Valproic Acid 250 mg/5mL Solution, 473 mL
🆔 Identity & classification
Where does this data come from?
🏷️ RxNorm drug class
This medicine belongs to the Mood Stabilizer class.
Where does this data come from?
🏭 Manufacturer & labeler
Where does this data come from?
🩺 Clinical
- Valproic acid is an anti-seizure medicine. It's used to treat several types of epileptic seizures — including complex partial seizures and absence seizures — either on its own or a...
- This is one of the most important things to discuss with your doctor before starting. Valproic acid carries serious risks for babies exposed before birth — it can cause birth defec...
- Can I take valproic acid if I'm pregnant or trying to get pregnant?
- The most common things people notice are nausea, stomach pain, shakiness (tremor), drowsiness, dizziness, and sometimes hair thinning. These are often manageable, and many improve...
Patient education
Supplement & herbal interactions
Some supplements/herbs that may interact with Valproic Acid — tap one for details:
Valproic Acid may be associated with lower levels of 9 nutrients — worth a chat with your pharmacist, not a cause for alarm.
Where does this data come from?
Ask a licensed pharmacist directly — free, answered by our team.
💊 What it looks like
Where does this data come from?
🧪 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.
Where does this data come from?
IACT rows and label-wide narrative are kept separate; availability and product-level specificity depend on the submitted label.Inactive ingredient FAQ
Are inactive ingredients the same for every manufacturer?
Why might an inactive ingredient be missing?
Can inactive ingredients matter?
💲 Pricing
A drug doesn't have one price. Each row is a different public payment system, and none is what you'd pay at the counter — that depends on your insurance. The ⓘ on each row explains what it measures.
| Price system | Per mL | Per package |
|---|---|---|
| Retail pharmacies payNADAC · weekly | $0.034 | $15.94 / 473 ml |
| Medicaid paysCMS SDUD · 12 mo | No recent Medicaid claims on file for this NDC — rare and low-volume NDCs are suppressed in the public data. | |
| Medicare drug plans payPart D · Q2 2026 | $0.0553 | $26.16 / 473 ml |
Where does this data come from?
🔁 Therapeutic equivalents
| Product | Labeler | Pack | NADAC/unit | TE | Status | Price vs. this |
|---|---|---|---|---|---|---|
| Valproic Acid 250 mg/5mL 00121-0675-16 | PAI | 473 ml | $0.033 | AA | Discontinued | save 3% |
| Valproic Acid 250 mg/5mLthis 62135-0196-47 | Chartwell | 473 ml | $0.034 | AA | Availability likely | — |
| Valproic Acid 250 mg/5mL 62559-0266-16 | ANI | 473 ml | $0.034 | AA | Availability likely | — |
| Valproic Acid 250 mg/5mL 70752-0202-12 | QUAGEN | 12 bottles | $0.034 | AA | Availability likely | — |
| Valproic Acid 250 mg/5mL 00116-4021-11 | Xttrium | 10 cups | — | — | FDA listed | — |
| Valproic Acid 500 mg/10mL 00121-1350-00 | PAI | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 00121-4675-00 | PAI | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 500 mg/10mL 62135-0874-24 | Chartwell | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 68999-0196-24 | Chartwell | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 500 mg/10mL 68999-0874-24 | Chartwell | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 70518-3805-00 | REMEDYREPACK | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 70518-4298-00 | REMEDYREPACK | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 71335-2250-01 | Bryant | 473 ml | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 72603-0253-01 | NorthStar | 473 ml | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 81033-0266-50 | Kesin | 100 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 60687-0942-17 | American | 10 cups | — | AA | FDA listed | — |
| Valproic Acid 250 mg/5mL 00904-7620-70 | Major | 10 cups | — | AA | FDA listed | — |
Where does this data come from?
⏳ Availability & generic status
This product is an FDA-approved generic. Other versions of the same drug are listed under Therapeutic equivalents, least expensive first.
Where does this data come from?
