Divalproex sodium
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Pratik Bahekar, MBBS [2]
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Black Box Warning
|
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete Boxed Warning.
Condition Name: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 warning and precautions]. 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 divalproex 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. 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). Divalproex sodium 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]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium 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 warning and precautions]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see contraindications]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. 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). Women should use effective contraception while using valproate [see warning and precautions]. A Medication Guide describing the risks of valproate is available for patients [see patient information]. 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 warning and precautions ]. |
Overview
Divalproex sodium is a mood stabilizer that is FDA approved for the {{{indicationType}}} of absence seizure, simple and complex, complex partial epileptic seizure, manic bipolar I disorder, migraine prophylaxis. There is a Black Box Warning for this drug as shown here. Common adverse reactions include abdominal pain, diarrhea, indigestion, loss of appetite, nausea, vomiting, asthenia, dizziness, feeling nervous, headache, insomnia, somnolence, tremor, amblyopia, blurred vision, diplopia, infectious disease, influenza.
Adult Indications and Dosage
FDA-Labeled Indications and Dosage (Adult)
- Absence seizure, Simple and complex
- Initial, 15 mg/kg/day PO, increase dosage by 5 to 10 mg/kg/day at 1-week intervals max 60 mg/kg/day
- Complex partial epileptic seizure
- Monotherapy, initial, 10 to 15 mg/kg/day PO, increase dosage 5 to 10 mg/kg/day at 1-week intervals max 60 mg/kg/day
- Manic bipolar I disorder
- Initial, 25 mg/kg/day PO once dail, max 60 mg/kg/day
- Migraine; Prophylaxis
- Initial, 500 mg PO once daily for 1 week, up to 1000 mg once daily
Off-Label Use and Dosage (Adult)
Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Divalproex sodium in adult patients.
Non–Guideline-Supported Use
- Alcohol withdrawal syndrome
- Bipolar I disorder, Maintenance
- Bipolar II disorder, Maintenance
- Headache disorder, chronicView additional information.
- Posttraumatic headache
- Schizoaffective disorder, bipolar type
There is limited information about Off-Label Non–Guideline-Supported Use of Divalproex sodium in adult patients.
Pediatric Indications and Dosage
FDA-Labeled Indications and Dosage (Pediatric)
- Safety in children less than 10 years of age have not been established
- Absence seizure, Simple and complex for 10 years or older
- Initial, 15 mg/kg/day PO, may increase dosage 5 to 10 mg/kg/day at 1-week intervals max 60 mg/kg/day, 50 to 100 mcg/mL
- Complex partial epileptic seizure for 10 years or older monotherapy
- Initial, 10 to 15 mg/kg/day PO, increase dosage 5 to 10 mg/kg/day at 1-week intervals max 60 mg/kg/day
- Complex partial epileptic seizure for 10 years or older
- Initial, 10 to 15 mg/kg/day PO, increase dosage 5 to 10 mg/kg/day at 1-week intervals to achieve optimal clinical response max 60 mg/kg/day
- For converstion to monotherapy initial, 10 to 15 mg/kg/day PO, may increase dosage 5 to 10 mg/kg/day at 1-week intervals, max 60 mg/kg/day
Off-Label Use and Dosage (Pediatric)
Guideline-Supported Use
There is limited information about Off-Label Guideline-Supported Use of Divalproex sodium in pediatric patients.
Non–Guideline-Supported Use
There is limited information about Off-Label Non–Guideline-Supported Use of Divalproex sodium in pediatric patients.
Contraindications
- Divalproex sodium extended-release tablets should not be administered to patients with hepatic disease or significant hepatic dysfunction.
- 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.
- Divalproex sodium extended-release tablets are contraindicated in patients with known urea cycle disorders.
- Contraindicated for use in prophylaxis of migraine headaches in pregnant women.
Warnings
|
WARNING: LIFE THREATENING ADVERSE REACTIONS
See full prescribing information for complete Boxed Warning.
