Valproic Acid

Dosage and Administration, Dosing in Patients Taking Rufinamide ( 2.3 ) 2/2016

These highlights do not include all the information needed to use VALPROIC ACID CAPSULES safely and effectively. See full prescribing information for VALPROIC ACID CAPSULES. VALPROIC ACID capsules for oral use Initial U.S. Approval: 1978 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) INDICATIONS AND USAGE Valproic Acid Capsules are an anti-epileptic drug 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) DOSAGE AND ADMINISTRATION Valproic acid capsules are 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) DOSAGE FORMS AND STRENGTHS Capsules: 250 mg valproic acid (3) CONTRAINDICATIONS Hepatic disease or significant hepatic dysfunction (4, 5.1) Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) (4, 5.1) Suspected POLG-related disorder in children under two years of age (4, 5.1) Known hypersensitivity to the drug (4, 5.12) Urea cycle disorders (4, 5.6) WARNINGS AND PRECAUTIONS Hepatotoxicity; evaluate high risk populations and monitor serum liver tests (5.1) Birth defects and decreased IQ following in utero exposure; only use to treat pregnant women with epilepsy if other medications are unacceptable; should not be administered to a woman of childbearing potential unless essential (5.2, 5.3, 5.4) Pancreatitis; valproic acid capsules should ordinarily be discontinued (5.5) Suicidal behavior or ideation; Antiepileptic drugs, including valproic acid capsules, 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 capsules (5.12) Somnolence in the elderly can occur. Valproic acid capsules dosage should be increased slowly and with regular monitoring for fluid and nutritional intake (5.14) ADVERSE REACTIONS 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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at …

2 DOSAGE AND ADMINISTRATION Valproic acid capsules are 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 ) 2.1 Epilepsy Valproic acid capsules are intended for oral administration. Valproic acid capsules should be swallowed whole without chewing to avoid local irritation of the mouth and throat. Patients should be informed to take valproic acid capsules 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 capsules are indicated as monotherapy and adjunctive therapy in complex partial seizures in adults and pediatric patients down to the age of 10 years, and in simple and complex absence seizures. As the valproic acid capsules 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 capsules have not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal 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 to 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 capsules 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 capsules 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 e …

3 DOSAGE FORMS AND STRENGTHS Valproic acid capsules, USP are supplied as 250 mg off-white colored soft gelatin capsules, imprinted with "U-S 250", packaged in bottles containing 100. Capsules: 250 mg valproic acid ( 3 )

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

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 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 Upsher-Smith Laboratories, LLC at 1-855-899-9180 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Epilepsy The data described in the following section were obtained using divalproex sodium 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 tablets 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 Divalproex 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 tablets monotherapy treatment of complex partial seizures. Since patients were being titrated off another antiepilepsy drug during t …

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 capsules ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 ) 7.1 Effects 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 and cholestyramine. Delaying the administration of cholestyramine relati …

8.1 Pregnancy Pregnancy Category D for epilepsy [see WARNINGS AND PRECAUTIONS (5.2, 5.3)]. Pregnancy Registry To collect information on the effects of in utero exposure to valproic acid, physicians should encourage pregnant patients taking valproic acid capsules to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry. This can be done by calling toll free 1-888-233-2334, and must be done by the patients themselves. Information on the registry can be found at the website, http://www.aedpregnancyregistry.org/. Fetal Risk Summary All pregnancies have a background risk of birth defects (about 3%), pregnancy loss (about 15%), or other adverse outcomes regardless of drug exposure. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects, but also malformations involving other body systems (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). 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 (5.3)]. Several published epidemiological studies have indicated that children exposed to valproate in uterohave lower IQ scores than children exposed to either another antiepileptic drug in utero or to no antiepileptic drugs in utero [see WARNINGS AND PRECAUTIONS (5.3)]. An observational study has suggested that exposure to valproate products during pregnancy may increase the risk of autism spectrum disorders. In this study, children born to mothers who had used valproate products during pregnancy had 2.9 times the risk (95% confidence interval [CI]: 1.7 to 4.9) of developing autism spectrum disorders compared to children born to mothers not exposed to valproate products during pregnancy. The absolute risks for autism spectrum disorders were 4.4% (95% CI: 2.6% to 7.5%) in valproate-exposed children and 1.5% (95% CI: 1.5% to 1.6%) in children not exposed to valproate products. Because the study was observational in nature, conclusions regarding a causal association between in utero valproate exposure and an increased risk of autism spectrum disorder cannot be considered definitive. In animal studies, offspring with prenatal exposure to valproate had structural malformations similar to those seen in humans and demonstrated neurobehavioral deficits. Clinical Considerations Neural tube defects are the congenital malformation most strongly associated with maternal valproate use. The risk of spina bifida following in utero valproate exposure is generally estimated as 1% to 2%, compared to an estimated general population risk for spina bifida of about 0.06% to 0.07% (6 to 7 in 10,000 births). Valproate can cause decreased IQ scores in children whose mothers were treated with valproate during pregnancy. Because of the risks of decreased IQ, neural tube defects, and other fetal adverse events, which may occur very early in pregnancy: Valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death (e.g., migraine). Valproate should not be used to treat women with epilepsy who are pregnant or who plan to become pregnant unless other treatments have failed to provide adequate symptom control or are otherwise unacceptable. In such women, the benefits of treatment with valproate during pregnancy may still outweigh the risks. When treating a pregnant woman or a woman of childbearing potential, carefully c …

12.1 Mechanism of Action Valproic acid dissociates to the valproate ion in the gastrointestinal tract. The mechanisms by which valproate exerts its antiepileptic 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).

11 DESCRIPTION Valproic acid, USP 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 is an antiepileptics for oral administration. Each soft gelatin capsule contains 250 mg valproic acid, USP. Chemical Structure Inactive Ingredients Peanut oil, gelatin, glycerin and titanium dioxide

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.

16 HOW SUPPLIED/STORAGE AND HANDLING Valproic acid capsules, USP 250 mg are off-white colored soft gelatin capsules, imprinted with "U-S 250", containing valproic acid, USP, and packaged in bottles of 100 capsules (NDC 0832-0310-11). Store at 20° to 25°C (68° to 77°F); excursions permitted to 15° to 30°C (59° to 86°F) [See USP Controlled Room Temperature]. Dispense in a tight, light-resistant container with a child-resistant closure.