📊 Medicare Part D spend CMS · PART D · 2026 (Q1)
📦 Packaging — all sizes for this product
| Package NDC | Description | Per unit | Per pack | Marketing start | Status |
|---|---|---|---|---|---|
| 62135-0196-47 You're viewing this | 473 mL in 1 BOTTLE (62135-196-47) | $0.0337 / mL | $15.94 | 2022-08-15 | Active |
| 62135-0196-24 | 2 TRAY in 1 BOX (62135-196-24) / 10 CUP in 1 TRAY / 5 mL in 1 CUP (62135-196-45) | — | — | 2024-05-28 | Active |
Pack size FAQ
What quantity is in NDC 62135-0196-47?
What NDC number is used to bill for this package of Valproic Acid 250 mg/5mL Solution?
Prices are the latest CMS NADAC pharmacy acquisition cost per NDC; per-pack figures are per-unit × pack quantity, shown only when the pack is denominated in the same measure NADAC prices.
📄 Full prescribing information FDA SPL
🚨 Boxed Warning ▾
WARNING: LIFE THREATENING ADVERSE REACTIONS Hepatotoxicity General Population: Hepatic failure resulting in fatalities has occurred in patients receiving valproate and its derivatives. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.
In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months [see Warnings and Precautions ( 5.1 ) ].
Children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those on multiple anticonvulsants, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
The incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Patients with Mitochondrial Disease: There is an increased risk of valproate-induced acute liver failure and resultant deaths in patients with hereditary neurometabolic syndromes caused by DNA mutations of the mitochondrial DNA Polymerase γ (POLG) gene (e.g. Alpers Huttenlocher Syndrome).
Valproic acid oral solution 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, valproic acid oral solution should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with valproic acid oral solution 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 plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable.
In such situations, effective contraception should be used [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) ]. A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information ( 17 ) ]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate.
Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation.
If pancreatitis is diagnosed, valp…
🎯 Indications and Usage ▾
1 INDICATIONS AND USAGE Valproic acid oral solution is indicated for: Monotherapy and adjunctive therapy of complex partial seizures; sole and adjunctive therapy of simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 )
1.1Epilepsy Valproic acid oral solution is 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. Valproic acid oral solution is 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 which 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. See Warnings and Precautions ( 5.1 ) for statement regarding fatal hepatic dysfunction.
1.2Important 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, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] .
⏱️ Dosage and Administration ▾
2 DOSAGE AND ADMINISTRATION Valproic acid oral solution is intended for oral administration. ( 2.1 ) Simple and Complex Absence Seizures: Start at 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/week until seizure control or limiting side effects ( 2.1 ) Safety of doses above 60 mg/kg/day is not established ( 2.1 , 2.2 )
2.1Epilepsy Valproic acid oral solution is intended for oral administration. Patients should be informed to take valproic acid oral solution 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. Valproic acid oral solution is 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 valproic acid oral solution 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) Valproic acid oral solution has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day.
The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).
No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions.
Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day.
If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50-100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. Concomitant antiepilepsy drug (AED) dosage can ordinarily be reduced by approximately 25% every 2 weeks.
This reduction may be started at initiation of valproic acid oral solution therapy, or delayed by 1 to 2 weeks if there is a concern that seizures are likely to occur with a reduction. The speed and duration of withdrawal of the concomitant AED can be highly variable, and patients should be monitored closely during this period for increased seizure frequency. Adjunctive Therapy Valproic acid oral solution may be added to the patient's regimen at a dosage of 10 to 15 mg/kg/day.
The dosage may be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL).
No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin in addition to divalproex sodium delayed-release…
💊 Dosage Forms and Strengths ▾
3 DOSAGE FORMS AND STRENGTHS Valproic acid oral solution, USP is available as a cherry-flavored, clear, pinkish-red oral solution containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 fluid ounces (473 mL), 5 mL Unit Dose Cups in trays of 20 cups and 10 mL Unit Dose Cups in trays of 20 cups. Valproic acid oral solution: Equivalent of 250 mg valproic acid per 5 mL as the sodium salt ( 3 )
⛔ Contraindications ▾
4 CONTRAINDICATIONS Valproic acid oral solution should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1 ) ]. Valproic acid oral solution is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions ( 5.1 ) ]. Valproic acid oral solution is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions ( 5.12 ) ].