Condition Name: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 warning and precautions]. 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 divalproex 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. 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). Divalproex sodium 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]. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium 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 warning and precautions]. Fetal Risk Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores following in utero exposure. Valproate is therefore contraindicated in pregnant women treated for prophylaxis of migraine [see contraindications]. Valproate should only be used to treat pregnant women with epilepsy or bipolar disorder if other medications have failed to control their symptoms or are otherwise unacceptable. 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). Women should use effective contraception while using valproate [see warning and precautions]. A Medication Guide describing the risks of valproate is available for patients [see patient information]. 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 warning and precautions ]. |
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. 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."
Adverse Reactions
Clinical Trials Experience
There is limited information regarding Divalproex sodium Clinical Trials Experience in the drug label.
Postmarketing Experience
There is limited information regarding Divalproex sodium Postmarketing Experience in the drug label.
Drug Interactions
There is limited information regarding Divalproex sodium Drug Interactions in the drug label.
Use in Specific Populations
Pregnancy
Pregnancy Category (FDA):
There is no FDA guidance on usage of Divalproex sodium in women who are pregnant.
Pregnancy Category (AUS):
There is no Australian Drug Evaluation Committee (ADEC) guidance on usage of Divalproex sodium in women who are pregnant.
Labor and Delivery
There is no FDA guidance on use of Divalproex sodium during labor and delivery.
Nursing Mothers
There is no FDA guidance on the use of Divalproex sodium in women who are nursing.
Pediatric Use
There is no FDA guidance on the use of Divalproex sodium in pediatric settings.
Geriatic Use
There is no FDA guidance on the use of Divalproex sodium in geriatric settings.
Gender
There is no FDA guidance on the use of Divalproex sodium with respect to specific gender populations.
Race
There is no FDA guidance on the use of Divalproex sodium with respect to specific racial populations.
Renal Impairment
There is no FDA guidance on the use of Divalproex sodium in patients with renal impairment.
Hepatic Impairment
There is no FDA guidance on the use of Divalproex sodium in patients with hepatic impairment.
Females of Reproductive Potential and Males
There is no FDA guidance on the use of Divalproex sodium in women of reproductive potentials and males.
Immunocompromised Patients
There is no FDA guidance one the use of Divalproex sodium in patients who are immunocompromised.
Administration and Monitoring
Administration
There is limited information regarding Divalproex sodium Administration in the drug label.
Monitoring
There is limited information regarding Divalproex sodium Monitoring in the drug label.
IV Compatibility
There is limited information regarding the compatibility of Divalproex sodium and IV administrations.
Overdosage
There is limited information regarding Divalproex sodium overdosage. If you suspect drug poisoning or overdose, please contact the National Poison Help hotline (1-800-222-1222) immediately.
Pharmacology
There is limited information regarding Divalproex sodium Pharmacology in the drug label.
Mechanism of Action
There is limited information regarding Divalproex sodium Mechanism of Action in the drug label.
Structure
There is limited information regarding Divalproex sodium Structure in the drug label.
Pharmacodynamics
There is limited information regarding Divalproex sodium Pharmacodynamics in the drug label.
Pharmacokinetics
There is limited information regarding Divalproex sodium Pharmacokinetics in the drug label.
Nonclinical Toxicology
There is limited information regarding Divalproex sodium Nonclinical Toxicology in the drug label.
Clinical Studies
There is limited information regarding Divalproex sodium Clinical Studies in the drug label.
How Supplied
There is limited information regarding Divalproex sodium How Supplied in the drug label.
Storage
There is limited information regarding Divalproex sodium Storage in the drug label.
Images
Drug Images
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Package and Label Display Panel
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Patient Counseling Information
There is limited information regarding Divalproex sodium Patient Counseling Information in the drug label.
Precautions with Alcohol
Alcohol-Divalproex sodium interaction has not been established. Talk to your doctor about the effects of taking alcohol with this medication.
Brand Names
There is limited information regarding Divalproex sodium Brand Names in the drug label.
Look-Alike Drug Names
There is limited information regarding Divalproex sodium Look-Alike Drug Names in the drug label.
Drug Shortage Status
Price
References
The contents of this FDA label are provided by the National Library of Medicine.