Valproate Sodium
FDA Drug Information • Also known as: Valproate Sodium
- Brand Names
- Valproate Sodium
- Dosage Form
- POWDER
- Product Type
- BULK INGREDIENT
⚠ Boxed Warning (Black Box)
WARNING: LIFE THREATENING ADVERSE REACTIONS 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 ) 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 severe seizure disorders accompanied by mental retardation, and those with organic brain disease. When valproate sodium injection 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. 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). Valproate sodium injection 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, valproate sodium injection should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with valproate sodium injection 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 ) and 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 )].Description
11 DESCRIPTION Valproate sodium is the sodium salt of valproic acid designated as sodium 2-propylpentanoate. Valproate sodium has the following structure: C 8 H 15 NaO 2 M.W. 166.2 Valproate sodium occurs as an essentially white and odorless, crystalline, deliquescent powder. Valproate sodium injection, USP is available in 5 mL single-dose vials for intravenous injection. Each mL contains valproate sodium equivalent to 100 mg valproic acid, edetate disodium 0.40 mg, and water for injection to volume. The pH is adjusted to 7.6 with sodium hydroxide and/or hydrochloric acid. The solution is clear and colorless. valpr-struc-01.jpg
What Is Valproate Sodium Used For?
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 )] .Dosage and Administration
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...Side Effects (Adverse Reactions)
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...Drug Interactions
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 valproate ( 7.2 ) Topiramate: Hyperammonemia and encephalopathy ( 5.9 , 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...Contraindications
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 )Pregnancy and Breastfeeding
8.1 Pregnancy Pregnancy Exposure Registry There is a pregnancy exposure registry that monitors pregnancy outcomes in women exposed to antiepileptic drugs (AEDs), including Valproate sodium, during pregnancy. Encourage women who are taking Valproate sodium 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...
Overdosage
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.
How Supplied
16 HOW SUPPLIED/STORAGE AND HANDLING Valproate Sodium Injection, equivalent to 100 mg of valproic acid per mL, is a clear, colorless solution supplied as: Manufacturer Product Number Unit of Sale Strength Each Unit PRX439405 NDC 63323-494-16 Available in trays of 10 vials. 500 mg per 5 mL (100 mg per mL) NDC 63323-494-41 5 mL Single-dose Vial Store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. Preservative Free. Unused portion of container should be discarded. The container closure is not made with natural rubber latex.
About This Information
This drug information is sourced from FDA-approved labeling via the openFDA database. It is intended for educational and reference purposes only. This is not medical advice. Always consult your healthcare provider before making decisions about medication. Drug information may be updated by the FDA; check with your pharmacist for the most current information.
What are side effects?
Side effects are unwanted reactions that can occur when taking a medication. They range from mild (headache, nausea) to severe (allergic reactions, organ damage). Not everyone experiences side effects, and severity varies. Report any concerning side effects to your doctor.
What are drug interactions?
Drug interactions occur when a medication is affected by another drug, food, or supplement. Interactions can make medications less effective or cause dangerous side effects. Always tell your doctor about all medications and supplements you take.