Valproic acid oral solution is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions ( 5.6 ) ]. For use in prophylaxis of migraine headaches: Valproic acid oral solution is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )]. Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) Known hypersensitivity to the drug ( 4 , 5.12 ) Urea cycle disorders ( 4 , 5.6 ) Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )
⚠️ Warnings and Cautions ▾
5 WARNINGS AND PRECAUTIONS Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 ) Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure; should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable ( 5.2 , 5.3 , 5.4 ) Pancreatitis; valproic acid oral solution should ordinarily be discontinued ( 5.5 ) Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid oral solution, increase the risk of suicidal thoughts or behavior ( 5.7 ) Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests ( 5.8 ) Hyperammonemia and hyperammonemic encephalopathy; measure ammonia level if unexplained lethargy and vomiting or changes in mental status, and also with concomitant topiramate use; consider discontinuation of valproate therapy ( 5.6 , 5.9 , 5.10 ) Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia.
This adverse reaction can also occur in patients using concomitant topiramate ( 5.11 ) Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue valproic acid oral solution ( 5.12 ) Somnolence in the elderly can occur. Valproic acid oral solution dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.14 )
5.1Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting.
In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months 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 valproic acid products are used in this patient group, they should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks.
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 Valproic acid oral solution 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…
🤒 Adverse Reactions ▾
6 ADVERSE REACTIONS The following serious adverse reactions are described below and elsewhere in the labeling: Hepatic failure [see Warnings and Precautions ( 5.1 ) ] Birth defects [see Warnings and Precautions ( 5.2 ) ] Decreased IQ and Neurodevelopmental Disorders following in utero exposure [see Warnings and Precautions ( 5.3 ) ] Pancreatitis [see Warnings and Precautions ( 5.5 ) ] Hyperammonemic encephalopathy [see Warnings and Precautions ( 5.6 , 5.9 , 5.10 ) ] Suicidal behavior and ideation [see Warnings and Precautions ( 5.7 ) ] Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.8 ) ] Hypothermia [see Warnings and Precautions ( 5.11 ) ] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.12 ) ] Somnolence in the elderly [see Warnings and Precautions ( 5.14 ) ] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.
Most common adverse reactions (reported >5%) are abdominal pain, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rhinitis, somnolence, thinking abnormal, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, weight loss. ( 6.1 ) The safety and tolerability of valproate in pediatric patients were shown to be comparable to those in adults ( 8.4 ).
To report SUSPECTED ADVERSE REACTIONS, contact Chartwell RX, LLC. 1-845-232-1683 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch
6.1Epilepsy The data described in the following section were obtained using divalproex sodium delayed-release tablets. Based on a placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures, divalproex sodium was generally well tolerated with most adverse reactions rated as mild to moderate in severity. Intolerance was the primary reason for discontinuation in the divalproex sodium-treated patients (6%), compared to 1% of placebo-treated patients.
Table 3 lists treatment-emergent adverse reactions which were reported by ≥ 5% of divalproex sodium- treated patients and for which the incidence was greater than in the placebo group, in a placebo- controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs.
Table 3. Adverse Reactions Reported by ≥ 5% of Patients Treated with Divalproex Sodium During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Reaction Divalpoex Sodium (n = 77) (%) Placebo (n = 70) (%) Body as a Whole Headache 31 21 Asthenia 27 7 Fever 6 4 Gastrointestinal System Nausea 48 14 Vomiting 27 7 Abdominal Pain 23 6 Diarrhea 13 6 Anorexia 12 0 Dyspepsia 8 4 Constipation 5 1 Nervous System Somnolence 27 11 Tremor 25 6 Dizziness 25 13 Diplopia 16 9 Amblyopia/Blurred Vision 12 9 Ataxia 8 1 Nystagmus 8 1 Emotional Lability 6 4 Thinking Abnormal 6 0 Amnesia 5 1 Respiratory System Flu Syndrome 12 9 Infection 12 6 Bronchitis 5 1 Rhinitis 5 4 Other Alopecia 6 1 Weight Loss 6 0 Table 4 lists treatment-emergent adverse reactions which were reported by ≥ 5% of patients in the high dose divalproex sodium group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures.
