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💊 VALPROATE SODIUM

☠ BLACK BOX WARNING
Generic: VALPROATE SODIUM
INTRAVENOUS FDA Label
☠
FDA BLACK BOX WARNING

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 mitocho…

Quick reference
RouteINTRAVENOUS
ManufacturerFresenius Kabi USA, LLC
SourceFDA Label
✅ Indications & Usage ›

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... [See full FDA label]

💉 Dosage & 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... [See full FDA label]

🚫 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 )

⚠️ Warnings & Precautions ›
  • 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... [See full FDA label]

🔴 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 pervers... [See full FDA label]

💊 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, m... [See full FDA label]

🤰 Pregnancy ›

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 seri... [See full FDA label]

👶 Pediatric Use ›

8.4 Pediatric Use Experience with oral valproate has indicated that pediatric patients under the age of two years are at a considerably increased risk of developing fatal hepatotoxicity, especially those with the aforementioned conditions [see Boxed Warning ] . The safety of valproate sodium has not been studied in individuals below the age of 2 years. If a decision is made to use valproate sodium in this age group, it should be used with extreme caution and as a sole agent. The benefits of therapy should be weighed against the risks. Above the age of 2 years, experience in epilepsy has indicated that the incidence of fatal hepatotoxicity decreases considerably in progressively older patient groups. Younger children, especially those receiving enzyme-inducing drugs, will require larger maintenance doses to attain targeted total and unbound valproate concentrations. The variability in free fraction limits the clinical usefulness of monitoring total serum valproic acid concentrations. Interpretation of valproic acid concentrations in children should include consideration of factors that affect hepatic metabolism and protein binding. Pediatric Clinical Trials No unique safety concerns were identified in the 35 patients age 2 to 17 years who received valproate sodium in clinical trials. One twelve-month study was conducted to evaluate the safety of divalproex sodium sprinkle capsules in the indication of partial seizures (169 patients aged 3 to 10 years). The safety and tolerability of divalproex sodium in pediatric patients were shown to be comparable to those in adults [see Adverse Reactions ( 6 )]. Juvenile Animal Toxicology In studies of valproate in immature animals, toxic effects not observed in adult animals included retinal dysplasia in rats treated during the neonatal period (from postnatal day 4) and nephrotoxicity in rats treated during the neonatal and juvenile (from postnatal day 14) periods. The no-effect dose for these findings was less than the maximum r... [See full FDA label]

👴 Geriatric Use ›

8.5 Geriatric Use No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. In a case review study of 583 patients, 72 patients (12%) were greater than 65 years of age. A higher percentage of patients above 65 years of age reported accidental injury, infection, pain, somnolence, and tremor. Discontinuation of valproate was occasionally associated with the latter two events. It is not clear whether these events indicate additional risk or whether they result from pre- existing medical illness and concomitant medication use among these patients. A study of elderly patients with dementia revealed drug related somnolence and discontinuation for somnolence [see Warnings and Precautions ( 5.13 )] . The starting dose should be reduced in these patients, and dosage reductions or discontinuation should be considered in patients with excessive somnolence [see Dosage and Administration ( 2.2 )] . No unique safety concerns were identified in the 21 patients > 65 years of age receiving valproate sodium in clinical trials.

🔬 Mechanism of Action ›

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).

📊 Pharmacokinetics ›

12.3 Pharmacokinetics Bioavailability Equivalent doses of intravenous (IV) valproate and oral valproate products are expected to result in equivalent C max , C min , and total systemic exposure to the valproate ion when the IV valproate is administered as a 60 minute infusion. However, the rate of valproate ion absorption may vary with the formulation used. These differences should be of minor clinical importance under the steady state conditions achieved in chronic use in the treatment of epilepsy. Administration of divalproex sodium tablets and IV valproate (given as a one hour infusion), 250 mg every 6 hours for 4 days to 18 healthy male volunteers resulted in equivalent AUC, C max , C min at steady state, as well as after the first dose. The T max after IV valproate sodium occurs at the end of the one hour infusion, while the T max after oral dosing with divalproex sodium occurs at approximately 4 hours. Because the kinetics of unbound valproate are linear, bioequivalence between valproate sodium and divalproex sodium up to the maximum recommended dose of 60 mg/kg/day can be assumed. The AUC and C max resulting from administration of IV valproate 500 mg as a single one hour infusion and a single 500 mg dose of divalproex sodium syrup to 17 healthy male volunteers were also equivalent. Patients maintained on valproic acid doses of 750 mg to 4,250 mg daily (given in divided doses every 6 hours) as oral divalproex sodium alone (n = 24) or with another stabilized antiepileptic drug [carbamazepine (n = 15), phenytoin (n = 11), or phenobarbital (n = 1)], showed comparable plasma levels for valproic acid when switching from oral divalproex sodium to IV valproate (1-hour infusion). Eleven healthy volunteers were given single infusions of 1,000 mg IV valproate over 5, 10, 30, and 60 minutes in a 4-period crossover study. Total valproate concentrations were measured; unbound concentrations were not measured. After the 5 minute infusions (mean rate of 2.8 mg/kg/min), mean ... [See full FDA label]

☠️ 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.

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