These Highlights Do Not Include All The Information Needed To Use Valproic Acid Safely And Effectively. See Full Prescribing Information For valproic Acid.

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)

Valproic acid 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)

Valproic acid 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)

Valproic Acid Oral Solution USP is available as clear, cherry-red oral solution with artificial cherry flavor containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt, supplied as follows:

NDC 0527-5250-70:  16 fl oz (473 mL) bottle

• Valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)].
• Valproic acid 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 is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)].
• Valproic acid is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)].
• For use in prophylaxis of migraine headaches: Valproic acid 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)].

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 and contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.

• 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 (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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]. When valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2)].

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

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.

The studies described in the following section were conducted using divalproex sodium tablets.

• 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.

Hepatotoxicity

Valproic Acid Oral Solution USP

(Val proe’ ik as’ id)

Read this Medication Guide before you start taking valproic acid 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?

Do not stop taking valproic acid without first talking to your healthcare provider.

Stopping valproic acid suddenly can cause serious problems.

Valproic acid can cause serious side effects, including:

1. Serious liver damage that can cause death, especially in children younger than 2 years old.

The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment.

Call your healthcare provider right away if you get any of the following symptoms:

• nausea or vomiting that does not go away
• loss of appetite
• pain on the right side of your stomach (abdomen)
• dark urine
• swelling of your face
• yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

2. Valproic acid may harm your unborn baby.

• If you take valproic acid 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 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 valproic acid 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. If the decision is made to use valproic acid, you should use effective birth control (contraception).
• Tell your healthcare provider right away if you become pregnant while taking valproic acid. You and your healthcare provider should decide if you will continue to take valproic acid while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking valproic acid, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling toll-free 1-888-233-2334 or by visiting the website, http://www.aedpregnancyregistry.org/. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

3. Inflammation of your pancreas that can cause death.

Call your healthcare provider right away if you have any of these symptoms:

• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away

4. Like other antiepileptic drugs, valproic acid may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop valproic acid without first talking to a healthcare provider. Stopping valproic acid 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).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What is valproic acid?

Valproic acid is a prescription medicine used alone or with other medicines, to treat:

• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types

Who should not take valproic acid?

Do not take valproic acid if you:

• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in valproic acid. See the end of this leaflet for a complete list of ingredients in valproic acid.
• have a genetic problem called urea cycle disorder
• are taking it to prevent migraine headaches and are either pregnant or may become pregnant because you are not using effective birth control (contraception)

What should I tell my healthcare provider before taking valproic acid?

Before you take valproic acid, tell your healthcare provider if you:

• have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
• drink alcohol
• are pregnant or breastfeeding. Valproic acid can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take valproic acid.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.

Taking valproic acid with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take valproic acid?

• Take valproic acid exactly as your healthcare provider tells you. Your healthcare provider will tell you how much valproic acid to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of valproic acid without talking to your healthcare provider.
• Do not stop taking valproic acid without first talking to your healthcare provider. Stopping valproic acid suddenly can cause serious problems.
• If you take too much valproic acid, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking valproic acid?

• Valproic acid can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking valproic acid, until you talk with your doctor. Taking valproic acid with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how valproic acid affects you. Valproic acid can slow your thinking and motor skills.

What are the possible side effects of valproic acid?

• See "What is the most important information I should know about valproic acid?"        

Valproic acid can cause serious side effects including:

• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of valproic acid.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of valproic acid include:

• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination

These are not all of the possible side effects of valproic acid. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Valproic Acid Oral Solution USP?

• Store at 20° to 25°C (68° to 77°F).  [See USP Controlled Room Temperature].

Keep valproic acid and all medicines out of the reach of children.

General information about the safe and effective use of valproic acid.

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

This Medication Guide summarizes the most important information about valproic acid. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about valproic acid that is written for health professionals.

For more information, call Lannett Company, Inc. at 1-844-834-0530.

What are the ingredients in Valproic Acid Oral Solution USP?

Active ingredient: valproic acid

Inactive ingredients: artificial cherry flavor, FD&C Red #40, glycerin, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitol solution and sucrose. Sodium hydroxide or hydrochloric acid may be added to adjust pH.

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

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

L6925D

Rev. 09/2020

Valproic Acid Oral Solution USP is available as clear, cherry-red oral solution with artificial cherry flavor containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 fl oz (473 mL).

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).

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.

• Pregnancy: Valproic acid 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)

• 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 should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid, 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 (5.12)
• Somnolence in the elderly can occur. Valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14)

STORAGE

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].

NDC 0527-5250-70

Valproic Acid

Oral Solution USP

250 mg/5 mL

Each 5 mL contains:

Equivalent of 250 mg valproic   

See enclosure for prescribing information.

Rx Only

16 fl oz (473 mL)

Lannett

Risk Summary

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

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

Clinical Considerations

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

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

Data

Human

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

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

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

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)].

