Divalproex sodium

1 INDICATIONS AND USAGE Divalproex sodium delayed-release capsules are an anti-epileptic drug indicated for: Monotherapy and adjunctive therapy of complex partial seizures and simple and complex absence seizures; adjunctive therapy in patients with multiple seizure types that include absence seizures ( 1 ) 1.1 Epilepsy Divalproex sodium delayed-release capsules are indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures. Divalproex sodium delayed-release capsules are also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types that include absence seizures. Simple absence is defined as very brief clouding of the sensorium or loss of consciousness accompanied by certain generalized epileptic discharges without other detectable clinical signs. Complex absence is the term used when other signs are also present. 1.2 Important Limitations Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable. Valproate should not be administered to a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ), Use in Specific Populations ( 8.1 ), and Patient Counseling Information ( 17 )]. For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )].

2 DOSAGE AND ADMINISTRATION Divalproex sodium delayed-release capsules may be swallowed whole or the contents may be sprinkled on soft food. The drug/food mixture should be swallowed immediately (avoid chewing) ( 2.2 ) Safety of doses above 60 mg/kg/day is not established ( 2.1 , 2.2 ) Complex Partial Seizures: Start at 10 mg/kg/day to 15 mg/kg/day, increasing at 1 week intervals by 5 mg/kg/day to 10 mg/kg/day to achieve optimal clinical response; if response is not satisfactory, check valproate plasma level; see full prescribing information for conversion to monotherapy ( 2.1 ) Absence Seizures: Start at 15 mg/kg/day, increasing at 1 week intervals by 5 mg/kg/day to 10 mg/kg/day until seizure control or limiting side effects ( 2.1 ) 2.1 Epilepsy Divalproex sodium delayed-release capsules are administered orally. As divalproex sodium dosage is titrated upward, concentrations of clonazepam, diazepam, ethosuximide, lamotrigine, tolbutamide, phenobarbital, carbamazepine, and/or phenytoin may be affected [see Drug Interactions ( 7.2 )] . Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Divalproex sodium delayed-release capsules have not been systematically studied as initial therapy. Patients should initiate therapy at 10 mg/kg/day to 15 mg/kg/day. The dosage should be increased by 5 mg/kg/week 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 mcg/mL 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 mg/kg/day to 15 mg/kg/day. The dosage should be increased by 5 mg/kg/week 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 mcg/mL 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 divalproex sodium delayed-release 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 Divalproex sodium delayed-release capsules may be added to the patient's regimen at a dosage of 10 mg/kg/day to 15 mg/kg/day. The dosage may be increased by 5 mg/kg/week 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 mcg/mL to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. If the total daily dose exceeds 250 mg, it should be given in divided doses. In a study of adjunctive therapy for complex partial seizures in which patients were receiving either carbamazepine or phenytoin…

5 WARNINGS AND PRECAUTIONS Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure: should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable ( 5.2 , 5.3 , 5.4 ) Pancreatitis: Divalproex sodium delayed-release capsules should ordinarily be discontinued ( 5.5 ) Suicidal behavior or ideation: Antiepileptic drugs, including divalproex sodium delayed-release 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 reactions, serious dermatologic reactions, and angioedema: discontinue divalproex sodium delayed-release capsules unless an alternate etiology is established ( 4 , 5.12 , 5.13 , 5.14 ) 5.1 Hepatotoxicity General Information on Hepatotoxicity Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serious or fatal hepatotoxicity may be preceded by non-specific symptoms such as malaise, weakness, lethargy, facial edema, anorexia, and vomiting. In patients with epilepsy, a loss of seizure control may also occur. Patients should be monitored closely for appearance of these symptoms. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months of valproate therapy. However, healthcare providers should not rely totally on serum biochemistry since these tests may not be abnormal in all instances, but should also consider the results of careful interim medical history and physical examination. Caution should be observed when administering valproate products to patients with a prior history of hepatic disease. Patients on multiple anticonvulsants, children, those with congenital metabolic disorders, those with severe seizure disorders accompanied by mental retardation, and those with organic brain disease may be at particular risk. See below, “Patients with Known or Suspected Mitochondrial Disease.” Experience has indicated that children under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions. When divalproex sodium delayed release capsules are used in this patient group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. In progressively older patient groups experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably. Patients with Known or Suspected Mitochondrial Disease Divalproex sodium delayed-release capsules is contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and children under two years of age who are clinically suspected of having a mitochondrial disorder [see Contraindications ( 4 )] . Valproate-induced acute liver failure and liver-related deaths have been reported in patients with hereditary neurometabolic syndromes caused by mutations in the gene for mitochondrial DNA polymerase γ (POLG) (e.g., Alpers-Huttenlocher Syndrome) at a higher rate than those without these syndromes. Most of the reported cases of liver failure in pa…

