Valproic

RECENT MAJOR CHANGES

RECENT MAJOR CHANGES SECTION

WARNING: LIFE THREATENING ADVERSE REACTIONS

BOXED WARNING SECTION

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 seve re 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 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 should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Valproic Acid for the development of acute liver injury with regular clinical assessments and serum liver testing. POLG mutation screening should be performed in accordance with current clinical practice [see Warnings and Precautions ( 5.1 )]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant women and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )] . Valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. In such situations, effective contraception should be used [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 )] . A Medication Guide describing the risks of valproate is available for patients [see Patient Counseling Information ( 17 )]. Pancreatitis Cases of life-threatening pancreatitis have been reported in both children and adults receiving valproate. Some of the cases have been described as hemorrhagic with a rapid progression from initial symptoms to death. Cases have been reported shortly after initial use as well as after several years of use. Patients and guardians should be warned that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis that require prompt medical evaluation. If pancreatitis is diagnosed, valproate should ordinarily be discontinued. Alternative treatment for the underlying medical condition should be initiated as clinically indicated [see Warnings and Precautions ( 5.5 )].

1 INDICATIONS AND USAGE

INDICATIONS & USAGE SECTION

2 DOSAGE AND ADMINISTRATION

DOSAGE & ADMINISTRATION SECTION

3 DOSAGE FORMS AND STRENGTHS

DOSAGE FORMS & STRENGTHS SECTION

Valproic Acid Capsules, USP, 250 mg. Each off-white colored soft gelatin capsule is imprinted with VALPROIC 250.

4 CONTRAINDICATIONS

CONTRAINDICATIONS SECTION

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 Warning and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )].

5 WARNINGS AND PRECAUTIONS

WARNINGS AND PRECAUTIONS SECTION

6 ADVERSE REACTIONS

ADVERSE REACTIONS SECTION

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 [ s ee Warnings and Precautions ( 5.3 ) ] Pancreatitis [ see Warnings and Precautions ( 5.5 ) ] Hyperammonemic encephalopathy [ see War nings and Precautions ( 5.6 , 5.9 , 5.10 ) ] Suicidal behavior and ideation [ see Warning s and Precautions ( 5.7 ) ] Bleeding and other hematopoietic disorders [ see Warnings and Precautions ( 5.8 )] Hypothermia [se e Warnings and Precautions ( 5.11 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [s ee 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.

7 DRUG INTERACTIONS

DRUG INTERACTIONS SECTION

8 USE IN SPECIFIC POPULATIONS

USE IN SPECIFIC POPULATIONS SECTION

10 OVERDOSAGE

OVERDOSAGE SECTION

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 2120 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.

11 DESCRIPTION

DESCRIPTION SECTION

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 Capsules, USP are antiepileptics for oral administration. Each soft gelatin capsule contains 250 mg valproic acid. Inactive Ingredients: peanut oil, gelatin, glycerin, and titanium dioxide.

12 CLINICAL PHARMACOLOGY

CLINICAL PHARMACOLOGY SECTION

13 NONCLINICAL TOXICOLOGY

NONCLINICAL TOXICOLOGY SECTION

14 CLINICAL STUDIES

CLINICAL STUDIES SECTION

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

15 REFERENCES

REFERENCES SECTION

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

16 HOW SUPPLIED/STORAGE AND HANDLING

HOW SUPPLIED SECTION

Valproic Acid Capsules, USP, 250 mg. Each off-white colored soft gelatin capsule is imprinted with VALPROIC 250 and made available in bottles of 100 capsules ( NDC 0591-4012-01). Store capsules at controlled room temperature 15° to 30°C (59° to 86°F), see USP. Dispense in tight, light-resistant container.

17 PATIENT COUNSELING INFORMATION

INFORMATION FOR PATIENTS SECTION

Advise the patient to read the FDA-approved patient labeling ( Medication Guide ). Hepatotoxicity Warn patients and guardians that nausea, vomiting, abdominal pain, anorexia, diarrhea, asthenia, and/or jaundice can be symptoms of hepatotoxicity and, therefore, require further medical evaluation promptly [see Warnings and Precautions ( 5.1 ) ] . Pancreatitis Warn patients and guardians that abdominal pain, nausea, vomiting, and/or anorexia can be symptoms of pancreatitis and, therefore, require further medical evaluation promptly [see Warnings and Precautions ( 5.5 ) ] . Birth Defects and Decreased IQ Inform pregnant women and women of childbearing potential (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 . 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 )]. Advise patients to read the Medication Guide, which appears as the last section of the labeling [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )] . Pregnancy Registry Advise women of childbearing potential to discuss pregnancy planning with their doctor and to contact their doctor immediately if they think they are pregnant. Encourage women who are taking Valproic Acid to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry if they become pregnant. This registry is collecting information about the safety of antiepileptic drugs during pregnancy. To enroll, patients can call the toll free number 1-888-233-2334 or visit the website, http://www.aedpregnancyregistry.org/ [see Use in Specific Populations ( 8.1 )] . Suicidal Thinking and Behavior Counsel patients, their caregivers, and families that AEDs, including Valproic Acid, 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. Multi o rgan 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 by: Catalent Pharma Solutions, LLC. 2725 Scherer Drive North St. Petersburg, FL 33716-1016 Manufactured for: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 Revised: May 2021 32075657-01

