New, easier-to-swallow capsule approved to treat bipolar disorder

September 15, 2008

FDA has approved Stavzor, delayed-release soft gelatin capsules of valproic acid, for the treatment of bipolar disorder.

Key Points

Banner Pharmacaps and Noven Pharmaceuticals have partnered to bring patients Stavzor, a new form of valproic acid that is similar to divalproex sodium. Delivered in soft-gel delayed-release capsules, the product is up to 40 percent smaller than Depakote and Depakote ER tablets at the 500 mg dosage. The Food and Drug Administration (FDA) has approved Stavzor for treatment of manic episodes associated with bipolar disorder as monotherapy and adjunctive therapy in multiple seizure types, and for prophylaxis of migraine headaches.

According to Dr. Miguel Martelli, a psychiatrist in private practice in Georgia, valproate is recommended by the American Psychiatric Association (APA) as a first-line therapy for patients experiencing manic episodes through bipolar disorder. Candace Smith, associate clinical professor and chair of clinical pharmacy practice at St. John's University, concurred and further stated that "patients will benefit from Stavzor's smaller-size capsule, which makes it easier to swallow," adding that "compliance will be greatly improved as a result." The manufacturer-conducted survey of 400 valproate users has reported that more than two-thirds reported difficulty swallowing other valproate formulations and 85 percent stated that they would have preferred a small soft-gel capsule.

The efficacy of Stavzor to treat acute mania, epilepsy, and migraine is described in the clinical trials below. Two three-week, placebo-controlled clinical studies were conducted to evaluate the effectiveness of valproate in the treatment of acute mania. Both studies had initiated valproate doses of 250 mg TID and titrated doses based on serum valproate levels. The results of both studies showed statistical significance of valproate compared to placebo and valproate study patients achieved ≥30 percent reduction in symptom score from baseline. One study that evaluated the efficacy of valproate in reducing the incidence of complex partial seizures led to the result that 45 percent of patients treated with valproate had a ≥50 percent reduction in complex partial seizure rate compared to 23 percent of placebo-treated patients. When patients were randomized to valproate in a study evaluating its efficacy on migraines, the result was that patients in the valproate groups had significantly lower migraine rates than the placebo group.

"In clinical practice, nausea is a significant adverse event that affects the majority of our patients, and Stavzor's enteric coated technology may help to decrease gastric irritability and nausea," Smith said.

It is recommended that elderly patients start at lower doses and titrate slowly, as clinical trials have reported somnolence as an adverse event that required discontinuation of the medication. Other important adverse events to note are the incidence of elevated liver enzymes and thrombocytopenia that may be dose-related. The probability of thrombocytopenia appears to correlate with increased total serum valproate levels: ≥110 mcg/mL (females) or ≥135 mcg/mL (males).

There are a number of clinically significant interactions that exist with valproic acid and other medications for which diligent monitoring of valproate concentrations is recommended. Phenytoin, carbamazepine, phenobarbital, and rifampin are hepatic enzyme-inducing drugs that may increase valproate clearance, while enzyme inhibitors such as felbamate may decrease valproate clearance. It is also recommended that valproate levels be monitored when aspirin and carbapenem antibiotics are co-administered. Additionally, dose adjustments to amitriptyline/nortriptyline, warfarin, and zidovudine may be necessary when used concomitant with Stavzor. Reports of hyperammonemia with and without encephalopathy have been reported in patients receiving valproic acid and topiramate.

Patients with hepatic disease or significant hepatic dysfunction should avoid products containing valproate, and this is included in the prescribing information as a black-box warning.

There have been reports of hepatic failure and subsequent death of patients with prior hepatic dysfunction who receive valproate products during the first six months of treatment. Another adverse event occurring in adults and children receiving valproate is life-threatening pancreatitis, with some cases rapidly progressing to death. It is stipulated that in women of childbearing potential, the benefits connected with use of Stavzor outweigh the risks of fetal injury.

Tips to Remember: Stavzor