4 CONTRAINDICATIONS Divalproex sodium delayed-release capsules is contraindicated in patients: with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1 )]. known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher Syndrome) and children under two years of age who are suspected of having a POLG-related disorder [see Warnings and Precautions ( 5.1 )]. withknownhypersensitivity to divalproex sodium, sodium valproate, or valproic acid. Reactions have included multiorgan hypersensitivity, serious dermatologic reactions, and angioedema [see Warnings and Precautions ( 5.12 , 5.13 , 5.14 )]. with known urea cycle disorders [see Warnings and Precautions ( 5.6 )]. being treated for prophylaxis of migraine headaches: who are pregnant or in women of childbearing potential who are not using effective contraception [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )]. 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 )

7 DRUG INTERACTIONS Hepatic enzyme-inducing drugs (e.g., phenytoin, carbamazepine, phenobarbital, primidone, rifampin) can increase valproate clearance, while enzyme inhibitors (e.g., felbamate) can decrease valproate clearance. Therefore increased monitoring of valproate and concomitant drug concentrations and dosage adjustment are indicated whenever enzyme-inducing or inhibiting drugs are introduced or withdrawn ( 7.1 ) Aspirin, carbapenem antibiotics, estrogen-containing hormonal contraceptives, methotrexate: Monitoring of valproate concentrations is recommended ( 7.1 ) Co-administration of valproate can affect the pharmacokinetics of other drugs (e.g. diazepam, ethosuximide, lamotrigine, phenytoin) by inhibiting their metabolism or protein binding displacement ( 7.2 ) Patients stabilized on rufinamide should begin valproate therapy at a low dose, and titrate to clinically effective dose ( 7.2 ) Dosage adjustment of amitriptyline/nortriptyline, propofol, warfarin, and zidovudine may be necessary if used concomitantly with divalproex sodium delayed-release capsules ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.10 , 7.3 ) Cannabidiol: ALT and/or AST elevation ( 7.4 ) 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 mg/kg to 16 mg/kg) with valproate to pediatric patients (n=6) revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone. The β-oxidation pathway consisting of 2-E-valproic acid, 3-OH-valproic acid, and 3-keto valproic acid was decreased from 25% of total metabolites excreted on valproate alone to 8.3% in the presence of aspirin. Caution should be observed if valproate and aspirin are to be co-administered. Carbapenem Antibiotics A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control. The mechanism of this interaction is not well understood. Serum valproic acid concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproic acid concentrations drop significantly or seizure control deteriorates [see Warnings and Precautions ( 5.15 )] . Estrogen-Containing Hormonal Contraceptives Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increa…

8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including divalproex sodium delayed-release capsules, during pregnancy. Encourage women who are taking divalproex sodium delayed-release capsules during pregnancy to enroll in the North American Antiepileptic Drug (NAAED) Pregnancy Registry by calling toll-free 1-888-233-2334 or visiting the website, http://www.aedpregnancyregistry.org/. This must be done by the patient herself. Risk Summary For use in prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Contraindications ( 4 )]. For use in epilepsy or bipolar disorder, valproate should not be used to treat women who are pregnant or who plan to become pregnant unless other medications have failed to provide adequate symptom control or are otherwise unacceptable [see Boxed Warning and Warnings and Precautions ( 5.2 , 5.3 )] . Women with epilepsy who become pregnant while taking valproate should not discontinue valproate abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life. Maternal valproate use during pregnancy for any indication increases the risk of congenital malformations, particularly neural tube defects including spina bifida, but also malformations involving other body systems (e.g., craniofacial defects including oral clefts, cardiovascular malformations, hypospadias, limb malformations). This risk is dose-dependent; however, a threshold dose below which no risk exists cannot be established. In utero exposure to valproate may also result in hearing impairment or hearing loss. Valproate polytherapy with other AEDs has been associated with an increased frequency of congenital malformations compared with AED monotherapy. The risk of major structural abnormalities is greatest during the first trimester; however, other serious developmental effects can occur with valproate use throughout pregnancy. The rate of congenital malformations among babies born to epileptic mothers who used valproate during pregnancy has been shown to be about four times higher than the rate among babies born to epileptic mothers who used other anti-seizure monotherapies [see Warnings and Precautions ( 5.2 ) and Data]. Epidemiological studies have indicated that children exposed to valproate in utero have lower IQ scores and a higher risk of neurodevelopmental disorders (NDDs), including autism spectrum disorder (ASD), intellectual disability (ID, defined as an IQ less than 70), and attention deficit/hyperactivity disorder (ADHD), compared to children exposed to either another AED in utero or to no AEDs in utero [see Warnings and Precautions ( 5.3 ) and Data]. In animal studies, valproate administration during pregnancy resulted in fetal structural malformations similar to those seen in humans and neurobehavioral deficits in the offspring at clinically relevant doses [see Data]. There have been reports of hypoglycemia in neonates and fatal cases of hepatic failure in infants following maternal use of valproate during pregnancy. Pregnant women taking valproate may develop hepatic failure or clotting abnormalities including thrombocytopenia, hypofibrinogenemia, and/or decrease in other coagulation factors, which may result in hemorrhagic complications in the neonate including death [see Warnings and Precautions ( 5.1 , 5.8 )]. Available prenatal diagnostic testing to detect neural tube and other defects should be offered to pregnant women using valproate. Evidence suggests that folic acid supplementation prior to conception and during the first trimester of pregnancy decreases the risk for congenital neural tube defects in the general population. It is not known whether the risk of neural tube defects or decreased IQ in the offspring of women receiving valproate…

