Indicated for:

Epilepsy:

• As 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.

• Use as sole and adjunctive therapy in the treatment of simple and complex absence seizures, and adjunctively in patients with multiple seizure types which 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.

Safety of doses above 60 mg/kg/day is not established.

For complex partial seizures: Depakene is for adults and children 10 years of age or older.

Depakene has not been systematically studied as initial therapy.

Due to a decrease in unbound clearance of valproate and possibly a greater sensitivity to somnolence in the elderly, the starting dose should be reduced in these patients. Dosage should be increased more slowly and with regular monitoring for fluid and nutritional intake, dehydration, somnolence, and other adverse reactions.

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.

Hepatic failure resulting in fatalities has occurred in patients receiving valproate. These incidents usually have occurred during the first six months of treatment. Serum liver tests should be performed prior to therapy and at frequent intervals thereafter, especially during the first six months.

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 month.

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 Depakene products are used in this patient group, they 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.

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). Depakene 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, Depakene should only be used after other anticonvulsants have failed. This older group of patients should be closely monitored during treatment with Depakene 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.

Depakene is contraindicated in patients with known urea cycle disorders (UCD).

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 valproate 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 Depakene, 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.

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.

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 Depakene (valproic acid) be monitored for blood counts and coagulation parameters prior to planned surgery and during pregnancy.

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.

Depakene 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
• In patients with known urea cycle disorders
• For use in prophylaxis of migraine headaches
• Depakene is contraindicated in women of childbearing potential who are not using effective contraception

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

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.

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.

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

Cholestyramine, when concurrently administered with valproic acid, led to, on average, a 14% decrease in plasma levels of valproic acid.

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

Co-administration of 1,200 mg/day of felbamate with valproate to patients with epilepsy increased valproate peak concentration by 35%.

Administration of valproate 36 hours after 5 nights of daily dosing with rifampin (600 mg) revealed a 40% increase in the oral clearance of valproate.

Administration of chlorpromazine to schizophrenic patients already receiving valproate (200 mg BID) revealed a 15% increase in trough plasma levels of valproate.

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

Patients receiving valproate and ethosuximide, especially along with other anticonvulsants, should be monitored for alterations in serum concentrations of both drugs.

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.

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

Reduce the dose of propofol when co-administering with valproate. Monitor patients closely for signs of increased sedation or cardiorespiratory depression.

Rufinamide clearance was decreased by valproate.

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

Valproate can decrease the plasma clearance of lorazepam.

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 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 is excreted in human milk.

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• Dosage greater than 60 mg/kg/day. GoToSource

• Use in children under 10 years of age. GoToSource

• Bipolar disorder. GoToSource

• Social anxiety disorder. GoToSource

• Migraine prophylaxis. GoToSource

• Cancer therapy. GoToSource

• Adjunctive therapy for delirium. GoToSource

Nail discoloration. GoToSource

Weight gain. GoToSource

Tremor, sedation, hair loss, impairment in liver function and sperm abnormalities. GoToSource

Male infertility. GoToSource

Birth defects. GoToSource

Thrombocytopenia (deficiency of platelets in the blood). GoToSource

Drug reaction with eosinophilia and systemic symptoms. GoToSource

Fractures. GoToSource

Decreased bone mineral density, osteopenia and osteoporosis. GoToSource

Liver failure. GoToSource

Hyperammonemic encephalopathy (excess of ammonia in the blood). GoToSource

Suicidal behavior and ideation. GoToSource

Pancreatitis (inflammation of the pancreas), fatal hepatotoxicity and aplastic anaemia (disorder in which the bone marrow fails to produce enough blood cells). GoToSource

Hypothermia (low body temperature). GoToSource

Lawsuits filed for birth defects and suicide.