Indicated for:

Mania:

• The treatment of the manic episodes associated with bipolar disorder.

A manic episode is a distinct period of abnormally and persistently elevated, expansive, or irritable mood. Typical symptoms of mania include pressure of speech, motor hyperactivity, reduced need for sleep, flight of ideas, grandiosity, poor judgment, aggressiveness, and possible hostility. The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials.

The safety and effectiveness of Depakote for long-term use in mania, i.e., more than 3 weeks, has not been demonstrated in controlled clinical trials. Therefore, healthcare providers who elect to use Depakote for extended periods should continually reevaluate the long-term usefulness of the drug for the individual patient.

Epilepsy:

• 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.

• Depakote is also indicated for use as sole and adjunctive therapy in the treatment of 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.

Depakote has not been systematically studied as initial therapy for complex partial seizures. 

Migraine:

• Prophylaxis of migraine headaches in adults. There is no evidence that Depakote is useful in the acute treatment of migraine headaches. Depakote is contraindicated for prophylaxis of migraine headaches in women who are pregnant.

No patients above the age of 65 years were enrolled in double-blind prospective clinical trials of mania associated with bipolar illness. There is insufficient information available to discern the safety and effectiveness of Depakote for the prophylaxis of migraines in patients over 65.

In elderly patients, dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

Antiepilepsy drugs should not be abruptly discontinued in patients in whom the drug is administered to prevent major seizures because of the strong possibility of precipitating status epilepticus with attendant hypoxia and threat to life.

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 divalproex sodium extended-release tablets are 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.

Depakote 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.

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 extended-release tablets are 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.

In patients over two years of age who are clinically suspected of having a hereditary mitochondrial disease, divalproex sodium extended-release tablets should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with divalproex sodium extended-release tablets 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.

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.

Antiepileptic drugs (AEDs), including Depakote, increase the risk of suicidal thoughts or behavior in patients taking these drugs for any indication. Patients treated with any AED for any indication should be monitored for the emergence or worsening of depression, suicidal thoughts or behavior, and/or any unusual changes in mood or behavior.

Hyperammonemic encephalopathy, sometimes fatal, has been reported following initiation of valproate therapy in patients with urea cycle disorders, a group of uncommon genetic abnormalities, particularly ornithine transcarbamylase deficiency.

Prior to the initiation of Depakote therapy, evaluation for UCD should be considered in the following patients: 1) those with a history of unexplained encephalopathy or coma, encephalopathy associated with a protein load, pregnancy-related or postpartum encephalopathy, unexplained mental retardation, or history of elevated plasma ammonia or glutamine; 2) those with cyclical vomiting and lethargy, episodic extreme irritability, ataxia, low BUN, or protein avoidance; 3) those with a family history of UCD or a family history of unexplained infant deaths (particularly males); 4) those with other signs or symptoms of UCD.

Valproate is associated with dose-related thrombocytopenia. Because of reports of cytopenias, inhibition of the secondary phase of platelet aggregation, and abnormal coagulation parameters, (e.g., low fibrinogen, coagulation factor deficiencies, acquired von Willebrand’s disease), measurements of complete blood counts and coagulation tests are recommended before initiating therapy and at periodic intervals. It is recommended that patients receiving Depakote be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy.

Hyperammonemia has been reported in association with valproate therapy and may be present despite normal liver function tests. In patients who develop unexplained lethargy and vomiting or changes in mental status, hyperammonemic encephalopathy should be considered and an ammonia level should be measured.

Hypothermia, defined as an unintentional drop in body core temperature to <35°C (95°F), has been reported in association with valproate therapy both in conjunction with and in the absence of hyperammonemia.

Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS), also known as Multiorgan Hypersensitivity, has been reported in patients taking valproate. DRESS may be fatal or life-threatening. 

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CMV viruses under certain experimental conditions. The clinical consequence, if any, is not known. Additionally, the relevance of these in vitro findings is uncertain for patients receiving maximally suppressive antiretroviral therapy. Nevertheless, these data should be borne in mind when interpreting the results from regular monitoring of the viral load in HIV infected patients receiving valproate or when following CMV infected patients clinically.

Depakote is contraindicated:

• In patients with hepatic disease or significant hepatic dysfunction
• 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
• In patients with known urea cycle disorders
• For use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception

There have been rare reports of medication residue in the stool. Some patients have had anatomic (including ileostomy or colostomy) or functional gastrointestinal disorders with shortened GI transit times. In some reports, medication residues have occurred in the context of diarrhea. It is recommended that plasma valproate levels be checked in patients who experience medication residue in the stool, and patients’ clinical condition should be monitored. If clinically indicated, alternative treatment may be considered.

Caution should be observed if valproate and aspirin are to be co-administered.

Carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) may reduce serum valproate concentrations to subtherapeutic  levels, resulting in loss of seizure control.

