Mail-order patients can save on Depakote^® (divalproex sodium)*

INDICATIONS^1-3

Mania

DEPAKOTE^® ER (divalproex sodium) extended-release tablets, for oral use, is a valproate and is indicated for the treatment of acute manic or mixed episodes associated with bipolar disorder, with or without psychotic features.

DEPAKOTE^® (divalproex sodium) delayed-release tablets, for oral use, is a valproate and is indicated for 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. 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 efficacy of DEPAKOTE ER is based in part on studies of DEPAKOTE in this indication, and was confirmed in a 3-week trial with patients meeting DSM-IV-TR criteria for bipolar I disorder, manic or mixed type, who were hospitalized for acute mania.

The efficacy of DEPAKOTE was established in 3-week trials with patients meeting DSM-III-R criteria for bipolar disorder who were hospitalized for acute mania.

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 or 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.

DEPAKOTE is indicated 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. 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.

DEPAKOTE^® Sprinkle Capsules (divalproex sodium delayed release capsules), for oral use, are 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 Sprinkle Capsules are 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.

Migraine

DEPAKOTE and DEPAKOTE ER are indicated for prophylaxis of migraine headaches. There is no evidence that DEPAKOTE ER or DEPAKOTE is useful in the acute treatment of migraine headaches.

Important Limitations

Because of the risk to the fetus of decreased IQ, neurodevelopmental disorders, neural tube defects, and other major congenital malformations, which may occur very early in pregnancy, 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.

For prophylaxis of migraine headaches, valproate is contraindicated in women who are pregnant and in women of childbearing potential who are not using effective contraception.

IMPORTANT SAFETY INFORMATION^1-3

• 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, ophthalmoplegia, or complicated migraine with occipital aura.
• Valproate is contraindicated for use in prophylaxis of migraine headaches in women who are pregnant and in women of childbearing potential who are not using effective contraception.
• Valproate is contraindicated in patients with known hypersensitivity to the drug.
• Valproate is contraindicated in patients with known urea cycle disorders (UCDs). 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, neurodevelopmental disorders, neural tube defects, and other major congenital malformations (e.g., craniofacial defects, hypospadias, cardiovascular and limb malformations). In epileptic mothers, 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 other medications have failed to provide adequate symptom control or are otherwise unacceptable, 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 thoughts, behavior, or acts of self-harm.
• Thrombocytopenia is dose-related. Decreases in other cell lines and myelodysplasia have also been associated with valproate. The probability of thrombocytopenia appears to increase significantly at total valproate concentrations of ≥110 ug/mL in females and ≥135 ug/mL in males or at 50 mg/kg/d. Check complete blood counts and coagulation times before starting therapy or surgery, at periodic intervals, and during pregnancy. Reduce dose or discontinue if hemorrhage, bruising, or hemostasis/coagulation disorder occur.
• 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.
• Drug Reaction with Eosinophilia and Systemic Syndrome (DRESS) / multi-organ hypersensitivity reactions have been reported and may be fatal or life-threatening. Patients typically present with fever, rash, and lymphadenopathy associated with other organ system involvement, e.g., hematologic abnormalities. Early symptoms may not include rash. Regardless, immediately evaluate and discontinue therapy for any signs of hypersensitivity.
• 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 patient’s clinical condition; alternative treatment may be considered.

ADVERSE EVENTS^1-3

• Most common adverse reactions (reported >5%) are abdominal pain, abnormal thinking, alopecia, amblyopia/blurred vision, amnesia, anorexia, asthenia, ataxia, back pain, bronchitis, constipation, depression, diarrhea, diplopia, dizziness, dyspepsia, dyspnea, ecchymosis, emotional lability, fever, flu syndrome, headache, increased appetite, infection, insomnia, nausea, nervousness, nystagmus, peripheral edema, pharyngitis, rash, rhinitis, somnolence, thrombocytopenia, tinnitus, tremor, vomiting, weight gain, and weight loss.

Keep DEPAKOTE and all other medications where children cannot reach them.