Indicated for:

Mania:

• Depakote ER is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

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. A mixed episode is characterized by the criteria for a manic episode in conjunction with those for a major depressive episode (depressed mood, loss of interest or pleasure in nearly all activities).

The effectiveness of valproate 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 ER for extended periods should continually reevaluate the long-term risk-benefits of the drug for the individual patient.

Epilepsy:

• Depakote ER is indicated as monotherapy and adjunctive therapy in the treatment of adult patients and pediatric patients down to the age of 10 years with complex partial seizures that occur either in isolation or in association with other types of seizures.

• Depakote ER is also indicated for use as sole and adjunctive therapy in the treatment of simple and complex absence seizures in adults and children 10 years of age or older, and adjunctively in adults and children 10 years of age or older 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 ER has not been systematically studied as initial therapy for complex partial seizures. 

Migraine:

• Depakote ER is indicated for prophylaxis of migraine headaches. There is no evidence that Depakote ER is useful in the acute treatment of migraine headaches.

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.

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 ER 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 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.

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

To prevent major seizures, valproate should not be discontinued abruptly, as this can precipitate status epilepticus with resulting maternal and fetal hypoxia and threat to life.

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 ER 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.

Antiepileptic drugs (AEDs), including Depakote ER, 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.

Depakote ER should not be administered to patients with hepatic disease or significant hepatic dysfunction.

Depakote ER 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

Depakote ER is contraindicated in patients with known urea cycle disorders.

For use in prophylaxis of migraine headaches: Depakote ER is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

Valproate is associated with dose-related thrombocytopenia. Valproate use has also been associated with decreases in other cell lines and myelodysplasia.

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. Hyperammonemia should also be considered in patients who present with hypothermia.

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.

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

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.

There are in vitro studies that suggest valproate stimulates the replication of the HIV and CM viruses under certain experimental conditions. The clinical consequence, if any, is not known.

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. This adverse reaction can also occur in patients using concomitant topiramate with valproate after starting topiramate treatment or after increasing the daily dose of topiramate.

Concomitant administration of topiramate and valproate has been associated with hyperammonemia with or without encephalopathy in patients who have tolerated either drug alone.

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. Serum valproate concentrations should be monitored frequently after initiating carbapenem therapy. Alternative antibacterial or anticonvulsant therapy should be considered if serum valproate concentrations drop significantly or seizure control deteriorates.

A study involving the co-administration of aspirin at antipyretic doses with valproate to pediatric patients revealed a decrease in protein binding and an inhibition of metabolism of valproate. Valproate free fraction was increased 4-fold in the presence of aspirin compared to valproate alone.

Estrogen-containing hormonal contraceptives may increase the clearance of valproate, which may result in decreased concentration of valproate and potentially increased seizure frequency. Prescribers should monitor serum valproate concentrations and clinical response when adding or discontinuing estrogen containing products.

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

A study involving the administration of a single dose of valproate (7 mg/kg) 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Rare postmarketing reports of concurrent use of valproate and amitriptyline resulting in an increased amitriptyline level have been received. Concurrent use of valproate and amitriptyline has rarely been associated with toxicity. 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.

Co-administration of valproate (1,500 mg daily) increased the free fraction of diazepam (10 mg) by 90% in healthy volunteers.

Valproate inhibits the metabolism of ethosuximide.

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.

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. Serum barbiturate concentrations should be obtained, if possible, and the barbiturate dosage decreased, if appropriate. Primidone, which is metabolized to a barbiturate, may be involved in a similar interaction with valproate.

Valproate has been found to be a weak inhibitor of some P450 isozymes, epoxide hydrase, and glucuronosyltransferases.

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

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. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.

Based on a population pharmacokinetic analysis, rufinamide clearance was decreased by valproate. Rufinamide concentrations were increased by <16% to 70%, dependent on concentration of valproate (with the larger increases being seen in pediatric patients at high doses or concentrations of valproate).

From in vitro experiments, the unbound fraction of tolbutamide was increased from 20% to 50% when added to plasma samples taken from patients treated with valproate.

In an in vitro study, valproate increased the unbound fraction of warfarin by up to 32.6%.

Since valproate may interact with concurrently administered drugs which are capable of enzyme induction, periodic plasma concentration determinations of valproate and concomitant drugs are recommended during the early course of therapy.

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. The clinical significance of these is unknown.

There have been reports of male infertility coincident with valproate therapy.

Valproate can cause major congenital malformations, particularly neural tube defects (e.g., spina bifida). In addition, valproate can cause decreased IQ scores and neurodevelopmental disorders following in utero exposure. Valproate is therefore contraindicated for prophylaxis of migraine headaches in pregnant
women and in women of childbearing potential who are not using effective contraception. 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 control or are otherwise unacceptable. In such situations, effective contraception should be used.

Valproate is excreted in human milk.

GoToSource

•  Use in patients under the age of 10. GoToSource

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

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.