GLAXO WELLCOME LANOXIN (DIGOXIN) NDA APPROVED FOR HEART FAILURE and atrial fibrillation after 61 years on the market; the NDA was approved Sept. 30. An indication for atrial flutter was dropped in the revised labeling for digoxin as recommended by FDA's Cardiovascular & Renal Drugs Advisory Committee at its May 1996 review of digoxin data ("The Pink Sheet" May 13, 1996, p. 17).

"Lanoxin is indicated for the treatment of mild to moderate heart failure. Lanoxin increases left ventricular ejection fraction and improves heart failure symptoms...while having no effect on mortality," labeling states. "Where possible, Lanoxin should be used with a diuretic and an angiotensin-converting enzyme inhibitor, but an optimal order for starting these drugs cannot be specified." The advisory committee had suggested that no order be specified. A second indication is "for the control of ventricular response rate in patients with chronic atrial fibrillation."

Lanoxin tablets were approved in 62.5 mcg, 125 mcg, 187.5 mcg, 250 mcg, 375 mcg, and 500 mcg strengths. The formal approval of Lanoxin allows companies to pursue approvals of generic versions of digoxin tablets through the ANDA process.

The drug was discovered at Wellcome labs in 1930 and was introduced in 1936. A grandfather clause allowed it to remain on the market without formal licensure. Injectable digoxin, introduced in 1954, and digoxin capsules, introduced in 1982, went through the FDA approval process. Digoxin in all of its forms is the fourth most prescribed drug in the U.S.; 3.5 mil scripts were written for the drug last year. The narrow therapeutic index of digoxin prevented generic competition but was a reason for FDA requesting a formal application.

In August 1990 FDA requested that Burroughs Wellcome submit an application for digoxin, and on Sept. 30, 1993 the company filed NDA 20-405. A May 1996 advisory committee was gathered to assist with the label rewrite. The application included a 7,788-patient Digitalis Investigation Group trial conducted by the National Heart, Blood & Lung Institute between February 1991 and December 1995. The study was designed to address concerns that digoxin may have an adverse effect on mortality, and showed that it did not.

In the DIG trial, combined secondary endpoints demonstrated the best effects of digoxin, reduction of congestive heart failure death and of chronic heart failure hospitalization. Labeling notes that trend, as well as "a 25% reduction in the number of hospitalizations for heart failure." Other secondary endpoints not in labeling showed a 14% reduction for digoxin in worsening heart failure but showed an increase of 26% in myocardial infarction mortality and an increase of 12% in presumed arrhythmic deaths.

Following the suggestion of the advisory committee, FDA included data for patients with chronic atrial fibrillation culled from studies in the literature. "Digoxin slows rapid ventricular response rate in a linear dose-response fashion from .25 to .75 mg/day. Digoxin should not be used for the treatment of multifocal atrial tachycardia," the label states.

A warning in revised digoxin labeling, previously a precaution, indicates that "because digoxin slows sinoatrial and [atrioventricular] conduction, the drug commonly prolongs the PR interval [and] may cause severe sinus bradycardia or sinoatrial block in patients with pre-existing incomplete AV block." Unlike the older label, the revised version suggests "insertion of a pacemaker before treatment with digoxin."

Another new warning cautions practitioners that "patients with certain disorders involving heart failure associated with preserved left ventricular ejection fraction may be particularly susceptible to toxicity of the drug." A previous warning against the use of digoxin for the treatment of obesity has been eliminated in the rewrite.

Slightly increased dosing schedules are part of the new digoxin label. Rapid digitalization with a loading dose for adults with CHF should be initiated with 500 to 750 mcg; previous labeling recommended 400 to 600 mcg.

"Additional doses of 125 to 375 mcg may be given cautiously at six- to eight-hour intervals until clinical evidence of an adequate effect is noted," labeling states, and adds that peak body stores, in a 70-kg patient, usually require 750 to 1,250 mcg. The previous label advocated 100 to 300 mcg additional doses and estimated peak body stores at 600 to 1,000 mcg. The recommended maintenance dose is increased to 250 mcg from 200 mcg.

Glaxo Lanoxin (digoxin) NDA approved for heart failure and atrial fibrillation; label rewritten.

More from Archive

More from Pink Sheet