MEDICATION GUIDE

SPL MEDGUIDE SECTION

Valproic Acid (val-proé-ik-as íd) Capsules Read this Medication Guide before you start taking Valproic Acid Capsules 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 Capsules? Do not stop taking Valproic Acid Capsules without first talking to your healthcare provider. Stopping valproic acid suddenly can cause serious problems. Valproic Acid Capsules 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 Capsules may harm your unborn baby. If you take Valproic Acid Capsules 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 Capsules 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 attention deficit/hyperactivity disorder. There may be other medicines to treat your condition that have a lower chance of causing birth defects and decreased IQ in your child, or other disorders in your child. Women who are pregnant must not take Valproic Acid Capsules to prevent migraine headaches. All women of child-bearing age (including girls from the start of puberty) should talk to their healthcare provider about using other possible treatments instead of Valproic Acid Capsules. If the decision is made to use Valproic Acid Capsules, you should use effective birth control (contraception). Tell your healthcare provider right away if you become pregnant while taking Valproic Acid Capsules. You and your healthcare provider should decide if you will continue to take Valproic Acid Capsules while you are pregnant. Pregnancy Registry: If you become pregnant while taking Valproic Acid Capsules, talk to your healthcare provider about registering with the North American Antiepileptic Drug Pregnancy Registry. You can enroll in this registry by calling 1-888-233-2334 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 Capsules 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 Capsules 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 do 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 are Valproic Acid Capsules? Valproic Acid Capsules come in capsule dosage form. Valproic Acid Capsules are a prescription medicines 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 Capsules? Do not take Valproic Acid Capsules 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 Capsules. See the end of this leaflet for a complete list of ingredients in Valproic Acid Capsules. 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 Capsules? Before you take Valproic Acid Capsules, 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 Capsules. 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 Capsules 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 Capsules? Take Valproic Acid Capsules exactly as your healthcare provider tells you. Your healthcare provider will tell you how much Valproic Acid Capsules 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 Capsules without first talking to your healthcare provider. Stopping Valproic Acid suddenly can cause serious problems. Swallow Valproic Acid Capsules whole. Do not crush or chew Valproic Acid Capsules. Tell your healthcare provider if you can not swallow Valproic Acid Capsules whole. You may need a different medicine. If you take too many Valproic Acid Capsules, call your healthcare provider or local Poison Control Center right away. What should I avoid while taking Valproic Acid Capsules? Valproic Acid Capsules can cause drowsiness and dizziness. Do not drink alcohol or take other medicines that make you sleepy or dizzy while taking Valproic Acid Capsules, until you talk with your doctor. Taking Valproic Acid Capsules 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 Capsules affect you. Valproic acid can slow your thinking and motor skills. What are the possible side effects of Valproic Acid Capsules? • See “What is the most important information I should know about Valproic Acid Capsules?” Valproic Acid Capsules 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, skin 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 Capsules 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 Capsules. 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 Capsules? Store Valproic Acid Capsules at 15° to 30°C (59° to 86°F). Keep Valproic Acid Capsules and all medicines out of the reach of children. General information about the safe and effective use of Valproic Acid Capsules Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use Valproic Acid Capsules for a condition for which it was not prescribed. Do not give Valproic Acid Capsules 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 Capsules. If you would like more information, talk with your healthcare provider. You can ask your pharmacist or healthcare provider for information about Valproic Acid Capsules that is written for health professionals. For more information, call 1-888-838-2872. What are the ingredients in Valproic Acid Capsules? Active ingredient: valproic acid Inactive ingredients: peanut oil, gelatin, glycerin, and titanium dioxide This Medication Guide has been approved by the U.S. Food and Drug Administration. Manufactured by: Catalent Pharma Solutions, LLC 2725 Scherer Drive North St. Petersburg, FL 33716-1016 Manufactured for: Teva Pharmaceuticals USA, Inc. Parsippany, NJ 07054 USA Revised: May 2021 Valproic Acid USP, 250 mg 32075841-01

REPACKAGING INFORMATION

SPL UNCLASSIFIED SECTION

Please reference the HOW SUPPLIED section listed above for a description of individual drug products listed below. This drug product has been received by Aphena Pharma Solutions - Tennessee, LLC in a manufacturer or distributor packaged configuration and repackaged in full compliance with all applicable cGMP regulations. The package configurations available from Aphena are listed below: 250mg NDC 71610-906-30, Bottles of 30 Capsules NDC 71610-906-53, Bottles of 60 Capsules NDC 71610-906-60, Bottles of 90 Capsules NDC 71610-906-70, Bottles of 120 Capsules NDC 71610-906-80, Bottles of 180 Capsules NDC 71610-906-90, Bottles of 240 Capsules Store between 20°-25°C (68°-77°F). See USP Controlled Room Temperature. Dispense in a tight light-resistant container as defined by USP. Keep this and all drugs out of the reach of children. Repackaged by: Cookeville, TN 38506 20250523AMH