Since patients were being titra…
🔄 Drug Interactions ▾
7 DRUG INTERACTIONS Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives: 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 valproic acid oral solution ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 )
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 ( 5.13 ) ].
Cholestyramine Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14% decrease in plasma levels of valproic acid in a study conducted in 6 healthy subjects administered valproic acid oral solution and cholestyramine. Delaying the administration of…
👥 Use in Specific Populations ▾
8 USE IN SPECIFIC POPULATIONS Pregnancy: Valproic acid oral solution can cause congenital malformations including neural tube defects, decreased IQ, and neurodevelopmental disorders ( 5.2 , 5.3 , 8.1 ) Pediatric: Children under the age of two years are at considerably higher risk of fatal hepatotoxicity ( 5.1 , 8.4 ) Geriatric: Reduce starting dose; increase dosage more slowly; monitor fluid and nutritional intake, and somnolence ( 5.14 , 8.5 )
8.1Pregnancy Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )]. For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions ( 5.2 , 5.3 )].
Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations).
This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. In utero exposure to valproate may also result in hearing impairment or hearing loss. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy.
The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions ( 5.2 ) and Data ( Human )]. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID, defined as an IQ < 70), and attention deficit/hyperactivity disorder (ADHD), compared to children exposed to either another AED in utero or to no AEDs in utero [see Warnings and Precautions ( 5.3 ) and Data] .
An observational study has suggested that exposure to valproate products during pregnancy increases the risk of autism spectrum disorders [see Data ( Human )] . In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data]. There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy.
Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.1 , 5.8 )]. Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population.
It is not known whether the risk of…
🆘 Overdosage ▾
10 OVERDOSAGE Overdosage with valproate may result in somnolence, heart block, deep coma, and hypernatremia. Fatalities have been reported; however, patients have recovered from valproate levels as high as 2,120 mcg/mL. In overdose situations, the fraction of drug not bound to protein is high and hemodialysis or tandem hemodialysis plus hemoperfusion may result in significant removal of drug.
The benefit of gastric lavage or emesis will vary with the time since ingestion. General supportive measures should be applied with particular attention to the maintenance of adequate urinary output. Naloxone has been reported to reverse the CNS depressant effects of valproate overdosage.
Because naloxone could theoretically also reverse the antiepileptic effects of valproate, it should be used with caution in patients with epilepsy.
🧬 Clinical Pharmacology ▾
12 CLINICAL PHARMACOLOGY
12.1Mechanism of Action Valproic acid 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.
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 divalproex sodium delayed-release tablet (increase in T max from 4 to 8 hours) than on the absorption of the divalproex sodium 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. 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 ( 2.1 ) ].
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 o…
📦 How Supplied / Storage and Handling ▾
16 HOW SUPPLIED/STORAGE AND HANDLING Valproic acid oral solution, USP is a clear pinkish-red, cherry-flavored liquid containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt, supplied as follows: 473 mL (16 fl oz) bottle NDC 62135-196-47 5 mL Unit Dose Cup NDC 62135-196-45 20 Unit Dose Cups of 5 mL each NDC 62135-196-24 10 mL Unit Dose Cup NDC 62135-874-59 20 Unit Dose Cups of 10 mL each NDC 62135-874-24 Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature]. Dispense in the original container or a USP tight container.
📋 Description ▾
11 DESCRIPTION Valproic acid is a carboxylic acid designated as 2-propylpentanoic acid. It is also known as dipropylacetic acid. Valproic acid has the following structure: Valproic acid (pKa 4.8) has a molecular weight of 144 and occurs as a colorless liquid with a characteristic odor.
It is slightly soluble in water (1.3 mg/mL) and very soluble in organic solvents. Valproic acid oral solution, USP is an antiepileptic for oral administration. The oral solution contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.
Inactive Ingredients Oral Solution: Glycerin, methylparaben, propylparaben, sodium hydroxide, sorbitol, sucrose, purified water, FD&C Red No. 40 and flavor wild cherry. image description
💬 Information for Patients ▾
17 PATIENT COUNSELING INFORMATION Advise the patient to read the FDA-approved patient labeling (Medication Guide). Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions ( 5.1 ) ]. Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions ( 5.5 ) ].
