproex sodium, 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 Reaction; serious dermatologic reactions, and angioedema: Discontinue divalproex sodium 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 is 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-related disorders should be suspected in patients with a family history or suggestive sym… [Excerpted — this section continues on DailyMed.]

🤒 Adverse Reactions ~3 min read ▾

6 ADVERSE REACTIONS 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 Lupin Pharmaceuticals, Inc. at 1-800-399-2561 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 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.

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 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.

Adverse Reaction Divalproex Sodium Delayed-Release Tablets (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 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,… [Excerpted — this section continues on DailyMed.]

🔄 Drug Interactions ~2 min read ▾

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 seiz… [Excerpted — this section continues on DailyMed.]

👥 Use in Specific Populations ~3 min read ▾

8 USE IN SPECIFIC POPULATIONS Pregnancy: Divalproex sodium delayed-release tablets can cause congenital malformations including 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 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 Preca utions ( 5.3 ) and Data] .

Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders 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, hypofibrinoge… [Excerpted — this section continues on DailyMed.]

🤰 Pregnancy ~3 min read ▾

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 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 Preca utions ( 5.3 ) and Data] .

Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders 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 aci… [Excerpted — this section continues on DailyMed.]

🧒 Pediatric Use ~2 min read ▾

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 Warning 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 Depakote ER Tablets * for the indications of mania (150 patients aged 10 to 17 years, 76 of whom were on Depakote ER Tablets * ) and migraine (304 patients aged 12 to 17 years, 231 of whom were on Depakote ER 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 Depakote ER 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 Depakote ER Tablets * for the indication of migraine (353 patients aged 12 to 17 years). One twelve-month study was conducted to evaluate the safety of Depakote Sprinkle Capsules * in the indication of partial seizures (169 patients aged 3 to 10 years). In these seven clinical trials, the safety and tolerability of 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 169 words ▾

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 122 words ▾

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 ~3 min read ▾

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 dise… [Excerpted — this section continues on DailyMed.]

🧬 Mechanism of Action 47 words ▾

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 187 words ▾

16 HOW SUPPLIED/STORAGE AND HANDLING Divalproex sodium delayed-release tablets USP are supplied as: 125 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L005" (in black ink) on one side and plain on the other side. Bottles of 100 NDC 68180-265-01 Bottles of 500 NDC 68180-265-02 Box containing 10 x 10's unit dose tablets NDC 68180-265-13 250 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L006" (in black ink) on one side and plain on the other side.

Bottles of 100 NDC 68180-266-01 Bottles of 500 NDC 68180-266-02 Bottles of 1000 NDC 68180-266-03 Box containing 10 x 10's unit dose tablets NDC 68180-266-13 500 mg (as valproic acid) pink colored, oval shaped, biconvex, enteric coated tablets, imprinted with "L007" (in black ink) on one side and plain on the other side. Bottles of 100 NDC 68180-267-01 Bottles of 500 NDC 68180-267-02 Bottles of 1000 NDC 68180-267-03 Box containing 10 x 10's unit dose tablets NDC 68180-267-13 Recommended storage Store at 25°C (77°F); excursions permitted to 15° to 30°C (59° to 86°F) [see USP Controlled Room Temperature].

📋 Description 144 words ▾

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: colloidal silicon dioxide, D&C Red No.

30, FD&C Blue No. 2, hydroxylpropyl cellulose, hypromellose, hypromellose phthalate, iron oxide black, iron oxide yellow, low substituted hydroxypropyl cellulose, magnesium stearate, microcrystalline cellulose, pregelatinised starch, propylene glycol, shellac, talc, titanium dioxide, triethyl citrate. Structure

💬 Information for Patients ~3 min read ▾

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… [Excerpted — this section continues on DailyMed.]

💬 Medication Guide ~3 min read ▾

MEDICATION GUIDE Divalproex Sodium (dye val' proe ex soe' dee um) Delayed-Release Tablets, for oral use Rx only 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 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. 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 duri… [Excerpted — this section continues on DailyMed.]