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)

Valproic acid 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)

Valproic acid 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)

Valproic Acid Oral Solution USP is available as clear, cherry-red oral solution with artificial cherry flavor containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt, supplied as follows:

NDC 0527-5250-70:  16 fl oz (473 mL) bottle

• Valproic acid should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions (5.1)].
• Valproic acid 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 is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions (5.12)].
• Valproic acid is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions (5.6)].
• For use in prophylaxis of migraine headaches: Valproic acid 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 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 (7.2)
• Topiramate: Hyperammonemia and encephalopathy (5.10, 7.3)

Advise the patient to read the FDA-approved patient labeling (Medication Guide).

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]. When valproic acid is used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups.

Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. Pediatric patients (i.e., between 3 months and 10 years) have 50% higher clearances expressed on weight (i.e., mL/min/kg) than do adults. Over the age of 10 years, children have pharmacokinetic parameters that approximate those of adults.

The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding.

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor.

Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from preexisting medical illness and concomitant medication use among these patients.

A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions (5.14)]. The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration (2.2)].

The following serious adverse reactions are described below and elsewhere in the labeling:

• Hepatic failure [see Warnings and Precautions (5.1)]
• Birth defects [see Warnings and Precautions (5.2)]
• Decreased IQ following in utero exposure [see Warnings and Precautions (5.3)]
• Pancreatitis [see Warnings and Precautions (5.5)]
• Hyperammonemic encephalopathy [see Warnings and Precautions (5.6, 5.9, 5.10)]
• Suicidal behavior and ideation [see Warnings and Precautions (5.7)]
• Bleeding and other hematopoietic disorders [see Warnings and Precautions (5.8)]
• Hypothermia [see Warnings and Precautions (5.11)]
• Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions (5.12)]
• Somnolence in the elderly [see Warnings and Precautions (5.14)]

Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice.

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.

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 and contains the equivalent of 250 mg valproic acid per 5 mL as the sodium salt.

The studies described in the following section were conducted using divalproex sodium tablets.

• 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.

Hepatotoxicity

Valproic Acid Oral Solution USP

(Val proe’ ik as’ id)

Read this Medication Guide before you start taking valproic acid 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?

Do not stop taking valproic acid without first talking to your healthcare provider.

Stopping valproic acid suddenly can cause serious problems.

Valproic acid can cause serious side effects, including:

1. Serious liver damage that can cause death, especially in children younger than 2 years old.

The risk of getting this serious liver damage is more likely to happen within the first 6 months of treatment.

Call your healthcare provider right away if you get any of the following symptoms:

• nausea or vomiting that does not go away
• loss of appetite
• pain on the right side of your stomach (abdomen)
• dark urine
• swelling of your face
• yellowing of your skin or the whites of your eyes

In some cases, liver damage may continue despite stopping the drug.

2. Valproic acid may harm your unborn baby.

• If you take valproic acid 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 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 valproic acid 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. If the decision is made to use valproic acid, you should use effective birth control (contraception).
• Tell your healthcare provider right away if you become pregnant while taking valproic acid. You and your healthcare provider should decide if you will continue to take valproic acid while you are pregnant.
• Pregnancy Registry: If you become pregnant while taking valproic acid, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling toll-free 1-888-233-2334 or by visiting the website, http://www.aedpregnancyregistry.org/. The purpose of this registry is to collect information about the safety of antiepileptic drugs during pregnancy.

3. Inflammation of your pancreas that can cause death.

Call your healthcare provider right away if you have any of these symptoms:

• severe stomach pain that you may also feel in your back
• nausea or vomiting that does not go away

4. Like other antiepileptic drugs, valproic acid may cause suicidal thoughts or actions in a very small number of people, about 1 in 500.

Call a healthcare provider right away if you have any of these symptoms, especially if they are new, worse, or worry you:

• thoughts about suicide or dying
• attempts to commit suicide
• new or worse depression
• new or worse anxiety
• feeling agitated or restless
• panic attacks
• trouble sleeping (insomnia)
• new or worse irritability
• acting aggressive, being angry, or violent
• acting on dangerous impulses
• an extreme increase in activity and talking (mania)
• other unusual changes in behavior or mood

How can I watch for early symptoms of suicidal thoughts and actions?

• Pay attention to any changes, especially sudden changes in mood, behaviors, thoughts, or feelings.
• Keep all follow-up visits with your healthcare provider as scheduled.

Call your healthcare provider between visits as needed, especially if you are worried about symptoms.

Do not stop valproic acid without first talking to a healthcare provider. Stopping valproic acid 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).

Suicidal thoughts or actions can be caused by things other than medicines. If you have suicidal thoughts or actions, your healthcare provider may check for other causes.

What is valproic acid?

Valproic acid is a prescription medicine used alone or with other medicines, to treat:

• complex partial seizures in adults and children 10 years of age and older
• simple and complex absence seizures, with or without other seizure types

Who should not take valproic acid?

Do not take valproic acid if you:

• have liver problems
• have or think you have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
• are allergic to divalproex sodium, valproic acid, sodium valproate, or any of the ingredients in valproic acid. See the end of this leaflet for a complete list of ingredients in valproic acid.
• have a genetic problem called urea cycle disorder
• are taking it to prevent migraine headaches and are either pregnant or may become pregnant because you are not using effective birth control (contraception)

What should I tell my healthcare provider before taking valproic acid?

