NEW ORLEANS — Conivaptan was safe and effective for treating hyponatremia in three phase III studies that together involved about 200 evaluable patients.
Based in part on these findings, the Food and Drug Administration issued an approvable letter for conivaptan last December. According to Yamanouchi Pharma America, the company developing the drug, the FDA said that it will license conivaptan for the treatment of hyponatremia if Yamanouchi provides additional safety data and meets certain other conditions. Yamanouchi sponsored the phase III studies.
Currently, no agent has FDA approval for treating hyponatremia, which affects 2%‐3% of all hospitalized patients and is more prevalent among patients with advanced heart failure and in the elderly. Hyponatremia is defined as a serum sodium concentration of less than 136 mEq/L, and is usually managed by restricting fluids.
Conivaptan is an antagonist for the arginine vasopressor receptor. Through this activity, the drug causes aquaresis and reduces vasomotor tone. Patients with heart failure often have abnormally high levels of arginine vasopressin, which promotes water reabsorption and helps produce the edema that often accompanies heart failure. Conivaptan can be administered either orally or intravenously; however, Yamanouchi is only seeking approval to market conivaptan with intravenous administration.
Results from the three studies were presented in posters at the annual scientific sessions of the American Heart Association. One study included 74 men and women at least 18 years old with a serum sodium level of 115‐130 mEq/L who were either hypervolemic or euvolemic. About 43% of the patients had hyponatremia secondary to heart failure, about 20% had idiopathic hyponatremia, and in the remainder it was due to other factors. About 74% of the patients were euvolemic.
Patients were randomized to treatment with 20 mg conivaptan orally b.i.d, 40 mg orally b.i.d, or placebo, and treatment continued for 5 days. Three patients dropped out during the study, one from each treatment group.
During the 5 days of treatment, serum sodium levels increased in the conivaptan group in a dose‐related manner and to levels that were significantly above those reached in the control group, reported Jala K. Ghali, M.D., director of clinical research at Cardiology Centers of Louisiana in Shreveport. The 20‐mg b.i.d dosage boosted sodium levels from a mean of 125 mEq/L at baseline to about 132 mEq/L after 5 days. The 40‐mg b.i.d. dosage raised sodium levels from a mean of 125 mEq/L at baseline to about 133 mEq/L after 5 days. In the placebo group, the starting sodium level averaged 124 mEq/L, which rose to about 127 mEq/L after 5 days.
Conivaptan was effective regardless of whether patients were euvolemic or hypervolemic at baseline, and regardless of the etiologic cause of hyponatremia. Both dosages were well tolerated; the rate of drug‐related adverse events was similar in the three treatment groups, Dr. Ghali reported.
The second study reported at the meeting was very similar in design to the first, except conivaptan was administered intravenously. The study initially treated 84 patients, of whom 66 completed a 4‐day course of treatment. The study enrolled adult men and women with a baseline serum sodium level of 115‐130 mEq/L. Two‐thirds of the patients were euvolemic, and 30% had heart failure as their etiology of hyponatremia. Patients were randomized to treatment with 40 mg/day conivaptan intravenously, 80 mg/day, or placebo.
After 4 days of treatment, serum sodium levels had increased significantly in both treatment groups, compared with the control patients, reported Joseph G. Verbalis, M.D., professor of medicine and chief of the division of endocrinology and metabolism at Georgetown University, Washington. Once again, the increases were dose dependent, and were very similar to those seen with oral dosing. And conivaptan was effective whether patients were euvolemic or hypervolemic, and regardless of the etiology of their hyponatremia.
Both dosages of the intravenous drug were also well tolerated. Although the incidence of drug‐related adverse effects were more than twice as common in patients treated with conivaptan, compared with those who received placebo, the effects were mild to moderate in severity, Dr. Verbalis said. Discontinuations due to adverse effects were similar in all three treatment groups.
The third study closely resembled the first oral‐administration study, but it was run in Europe. It enrolled 89 patients, of whom 72 completed the 5‐day treatment. This study enrolled adult men and women with serum sodium levels of less than 130 mEq/L. About 58% of the patients were euvolemic at baseline, and 30% had heart failure as their cause of hyponatremia. Patients were randomized to receive 20 mg oral conivaptan b.i.d, 40 mg b.i.d., or placebo.