Divalproex (Depakote ER) Risks, Warnings, and Complications

LIVER TOXICITY: Divalproex can cause serious liver problems, including liver failure. These problems usually occur in the first 6 months of treatment. The risk is higher in people with a history of liver disease, those taking multiple anticonvulsants, those with severe seizure disorders, people with mental retardation, organic brain disease, mitochondrial disorders, or congenital metabolic disorders, and children younger than 2 years of age. Symptoms of liver injury can include unusual tiredness, weakness, facial swelling, loss of appetite, nausea, and vomiting. 

Your doctor will order tests to check liver function before starting divalproex therapy and frequently during treatment. Keep all your medical and lab appointments while taking divalproex.

PANCREATITIS: There are reports of life-threatening pancreatitis (inflammation of the pancreas) in people who took divalproex. This complication can occur shortly after starting treatment or after being on divalproex for many years. Tell your doctor immediately if you develop symptoms such as stomach pain, nausea, vomiting, and loss of appetite. 

FETAL TOXICITY: Divalproex can cause serious birth defects, particularly neural tube defects, craniofacial defects, cardiovascular defects, and limb abnormalities. The rate of birth defects with the use of Depakote ER during pregnancy (and other formulations of divalproex) is 4 times higher compared to other anticonvulsants. 

Exposure to divalproex in utero (during pregnancy) has been found to cause low IQ scores in children compared to exposure to other antiepileptics such as lamotrigine, carbamazepine, and phenytoin. 

Untreated seizures can be harmful to both a pregnant woman and her unborn baby. However, because congenital defects can occur very early during pregnancy, pregnant women should not take divalproex and should be treated with alternative medications. Women of childbearing age are only given divalproex when other medications have not worked. If you are of childbearing age, take this medication with extreme caution. Your healthcare provider will recommend using effective birth control to prevent pregnancy while you are on valproate therapy. 

UREA CYCLE DISORDERS: People with a set of rare conditions called urea cycle disorders should not take divalproex. Tell your doctor if you have ever had unexplained or pregnancy-related encephalopathy (brain dysfunction) or mental retardation, coma, elevated blood ammonia or glutamine levels, cyclical vomiting and lethargy, extreme irritability, loss of coordination, or low BUN levels on blood tests. Also, tell your doctor if you have a family history of a urea cycle disorder or unexplained infant deaths, especially in male babies. 

SUICIDAL THOUGHTS AND BEHAVIORS: Taking Depakote ER (divalproex) and other antiepileptics can increase the risk of suicidal thoughts and behaviors. This can happen as early as one week after starting the medicine. Call your doctor right away if you notice worsening depression, unusual changes in mood or behavior, or thoughts or actions of harming yourself.

BLEEDING DISORDERS: Divalproex can cause thrombocytopenia (low platelets) and bleeding. This risk is greater at higher doses. Your doctor will order a complete blood count and coagulation tests before prescribing this medicine to you and periodically during treatment. Tell your doctor immediately if you develop any unusual bleeding or bruising while on divalproex.

HIGH AMMONIA LEVELS: Divalproex can lead to increased ammonia levels in the blood even when liver function is normal. Taking divalproex with an antiepileptic drug called topiramate is associated with an increased risk of high ammonia, with or without encephalopathy (brain dysfunction). This can happen even in people who tolerated either drug alone without problems. In most cases, the symptoms resolve when one of the drugs is discontinued. 

Symptoms of high ammonia can include lethargy, vomiting, and mental status changes such as thinking abnormalities and confusion. If you develop hyperammonemia (high ammonia), you may need to discontinue divalproex.

LOW BODY TEMPERATURE: Divalproex can lead to hypothermia (a drop in body temperature below 35 degrees Centigrade or 95 degrees Fahrenheit). This can occur with or without high ammonia levels. It is more likely in people who are also taking topiramate along with divalproex. It can occur after starting topiramate or when the dose of topiramate is increased. You may need to stop taking divalproex if you develop hypothermia. 

SERIOUS ALLERGIC REACTIONS: Rarely, divalproex can cause a severe allergic reaction called a drug reaction with eosinophilia and systemic symptoms (DRESS), which can involve multiple organs and may be fatal. Seek emergency medical care if you develop a fever, rash, facial swelling, and swollen glands. 

DRUG INTERACTIONS: Concomitant treatment with carbapenem antibiotics (for example, meropenem, imipenem, and ertapenem) can lead to low blood levels of divalproex. This can result in a return of seizures. Your doctor will monitor total valproate concentrations frequently during treatment. They may prescribe other antibiotics to treat bacterial infections if you are on divalproex.

SIDE EFFECTS IN ELDERLY PATIENTS: Older adults are more likely to experience side effects such as sleepiness, reduced appetite, and weight loss from divalproex. If you are an elderly person, your doctor will prescribe a lower initial dose of the medicine, increase the dose gradually, and monitor you carefully for adverse effects.

LABORATORY TEST RESULTS: Divalproex can cause false test results on urine ketone testing and thyroid function tests. Tell all your healthcare providers and lab personnel you are taking this medication.

EFFECT ON VIRAL INFECTIONS: In laboratory experiments, divalproex has been found to stimulate the growth of HIV and CMV viruses. The real-world relevance of these findings is unclear. Your doctor will keep this in mind if you are HIV-positive or CMV-infected.

OTHER MEDICAL PROBLEMS: Divalproex can cause other problems, such as decreased bone mineral density, decreased carnitine concentrations, and medication residue in stool. Talk to your doctor or pharmacist if these effects of divalproex sodium are of concern to you.