Before you take valproic acid, tell your healthcare provider if you:

• have a genetic liver problem caused by a mitochondrial disorder (e.g., Alpers-Huttenlocher syndrome)
• drink alcohol
• are pregnant or breastfeeding. Valproic acid can pass into breast milk. Talk to your healthcare provider about the best way to feed your baby if you take valproic acid.
• have or have had depression, mood problems, or suicidal thoughts or behavior
• have any other medical conditions

Tell your healthcare provider about all the medicines you take, including prescription and non-prescription medicines, vitamins, herbal supplements and medicines that you take for a short period of time.

Taking valproic acid with certain other medicines can cause side effects or affect how well they work. Do not start or stop other medicines without talking to your healthcare provider.

Know the medicines you take. Keep a list of them and show it to your healthcare provider and pharmacist each time you get a new medicine.

How should I take valproic acid?

• Take valproic acid exactly as your healthcare provider tells you. Your healthcare provider will tell you how much valproic acid to take and when to take it.
• Your healthcare provider may change your dose.
• Do not change your dose of valproic acid without talking to your healthcare provider.
• Do not stop taking valproic acid without first talking to your healthcare provider. Stopping valproic acid suddenly can cause serious problems.
• If you take too much valproic acid, call your healthcare provider or local Poison Control Center right away.

What should I avoid while taking valproic acid?

• Valproic acid can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking valproic acid, until you talk with your doctor. Taking valproic acid with alcohol or drugs that cause sleepiness or dizziness may make your sleepiness or dizziness worse.
• Do not drive a car or operate dangerous machinery until you know how valproic acid affects you. Valproic acid can slow your thinking and motor skills.

What are the possible side effects of valproic acid?

• See "What is the most important information I should know about valproic acid?"        

Valproic acid can cause serious side effects including:

• Bleeding problems: red or purple spots on your skin, bruising, pain and swelling into your joints due to bleeding or bleeding from your mouth or nose.
• High ammonia levels in your blood: feeling tired, vomiting, changes in mental status.
• Low body temperature (hypothermia): drop in your body temperature to less than 95°F, feeling tired, confusion, coma.
• Allergic (hypersensitivity) reactions: fever, skin rash, hives, sores in your mouth, blistering and peeling of your skin, swelling of your lymph nodes, swelling of your face, eyes, lips, tongue, or throat, trouble swallowing or breathing.
• Drowsiness or sleepiness in the elderly. This extreme drowsiness may cause you to eat or drink less than you normally would. Tell your doctor if you are not able to eat or drink as you normally do. Your doctor may start you at a lower dose of valproic acid.

Call your healthcare provider right away, if you have any of the symptoms listed above.

The common side effects of valproic acid include:

• nausea
• headache
• sleepiness
• vomiting
• weakness
• tremor
• dizziness
• stomach pain
• blurry vision
• double vision
• diarrhea
• increased appetite
• weight gain
• hair loss
• loss of appetite
• problems with walking or coordination

These are not all of the possible side effects of valproic acid. For more information, ask your healthcare provider or pharmacist.

Tell your healthcare provider if you have any side effect that bothers you or that does not go away.

Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store Valproic Acid Oral Solution USP?

• Store at 20° to 25°C (68° to 77°F).  [See USP Controlled Room Temperature].

Keep valproic acid and all medicines out of the reach of children.

General information about the safe and effective use of valproic acid.

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

This Medication Guide summarizes the most important information about valproic acid. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about valproic acid that is written for health professionals.

For more information, call Lannett Company, Inc. at 1-844-834-0530.

What are the ingredients in Valproic Acid Oral Solution USP?

Active ingredient: valproic acid

Inactive ingredients: artificial cherry flavor, FD&C Red #40, glycerin, methylparaben, propylparaben, purified water, sodium hydroxide, sorbitol solution and sucrose. Sodium hydroxide or hydrochloric acid may be added to adjust pH.

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

Distributed by:

Lannett Company, Inc.

Philadelphia, PA 19136

L6925D

Rev. 09/2020

Valproic Acid Oral Solution USP is available as clear, cherry-red oral solution with artificial cherry flavor containing the equivalent of 250 mg valproic acid per 5 mL as the sodium salt in bottles of 16 fl oz (473 mL).

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).

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.

• Pregnancy: Valproic acid 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)

• 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 should ordinarily be discontinued (5.5)
• Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid, 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 (5.12)
• Somnolence in the elderly can occur. Valproic acid dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14)

STORAGE

Store at 20° to 25°C (68° to 77°F). [See USP Controlled Room Temperature].

NDC 0527-5250-70

Valproic Acid

Oral Solution USP

250 mg/5 mL

Each 5 mL contains:

Equivalent of 250 mg valproic   

See enclosure for prescribing information.

Rx Only

16 fl oz (473 mL)

Lannett

Risk Summary

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

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

Clinical Considerations

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

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

Data

Human

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

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

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

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)].