Valproate

1 INDICATIONS AND USAGE Valproate sodium injection is indicated as an intravenous alternative in patients in whom oral administration of valproate products is temporarily not feasible in the following conditions: • 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 Valproate sodium injection is indicated as an intravenous alternative in patients for whom oral administration of valproate products is temporarily not feasible in the following conditions: Valproate sodium injection is indicated as monotherapy and adjunctive therapy in the treatment of patients with complex partial seizures that occur either in isolation or in association with other types of seizures. Valproate sodium injection is also indicated for use as sole and adjunctive therapy in the treatment of patients with 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. See Warnings and Precautions ( 5.1 ) for statement regarding fatal hepatic dysfunction. 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 )] .

12.1 Mechanism of Action Valproate sodium exists as the valproate ion in the blood. 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).

2 DOSAGE AND ADMINISTRATION Valproate sodium injection is intended for intravenous use only. • Epilepsy o Complex Partial Seizures in Adults and Children 10 years of age or older: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response. Maximum recommended dose is 60 mg/kg/day ( 2.1 ). o Simple and Complex Absence Seizures: Initial dose is 10 to 15 mg/kg/day, increasing at 1 week intervals by 5 to 10 mg/kg/day to achieve optimal clinical response. Maximum recommended dose is 60 mg/kg/day ( 2.1 ). 2.1 Epilepsy Valproate sodium injection is for intravenous use only. Use of valproate sodium injection for periods of more than 14 days has not been studied. Patients should be switched to oral valproate products as soon as it is clinically feasible. Valproate sodium injection should be administered as a 60 minute infusion (but not more than 20 mg/min) with the same frequency as the oral products, although plasma concentration monitoring and dosage adjustments may be necessary. In one clinical safety study, approximately 90 patients with epilepsy and with no measurable plasma levels of valproate were given single infusions of valproate sodium injection (up to 15 mg/kg and mean dose of 1,184 mg) over 5 to 10 minutes (1.5 to 3 mg/kg/min). Patients generally tolerated the more rapid infusions well [see Adverse Reactions ( 6.1 )] . This study was not designed to assess the effectiveness of these regimens. For pharmacokinetics with rapid infusions, see Clinical Pharmacology ( 12.3 ). Initial Exposure to Valproate The following dosage recommendations were obtained from studies utilizing oral divalproex sodium products. Complex Partial Seizures For adults and children 10 years of age or older. Monotherapy (Initial Therapy) Valproate sodium injection has not been systematically studied as initial therapy. Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 to 100 mcg/mL). No recommendation regarding the safety of valproate for use at doses above 60 mg/kg/day can be made. The probability of thrombocytopenia increases significantly at total trough valproate plasma concentrations above 110 mcg/mL in females and 135 mcg/mL in males. The benefit of improved seizure control with higher doses should be weighed against the possibility of a greater incidence of adverse reactions. Conversion to Monotherapy Patients should initiate therapy at 10 to 15 mg/kg/day. The dosage should be increased by 5 to 10 mg/kg/week to achieve optimal clinical response. Ordinarily, optimal clinical response is achieved at daily doses below 60 mg/kg/day. If satisfactory clinical response has not been achieved, plasma levels should be measured to determine whether or not they are in the usually accepted therapeutic range (50 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 valproate sodium injection 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 Valproate sodium injection 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 do

