Neurex Corlopam Phase IV studies will examine fenoldopam/beta blocker interaction.

NEUREX CORLOPAM CONCOMITANT USE STUDY WITH BETA BLOCKERS will be conducted by the company in Phase IV. Corlopam (fenoldopam mesylate) 10 mg/mL injection was approved Sept. 23 for management of severe hypertension in hospital settings. FDA has suggested that Neurex "contact the Division of Cardio-Renal Drug Products to schedule a meeting to discuss the objectives and design of the trial."

In its June 26 approval recommendation for Corlopam, FDA's Cardiovascular & Renal Drugs Advisory Committee asked that the company provide more data on the effect of concomitant use of Corlopam with beta blockers ("The Pink Sheet" June 30, T&G-2). The company said in July that it "promptly responded to a request for information on this subject" and "provided data from studies already conducted," adding that FDA had not requested any further information ("The Pink Sheet" Aug. 4, T&G-7). Neurex agreed to conduct the Phase IV study in an Aug. 8 submission to FDA.

"Use of beta-blockers in conjunction with Corlopam has not been studied in hypertensive patients and, if possible, concomitant use should be avoided," the drug's labeling states. "If the drugs are used together, caution should be exercised because unexpected hypotension could result from beta-blocker inhibition of the reflex response to fenoldopam."

Corlopam is Neurex' first product approval. Because the company was not expecting approval until next summer, it is not yet ready to launch the product. "Final market launch plans are currently being reviewed and will be communicated in the near future," Neurex said.

The Menlo Park, California-based company said in July that it expected to receive an "approvable" letter at the start of the fourth quarter, near the product's user fee goal date. Neurex resubmitted the NDA for fenoldopam on June 21, 1996.

Corlopam I.V. is indicated "for the in-hospital, short term (up to 48 hours) management of severe hypertension when rapid, but quickly reversible, emergency reduction of blood pressure is clinically indicated, including malignant hypertension with deteriorating end-organ function," the package insert states, adding that "transition to oral therapy with another agent can begin at any time after blood pressure is stable during Corlopam infusion."

In the pivotal Corlopam trial, "there were dose-related, rapid-onset decreases in systolic and diastolic blood pressures and increases in heart rate," labeling states. After 15 minutes of infusion, Corlopam .03-.3 mcg/kg/min was associated with a decrease in systolic blood pressure of 7-19 mm Hg and 8-21 mm Hg in diastolic BP. After four hours of infusion, decreases in systolic BP ranged from 20 to 37 mm Hg and 18 to 29 mm Hg in diastolic. Corlopam infusion increased heart rate by approximately 11 beats per minute.

The package insert also discusses two open-label studies comparing Corlopam to nitroprusside, which showed a response rate of 79% for fenoldopam and 77% for nitroprusside. Response was defined as a decline in supine diastolic blood pressure to less than 110 mm Hg if the baseline were between 120 and 150 mg Hg, or by >= 40 mg Hg if the baseline were >= 150 mm Hg.

"In controlled clinical studies of severe hypertension in patients with end-organ damage, 3% (4/137) of patients withdrew because of excessive falls in blood pressure," labeling adds. The most common adverse events associated with Corlopam use are headache, cutaneous dilation (flushing), nausea and hypotension, each of which was reported in more than 5% of patients, labeling notes. Labeling warns that the product contains sodium metabisulfite, which may cause "allergic-type reactions including anaphylactic symptoms and life-threatening or less severe asthmatic episodes in certain susceptible people."

Labeling contains an initial Corlopam dose table from which a dose "that produces the desired magnitude and rate of blood pressure in a given clinical situation" should be chosen, and notes that doses of .01 to 1.6 mcg/kg/min have been studied. While "doses below .1 mcg/kg/min have very modest effects and appear only marginally useful in this population," lower initial doses of .03 to .1 mcg/kg/min "titrated slowly have been associated with less reflex tachycardia than have higher initial doses," labeling states. "In general, as the initial dose increases, there is a greater and more rapid blood pressure reduction." Moreover, "most of the effect of a given infusion rate is attained in 15 minutes," labeling adds.