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.

Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone.

A clinically significant reduction in serum valproic acid concentration has been reported in patients receiving carbapenem antibiotics (for example, ertapenem, imipenem, meropenem; this is not a complete list) and may result in loss of seizure control.

Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency.

A decrease in valproate dosage may be necessary when felbamate therapy is initiated.

Valproate dosage adjustment may be necessary when it is co-administered with rifampin.

Monitoring of amitriptyline levels should be considered for patients taking valproate concomitantly with amitriptyline. Consideration should be given to lowering the dose of amitriptyline/nortriptyline in the presence of valproate.

Serum levels of carbamazepine (CBZ) decreased 17% while that of carbamazepine-10,11- epoxide (CBZ-E) increased by 45% upon co-administration of valproate and CBZ to epileptic patients.

The concomitant use of valproate and clonazepam may induce absence status in patients with a history of absence type seizures.

Valproate inhibits the metabolism of ethosuximide.

Valproate was found to inhibit the metabolism of phenobarbital. There is evidence for severe CNS depression, with or without significant elevations of barbiturate or valproate serum concentrations. All patients receiving concomitant barbiturate therapy should be closely monitored for neurological toxicity.

In patients with epilepsy, there have been reports of breakthrough seizures occurring with the combination of valproate and phenytoin.

The dose of lamotrigine should be reduced when co-administered with valproate. Serious skin reactions (such as Stevens-Johnson syndrome and toxic epidermal necrolysis) have been reported with concomitant lamotrigine and valproate administration.

The concomitant use of valproate and propofol may lead to increased blood levels of propofol. Reduce the dose of propofol when co-administering with valproate.

Rufinamide clearance was decreased by valproate.

Concomitant administration of valproate and topiramate has been associated with hyperammonemia with and without encephalopathy.

Valproate is partially eliminated in the urine as a keto-metabolite which may lead to a false interpretation of the urine ketone test.

There have been reports of altered thyroid function tests associated with valproate.

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. 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 can cause fetal harm when administered to a pregnant woman. Pregnancy registry data show that maternal valproate use can cause neural tube defects and other structural abnormalities (e.g., craniofacial defects, cardiovascular malformations, hypospadias, limb malformations). The rate of congenital malformations among babies born to mothers using valproate is about four times higher than the rate among babies born to epileptic mothers using other anti-seizure monotherapies.

Because of the risk to the fetus of decreased IQ, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, valproate should not be administered to a woman of childbearing potential unless the drug is essential to the management of her medical condition.

Valproate can cause decreased IQ scores following in utero exposure. Published epidemiological studies have indicated that children exposed to valproate in utero have lower cognitive test scores than children exposed in utero to either another antiepileptic drug or to no antiepileptic drugs.

Valproate is excreted in human milk.

GoToSource

• Long-term use for mania (more than 3 weeks). GoToSource

• Use in patients under the age of 10. GoToSource

• Acute treatment of migraine headaches. GoToSource

• Alcohol withdrawal and relapse prevention. GoToSource

• Behavioral problems in patients with congenital rubinstein-taybi syndrome. GoToSource

• Post-traumatic stress disorder. GoToSource

• Borderline personality disorder. GoToSource

• Adjunctive treatment for schizophrenia. GoToSource

• Fibromyalgia. GoToSource

• Pathologic aggression. GoToSource

• Behavioral and psychological symptoms of dementia. GoToSource

• Agitation associated with major depression. GoToSource

• Post-herpetic neuralgia. GoToSource

• Restless legs syndrome. GoToSource

Suicidal ideation and behavior. GoToSource

Pancreatitis (inflammation of the pancreas). GoToSource

Congenital malformations and fetal deaths. GoToSource

Eosinophilic pleural effusion (fluid in lining of lungs). GoToSource

Accelerated brain volume loss with use over 1 year in patients with alzheimer’s disease. GoToSource 

Neutropenia (low white blood cells). GoToSource

Serotonin syndrome and neuroleptic malignant syndrome (life-threatening adverse reactions). GoToSource

New-onset diabetes mellitus. GoToSource

Stomatitis (mouth and lip inflammation). GoToSource

Hyperammonemic encephalopathy (excess ammonia in blood). GoToSource

Thrombocytopenia (low blood platelet count). GoToSource

Liver injury and failure. GoToSource

Nail pigmentation. GoToSource

Weight gain. GoToSource

Decreased sperm count and male infertility. GoToSource

Hair loss. GoToSource

Hyperandrogenism (excessive levels of androgens in the body). GoToSource

Osteoporosis and osteopenia. GoToSource

Multiorgan hypersensitivity reactions (life-threatening drug reaction). GoToSource

Lawsuits filed for birth defects, pancreatitis, liver failure and stevens-johnson syndrome.