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IMPORTANT SAFETY INFORMATION1-3
Warning: Life-Threatening Adverse Reactions
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.
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 Depakote (divalproex sodium) Tablets for Oral use, Depakote ER (divalproex sodium) Tablet, Extended Release for Oral use or Depakote Sprinkle Capsules (divalproex sodium delayed release capsules), for oral use 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). Depakote ER and Depakote Sprinkles Capsules are contraindicated in patients known to have mitochondrial disorders caused by POLG mutations and in children under two years of age who are clinically suspected of having a mitochondrial disorder. In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, Depakote ER or Depakote Sprinkle Capsules are only to be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakote ER or Depakote Sprinkle Capsules 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.
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.
Depakote and Depakote ER are therefore contraindicated in pregnant women treated for prophylaxis of migraine. 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.
Depakote Sprinkle Capsules should only be used to treat pregnant women with epilepsy 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.
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.
- Valproate should not be administered to patients with hepatic disease or dysfunction. Immediately discontinue drug if significant hepatic dysfunction is suspected or apparent. Progression of dysfunction has occurred in spite of discontinuation of valproate.
- Valproate is contraindicated in patients known to have mitochondrial disorders caused by mutations in mitochondrial DNA polymerase γ (POLG; e.g., Alpers-Huttenlocher syndrome) and in children under two years of age who are suspected of having a POLG-related disorder. POLG-related disorder symptoms may include unexplained encephalopathy, refractory epilepsy (focal, myoclonic), status epilepticus at presentation, developmental delays, psychomotor regression, axonal sensorimotor neuropathy, myopathy cerebellar ataxia, opthalmoplegia, or complicated migraine with occipital aura.
- Depakote and Depakote ER are contraindicated for use in prophylaxis of migraine headaches in pregnant women.
- Valproate is contraindicated in patients with known hypersensitivity to the drug.
- Valproate is contraindicated in patients with known urea cycle disorders (UCDs), a group of uncommon genetic abnormalities. Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate. Symptoms of unexplained hyperammonemic encephalopathy during valproate therapy require prompt treatment (including discontinuation of valproate).
- Valproate can cause decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy. The rate of congenital malformations with in utero exposure is about four times higher compared to the rate with in utero exposure to other anti-seizure monotherapies. Lower cognitive test scores, including decreased IQ scores were associated with in utero valproate exposure compared with in utero exposure to either another or no antiepileptic drug. Unless essential to their medical management or failure of other treatments, women of childbearing potential should not receive valproate.
- Valproate can increase the risk of suicidal thoughts or behavior. Patients treated with any AED should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or unusual changes in mood or behavior. Counsel patients and families to be alert for and to immediately report depression, any unusual changes in mood or behavior, or suicidal thought, behavior, or acts of self-harm.
- Adverse effects (particularly elevated liver enzymes and thrombocytopenia) may be dose related. The probability of thrombocytopenia appears to increase significantly at total trough valproate plasma concentrations of ≥110 μg/mL in females and ≥135 μg/mL in males. Hemorrhage, bruising, or a disorder of homeostasis/coagulation is an indication for reduction of dosage or withdrawal of therapy.
- Hyperammonemia has been associated with valproate; it may be present despite normal liver function tests and should be considered if hypothermia occurs. Asymptomatic elevations of ammonia are more common and require close monitoring. Discontinue valproate if ammonia increases.
- Concomitant administration of topiramate and valproate has been associated with hyperammonemia (with or without encephalopathy) in patients who have tolerated either drug alone.
- Hypothermia has been associated with valproate therapy both in conjunction with, and in the absence of, hyperammonemia. It can occur after starting topiramate treatment or after increasing the daily dose of topiramate. Consider stopping valproate if hypothermia develops.
- Multi-organ hypersensitivity reactions have occurred in association to the initiation of valproate therapy in adult and pediatric patients. Signs and symptoms were diverse; however, patients typically presented with fever and rash associated with other organ system involvement. If suspected, discontinue valproate.
- Carbapenem antibiotics (such as: ertapenem, imipenem, meropenem) may reduce serum valproate concentrations to subtherapeutic levels, resulting in loss of seizure control.
- In a clinical trial, somnolence was associated with valproate in some elderly dementia patients along with reduced nutritional intake, weight loss, and a trend to have a lower baseline albumin concentration, higher BUN, and lower valproate clearance. Discontinuation occurred in some patients.
- Valproate may interact with drugs capable of enzyme induction; check valproate and concomitant drug levels periodically in the early course of therapy.
- Rare reports of medication residue in the stool have occurred; some in patients with anatomic (ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times or in the context of diarrhea. If medication residue occurs, monitor plasma valproate levels and patients' clinical condition; alternative treatment may be considered.
ADVERSE EVENTS1-3
Most common adverse reactions (reported ≥5%) reported in adult studies are thrombocytopenia, nausea, somnolence, dizziness, vomiting, asthenia, abdominal pain, dyspepsia, rash, diarrhea, increased appetite, tremor, weight gain, back pain, alopecia, headache, fever, anorexia, constipation, diplopia, amblyopia/blurred vision, ataxia, nystagmus, emotional lability, abnormal thinking, amnesia, flu syndrome, infection, bronchitis, rhinitis, ecchymosis, peripheral edema, pain, insomnia, nervousness, depression, pharyngitis, dyspnea, tinnitus, accidental injury, and weight loss.
Keep Depakote and all other medications where children cannot reach them.
- Depakote [package insert].
- Depakote ER [package insert].
- Depakote Sprinkle Capsules [package insert].
SAFETY CONSIDERATIONS
Life-threatening adverse reactions have been reported with Depakote:
- 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.
- Fetal Risk, particularly neural tube defects, other major malformations and decreased IQ.
- Pancreatitis, including some hemorrhagic cases.
- Contraindicated for use in patients with: hepatic disease or significant hepatic dysfunction, mitochondrial disorders (POLG e.g. Alpers) and children under 2 years of age suspected of having a POLG-related disorder, known urea cycle disorders (UCD), particularly ornithine transcarbamylase deficiency, known hypersensitivity or pregnant patients treated for prophylaxis of migraine headaches.
- In the presence of significant hepatic dysfunction, suspected or apparent, discontinue therapy immediately. Hepatic dysfunction can progress despite discontinuation of therapy.
- Should not be administered to a women of childbearing potential unless essential to treatment as other treatment options have failed or are otherwise unacceptable.
- In the presence of pancreatitis, discontinue therapy.