🍼 Nursing Mothers 117 words ▾

8.3Females and Males of Reproductive Potential Contraception Women of childbearing potential should use effective contraception while taking valproate [see Boxed Warning , Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.1 )] . This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications ( 4 )]. Infertility There have been reports of male infertility coincident with valproate therapy [see Adverse Reactions ( 6.4 )] .

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

🧬 Pharmacokinetics ~3 min read ▾

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 diseases, in patients with renal impairment, and in the presence of other drugs (e.g., aspirin). Conversely, valproate may displace certain protein-bound drugs (e.g., phenytoin, carbamazepine, warfarin, and tolbutamide) [see Drug Interactions ( 7.2 ) for more detailed information on the pharmacokinetic interactions of valproate with other drugs]. CNS Distribution: Valproate concentrations in cerebrospinal fluid (CSF) approximate unbound concentrations in plasma (about 10% of total concentration).

Metabolism Valproate is metabolized almost entirely by the liver. In adult patients on monotherapy, 30 to 50% of an administered dose appears in urine as a glucuronide conjugate. Mitochondrial β-oxidation is the other major metabolic pathway, typically accounting for over 40% of the dose.

Usually, less than 15 to 20% of the dose is eliminated by other oxidative mechanisms. Less than 3% of an administered dose is excreted unchanged in urine. The relationship between dose and total valproate concentration is nonlinear; concentration does not increase proportionally with the dose, but rather, increases to a lesser extent due to saturable plasma protein binding.

The kinetics of unbound drug are linear. Elimination Mean plasma clearance and volume of distribution for total valproate are

0.56L/hr/1.73 m 2 and 11 L/1.73 m 2 , respectively. Mean plasma clearance and volume of distribution for free valproate are

4.6L/hr… [Excerpted — this section continues on DailyMed.]

🧬 Pharmacodynamics 156 words ▾

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 )].

🔬 Clinical Studies ~3 min read ▾

14 CLINICAL STUDIES

14.1Mania The effectiveness of divalproex sodium delayed-release tablets for the treatment of acute mania was demonstrated in two 3-week, placebo controlled, parallel group studies. (1) Study 1: The first study enrolled adult patients who met DSM-III-R criteria for bipolar disorder and who were hospitalized for acute mania. In addition, they had a history of failing to respond to or not tolerating previous lithium carbonate treatment.

Divalproex sodium delayed-release tablets were initiated at a dose of 250 mg tid and adjusted to achieve serum valproate concentrations in a range of 50 to 100 mcg/mL by day 7. Mean divalproex sodium delayed-release tablet doses for completers in this study were 1,118, 1,525, and 2,402 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Young Mania Rating Scale (YMRS; score ranges from 0 to 60), an augmented Brief Psychiatric Rating Scale (BPRS-A), and the Global Assessment Scale (GAS).

Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 6. Study 1 YMRS Total Score Group Baseline Mean score at baseline BL to Wk 3 Change from baseline to Week 3 (LOCF) Difference Difference in change from baseline to Week 3 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo Placebo 28.8 +

0.2Divalproex sodium delayed-release tablets 28.5 - 9.5

9.7BPRS-A Total Score Group Baseline BL to Wk 3 Difference Placebo 76.2 +

1.8Divalproex sodium delayed-release tablets 76.4 - 17.0

18.8GAS Score Group Baseline BL to Wk 3 Difference Placebo 31.8

0.0Divalproex sodium delayed-release tablets 30.3 +18.1

18.1Divalproex sodium delayed-release tablets were statistically significantly superior to placebo on all three measures of outcome. (2) Study 2: The second study enrolled adult patients who met Research Diagnostic Criteria for manic disorder and who were hospitalized for acute mania. Divalproex sodium delayed-release tablets were initiated at a dose of 250 mg tid and adjusted within a dose range of 750 to 2,500 mg/day to achieve serum valproate concentrations in a range of 40 to 150 mcg/mL.