8.3 Females and Males of Reproductive Potential Contraception Women of childbearing potential should use effective contraception while taking valproate [see Boxed Warning, Warnings and Precautions ( 5.4 ), Drug Interactions ( 7 ), and Use in Specific Populations ( 8.1 )]. This is especially important when valproate use is considered for a condition not usually associated with permanent injury or death such as prophylaxis of migraine headaches [see Contraindications ( 4 )]. Infertility There have been reports of male infertility coincident with valproate therapy [see Adverse Reactions ( 6.2 )]. In animal studies, oral administration of valproate at clinically relevant doses resulted in adverse reproductive effects in males [see Nonclinical Toxicology ( 13.1 )].

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 and Neurodevelopmental Disorders Following in utero Exposure [see Warnings and Precautions ( 5.3 )] Pancreatitis [see Warnings and Precautions ( 5.5 )] Hyperammonemic Encephalopathy [see Warnings and Precautions ( 5.6 , 5.9 , 5.10 )] Suicidal Behavior and Ideation [see Warnings and Precautions ( 5.7 )] Bleeding and Other Hematopoietic Disorders [see Warnings and Precautions ( 5.8 )] Hypothermia [see Warnings and Precautions ( 5.11 )] Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan Hypersensitivity Reactions [see Warnings and Precautions ( 5.12 )] Serious Dermatologic Reactions [see Warnings and Precautions ( 5.13 )] Angioedema [see Warnings and Precautions ( 5.14 )] Somnolence in the Elderly [see Warnings and Precautions ( 5.16 )] Because clinical studies are conducted under widely varying conditions, adverse reaction rates observed in the clinical studies of a drug cannot be directly compared to rates in the clinical studies of another drug and may not reflect the rates observed in practice. Most common adverse reactions (reported greater than or equal to 15% for any indication) are abdominal pain, alopecia, asthenia, diarrhea, diplopia, dizziness, headache, infection, insomnia, nausea, somnolence, thrombocytopenia, tremor, vomiting ( 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 Ajanta Pharma USA Inc. at 1-855-664-7744 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch 6.1 Epilepsy 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. In a long term (12-month) safety study in pediatric patients (n=169) between the ages of 3 and 10 years old, no clinically meaningful differences in the adverse event profile were observed when compared to adults. Table 2 lists treatment-emergent adverse reactions which were reported by greater than or equal to 5% of divalproex sodium-treated patients and for which the incidence was greater than in the placebo group, in the placebo-controlled trial of adjunctive therapy for treatment of complex partial seizures. Since patients were also treated with other antiepilepsy drugs, it is not possible, in most cases, to determine whether the following adverse reactions can be ascribed to divalproex sodium alone, or the combination of divalproex sodium and other antiepilepsy drugs. Table 2. Adverse Reactions Reported by Greater Than or Equal to 5% of Patients Treated with Valproate During Placebo-Controlled Trial of Adjunctive Therapy for Complex Partial Seizures Body System/Event 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 3 lists treatment-emergent adverse reactions which were reported by greater than or equal to 5% of patients in the high dose valproate group, and for which the incidence was greater than in the low dose group, in a controlled trial of divalproex sodium monotherapy treatment of complex partial seizures. Since patients were…