Birth Defects Decreased IQ, and Neurodevelopmental Disorders Inform pregnant women and women of childbearing potential (including girls beginning the onset of puberty) that use of valproate during pregnancy increases the risk of birth defects decreased IQ, and neurodevelopmental disorders in children who were exposed in utero [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 ) ]. Advise women to use effective contraception while taking valproate. When appropriate, counsel these patients about alternative therapeutic options.
This is particularly important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headache [see Contraindications ( 4 )] . Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including valproic acid oral solution, may increase the risk of suicidal thoughts and behavior and to be alert for the emergence or worsening of symptoms of depression, any unusual changes in mood or behavior, or the emergence of suicidal thoughts, behavior, or thoughts about self-harm.
Instruct patients, caregivers, and families to report behaviors of concern immediately to the healthcare providers [ see Warnings and Precautions ( 5.7 ) ]. Hyperammonemia Inform patients of the signs and symptoms associated with hyperammonemic encephalopathy and to notify the prescriber if any of these symptoms occur [see Warnings and Precautions ( 5.9 , 5.10 ) ]. CNS Depression Since valproate products may produce CNS depression, especially when combined with another CNS depressant (e.g., alcohol), advise patients not to engage in hazardous activities, such as driving an automobile or operating dangerous machinery, until it is known that they do not become drowsy from the drug.
Multiorgan Hypersensitivity Reactions Instruct patients that a fever associated with other organ system involvement (rash, lymphadenopathy, etc.) may be drug-related and should be reported to the physician immediately [see Warnings and Precautions ( 5.12 ) ]. Manufactured for: Chartwell RX, LLC. Congers, NY 10920 L70753 Revision 03
💬 Medication Guide ▾
MEDICATION GUIDE VALPROIC ACID (val proe’ ik as’id) ORAL SOLUTION, USP Read this Medication Guide before you start taking valproic acid oral solution and each time you get a refill. There may be new information. This information does not take the place of talking to your healthcare provider about your medical condition or treatment.
What is the most important information I should know about valproic acid oral solution? Do not stop taking valproic acid oral solution without first talking to your healthcare provider. Stopping valproic acid oral solution suddenly can cause serious problems.
Valproic acid oral solution can cause serious side effects, including: Serious liver damage that can cause death, especially in children younger than 2 years old. The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment. Call your healthcare provider right away if you get any of the following symptoms: nausea or vomiting that does not go away loss of appetite pain on the right side of your stomach (abdomen) dark urine swelling of your face yellowing of your skin or the whites of your eyes In some cases, liver damage may continue despite stopping the drug.
Valproic acid oral solution may harm your unborn baby. If you take valproic acid oral solution during pregnancy for any medical condition, your baby is at risk for serious birth defects that affect the brain and spinal cord and are called spina bifida or neural tube defects. These defects occur in 1 to 2 out of every 100 babies born to mothers who use this medicine during pregnancy.
These defects can begin in the first month, even before you know you are pregnant. Other birth defects that affect the structures of the heart, head, arms, legs, and the opening where the urine comes out (urethra) on the bottom of the penis can also happen. 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 valproic acid oral solution during pregnancy for any medical condition, your child is at risk for having a lower IQ and may be at risk for developing autism or a 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 valproic acid oral solution 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 valproic acid oral solution.
If the decision is made to use valproic acid oral solution, you should use effective birth control (contraception). Tell your healthcare provider right away if you become pregnant while taking valproic acid oral solution. You and your healthcare provider should decide if you will continue to take valproic acid oral solution while you are pregnant.
Inflammation of your pancreas that can cause death. Call your healthcare provider right away if you have any of these symptoms: severe stomach pain that you may also feel in your back nausea or vomiting that does not go away Like other antiepileptic drugs, valproic acid oral solution may cause suicidal thoughts or actions in a very small number of people, about 1 in 500. Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you: thoughts about suicide or dying attempts to commit suicide new or worse depression new or worse anxiety feeling agitated or restless panic attacks trouble sleeping (insomnia) new or worse irritability acting aggressive, being angry, or violent acting on dangerous impulses an extreme increase in activity and talking (mani…