Mean divalproex sodium delayed-release tablet doses for completers in this study were 1,116, 1,683, and 2,006 mg/day at Days 7, 14, and 21, respectively. Study 2 also included a lithium group for which lithium doses for completers were 1,312, 1,869, and 1,984 mg/day at Days 7, 14, and 21, respectively. Patients were assessed on the Manic Rating Scale (MRS; score ranges from 11 to 63), and the primary outcome measures were the total MRS score, and scores for two subscales of the MRS, i.e., the Manic Syndrome Scale (MSS) and the Behavior and Ideation Scale (BIS).

Baseline scores and change from baseline in the Week 3 endpoint (last-observation-carry-forward) analysis were as follows: Table 7. Study 2 MRS Total Score Group Baseline Mean score at baseline BL to Day 21 Change from baseline to Day 21 (LOCF) Difference Difference in change from baseline to Day 21 endpoint (LOCF) between divalproex sodium delayed-release tablets and placebo and lithium and placebo Placebo 38.9 -

4.4Lithium 37.9 - 10.5

6.1Divalproex sodium delayed-release tablets 38.1 - 9.5

5.1MSS Total Score Group Baseline BL to Day 21 Difference Placebo 18.9 -

2.5Lithium 18.5 - 6.2

3.7Divalproex sodium delayed-release tablets 18.9 - 6.0

3.5BIS Total Score Group Baseline BL to Day 21 Difference Placebo 16.4 -

1.4Lithium 16.0 - 3.8

2.4Divalproex sodium delayed-release tablets 15.7 – 3.2

1.8Divalproex sodium delayed-release tablets were statistically significantly superior to placebo on all three measures of outcome. An exploratory analysis for age and gender effects on outcome did not suggest any differential responsiveness on the basis of age or gender. A comparison of the percentage of patients showing ≥ 30% reduction in the symptom score from baseline in each treatment group, separated by study, is shown in Figure 1.

Figur… [Excerpted — this section continues on DailyMed.]

🧪 Nonclinical Toxicology ~1 min read ▾

13 NONCLINICAL TOXICOLOGY

13.1Carcinogenesis, Mutagenesis, and Impairment of Fertility Carcinogenesis Valproate was administered orally to rats and mice at doses of 80 and 170 mg/kg/day (less than the maximum recommended human dose on a mg/m 2 basis) for two years. The primary findings were an increase in the incidence of subcutaneous fibrosarcomas in high-dose male rats receiving valproate and a dose-related trend for benign pulmonary adenomas in male mice receiving valproate. Mutagenesis Valproate was not mutagenic in an in vitro bacterial assay (Ames test), did not produce dominant lethal effects in mice, and did not increase chromosome aberration frequency in an in vivo cytogenetic study in rats.

Increased frequencies of sister chromatid exchange (SCE) have been reported in a study of epileptic children taking valproate; this association was not observed in another study conducted in adults. Impairment of Fertility In chronic toxicity studies in juvenile and adult rats and dogs, administration of valproate resulted in testicular atrophy and reduced spermatogenesis at oral doses of 400 mg/kg/day or greater in rats (approximately equal to or greater than the maximum recommended human dose (MRHD) on a mg/m 2 basis) and 150 mg/kg/day or greater in dogs (approximately equal to or greater than the MRHD on a mg/m 2 basis).

Fertility studies in rats have shown no effect on fertility at oral doses of valproate up to 350 mg/kg/day (approximately equal to the MRHD on a mg/m 2 basis) for 60 days.

📚 References 33 words ▾

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

📄 Recent Major Changes 26 words ▾

RECENT MAJOR CHANGES Contraindications ( 4 ) 5/2025 Warnings and Precautions ( 5.2 , 5.3 ) 3/2026 Warnings and Precautions ( 5.13 , 5.14 ) 5/2025

📄 Package Label / Principal Display Panel 45 words ▾

Divalproex Sodium Delayed-release Tablets USP, 125 mg Rx Only NDC 68180-265-01 100 Tablets Divalproex Sodium Delayed-release Tablets USP, 250 mg Rx Only NDC 68180-266-01 100 Tablets Divalproex Sodium Delayed-release Tablets USP, 500 mg Rx Only NDC 68180-267-01 100 Tablets Fig 6 Fig 7 Figure 8