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 , 5.8 , 5.9 )] • Bleeding and other hematopoietic disorders [see Warnings and Precautions ( 5.7 )] • Hypothermia [see Warnings and Precautions ( 5.10 )] • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reactions [see Warnings and Precautions ( 5.11 )] • Somnolence in the elderly [see Warnings and Precautions ( 5.13 )] 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. The adverse reactions that can result from valproate sodium use include all of those associated with oral forms of valproate. The following describes experience specifically with valproate sodium. Valproate sodium has been generally well tolerated in clinical trials involving 111 healthy adult male volunteers and 352 patients with epilepsy, given at doses of 125 to 6,000 mg (total daily dose). A total of 2% of patients discontinued treatment with valproate sodium due to adverse reactions. The most common adverse reactions leading to discontinuation were 2 cases each of nausea/vomiting and elevated amylase. Other adverse reactions leading to discontinuation were hallucinations, pneumonia, headache, injection site reaction, and abnormal gait. Dizziness and injection site pain were observed more frequently at a 100 mg/min infusion rate than at rates up to 33 mg/min. At a 200 mg/min rate, dizziness and taste perversion occurred more frequently than at a 100 mg/min rate. The maximum rate of infusion studied was 200 mg/min. Adverse reactions reported by at least 0.5% of all subjects/patients in clinical trials of valproate sodium are summarized in Table 1 . Table 1. Adverse Reactions Reported During Studies of Valproate Sodium Body System/Reaction N = 463 % Body as a Whole Headache 4.3 Injection Site Pain 2.6 Injection Site Reaction 2.4 Chest Pain 1.7 Pain (unspecified) 1.3 Injection Site Inflammation 0.6 Cardiovascular Vasodilation 0.9 Dermatologic Sweating 0.9 Digestive System Nausea 3.2 Vomiting 1.3 Abdominal Pain 1.1 Diarrhea 0.9 Nervous System Dizziness 5.2 Somnolence 1.7 Euphoria 0.9 Nervousness 0.9 Paresthesia 0.9 Hypesthesia 0.6 Tremor 0.6 Respiratory Pharyngitis 0.6 Special Senses Taste Perversion 1.9 In a separate clinical safety trial, 112 patients with epilepsy were given infusions of valproate (up to 15 mg/kg) over 5 to 10 minutes (1.5 to 3 mg/kg/min). The common adverse reactions (> 2%) were somnolence (10.7%), dizziness (7.1%), paresthesia (7.1%), asthenia (7.1%), nausea (6.3%), and headache (2.7%). While the incidence of these adverse reactions was generally higher than in Table 1 (experience encompassing the standard, much slower infusion rates), e.g., somnolence (1.7%), dizziness (5.2%), paresthesia (0.9%), asthenia (0%), nausea (3.2%), and headache (4.3%), a direct comparison between the incidence of adverse reactions in the 2 cohorts cannot be made because of differences in patient populations and study designs. Ammonia levels have not been systematically studied after IV valproate, so that an estimate of the incidence of hyperammonemia after IV valproate sodium cannot be provided. Hyperammonemia with encephalopathy has been reported in 2 patients after infusions of valproate sodium. Adverse reactions occurring in at least 5% of patients treated with divalproex sodium in Monotherapy or Adjunctive Complex Partial Seizures Trials: • Abdominal pain, alopecia, amblyopia/blurred vi

5 WARNINGS AND PRECAUTIONS • Hepatotoxicity; evaluate high risk populations and monitor serum liver tests ( 5.1 ) • Birth defects, decreased IQ, and neurodevelopmental disorders following in utero exposure; should not be used to treat women with epilepsy or bipolar disorder who are pregnant or who plan to become pregnant or to treat a woman of childbearing potential unless other medications have failed to provide adequate symptom control or are otherwise unacceptable ( 5.2 , 5.3 , 5.4 ) • Pancreatitis; valproate sodium should ordinarily be discontinued ( 5.5 ) • Bleeding and other hematopoietic disorders; monitor platelet counts and coagulation tests ( 5.7 ) • 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 , 5.8 , 5.9 ) • Hypothermia; Hypothermia has been reported during valproate therapy with or without associated hyperammonemia. This adverse reaction can also occur in patients using concomitant topiramate ( 5.10 ) • Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS)/Multiorgan hypersensitivity reaction; discontinue valproate sodium ( 5.11 ) • Somnolence in the elderly can occur. Valproate sodium dosage should be increased slowly and with regular monitoring for fluid and nutritional intake ( 5.13 ) 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 valproate sodium 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. Use of valproate sodium has not been studied in children below the age of 2 years. 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 Valproate 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 patients with these syndromes have been identifie

4 CONTRAINDICATIONS • Valproate sodium injection should not be administered to patients with hepatic disease or significant hepatic dysfunction [see Warnings and Precautions ( 5.1 )] . • Valproate sodium injection 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 )] . • Valproate sodium injection is contraindicated in patients with known hypersensitivity to the drug [see Warnings and Precautions ( 5.11 )] . • Valproate sodium injection is contraindicated in patients with known urea cycle disorders [see Warnings and Precautions ( 5.6 )] . • For use in prophylaxis of migraine headaches: Valproate sodium injection is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception [see Warnings and Precautions ( 5.2 , 5.3 , 5.4 ) and Use in Specific Populations ( 8.1 )] . • Hepatic disease or significant hepatic dysfunction ( 4 , 5.1 ) • Known mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG) ( 4 , 5.1 ) • Suspected POLG-related disorder in children under two years of age ( 4 , 5.1 ) • Known hypersensitivity to the drug ( 4 , 5.11 ) • Urea cycle disorders ( 4 , 5.6 ) • Prophylaxis of migraine headaches: Pregnant women, women of childbearing potential not using effective contraception ( 4 , 8.1 )

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 serum concentrations 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. 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.