Source: FDA Structured Product Labeling, mirrored from DailyMed / openFDA. Prefer the government’s original formatting? View this label on DailyMed ↗

Medicare Part D spend CMS · PART D · 2026 (Q1)

Medicare Part D (outpatient prescription) spending for Divalproex Sodium — the program that covers self-administered drugs. 14 manufacturers.
⚠️ Drug-level data: CMS publishes Part D spending by drug, not by NDC — these figures combine every manufacturer, strength and package size sold under the name Divalproex Sodium. That’s a different level of aggregation than the Medicaid card above, which is specific to this exact 11-digit NDC (pack size included), so the two aren’t directly comparable.
Period
Total Part D spend
$32.54M
Claims incl. refills
863.4K
Beneficiaries
312.7K
Spend / beneficiary
$104.05
Spend / claim
$37.68
Trend by period
💵 About the dollar figures: spending is what Part D plans paid before confidential manufacturer rebates, so the program’s real net cost is lower. A blank patient count means fewer than 11 people — CMS hides counts that small to protect privacy. Source: CMS Medicare Quarterly Part D Spending by Drug (data.cms.gov), updated quarterly.

About this NDC listing & data coverage

Finished prescription product No longer marketed (per FDA listing data)
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.
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HCPCS J-code billing crosswalk — Not published for this NDC Most self-administered / retail products have no J-code — that is normal.
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“Not published” reflects what the public FDA / CMS / NLM sources provide for this exact package code — it is a property of the data feeds, not a judgment about the product.

Questions about this listing

Why is there no price listed?
The pricing shown on our NDC pages comes from CMS NADAC, a voluntary survey of retail community pharmacy invoices. CMS does not publish a NADAC for every NDC — packages outside the retail survey (institutional and hospital products, bulk packages, discontinued items, and many OTC items) may never receive one. A missing price reflects the survey's scope, not this product's actual cost, and does not mean the product is free or unavailable.
What does the discontinued status mean for this NDC?
The labeler reported a marketing end date (or the listing was delisted), so this specific package is no longer actively marketed. Remaining stock may still be dispensed for a time, and the NDC stays valid for historical records and claims — but data feeds (pricing, labeling) typically stop updating for it. Other package sizes or other manufacturers' versions of the same medication may still be marketed — see the equivalents section where available.
Is the NDC printed on the package the same as the 11-digit billing NDC?
Yes, they identify this exact package in different formats. The form printed on the packaging and shown on DailyMed is the one the FDA registered. Insurance claims use a fixed 11-digit 5-4-2 format, so the short segment is padded with a leading zero and the dashes are dropped. The Identity section at the top of this page lists each form of this code.
Does this product come in other package sizes?
Yes — the FDA directory lists 3 other package presentations of this same product, including 10 tablets (68180-0267-11), 500 tablets (68180-0267-02), 1000 tablets (68180-0267-03). Each has its own NDC and its own page — see the package list near the top of this page.
Who lists this product with the FDA?
Lupin Pharmaceuticals, Inc. is the labeler of record for this NDC — the company under whose FDA-assigned code the package is listed. The labeler may be the manufacturer itself or a distributor marketing the product under its own code.
Do I need a prescription for this product?
This NDC is listed with FDA as a prescription product, so it is dispensed under a prescriber's order. Your pharmacist can tell you whether any over-the-counter forms of the same medication exist.
This page identifies an FDA-listed package (the NDC) and reports public regulatory and pricing data about the listing. It is reference information, not a medical recommendation — talk to your pharmacist or prescriber about your own medication.
Where does this data come from?
Listing facts (marketing category, packager status, marketing dates) from the FDA openFDA NDC Directory; label availability from DailyMed; pricing coverage from CMS NADAC; equivalence scope from the FDA Orange Book.
← 68180-0266-01 · Lupin 68180-0273-01 · Lupin →
For educational and professional reference only — not medical advice. Pricing reflects published NADAC and CMS ASP (free public data) and may differ from your acquisition cost; always verify before billing or dispensing.