BOOTS' MANOPLAX APPROVED AS BACK-UP TO STANDARD CHF THERAPY; VASODILATOR IS CLEARED FOR PATIENTS UNRESPONSIVE TO OTHER DRUGS OR INTOLERANT TO ACEs

The approval of Boots' Manoplax (flosequinan) builds on the treatment of congestive heart failure by providing a therapy for patients who do not respond well to standard CHF drugs. The approval also gives an alternative to patients who are intolerant to angiotensin-converting enzyme inhibitors. The NDA for Manoplax (19-960) was approved on Dec. 30 after a review of just over two years. Boots submitted the NDA in September 1990. Manoplax will be available in March "through a national joint marketing effort" by Boots and Parke-Davis, Boots said in a Dec. 31 press release. Manoplax is indicated "in the management of congestive heart failure in patients not responding adequately to diuretics (with or without digitalis), in patients who cannot tolerate an angiotensin-converting enzyme (ACE) inhibitor, and in patients who have not responded adequately to a regimen including an ACE inhibitor," draft labeling states. FDA has approved a broader indication for Manoplax than the one recommended by the agency's Cardiovascular and Renal Drugs Advisory Committee at its Oct. 24, 1991 meeting. Although the committee agreed that flosequinan demonstrated sufficient efficacy for use in treating congestive heart failure patients who remain symptomatic after treatment with other therapies, it recommended restricting Manoplax' use only to patients intolerant to ACE inhibitors because a meta-analysis showed that patients taking the drug may have an increased mortality risk compared to placebo ("The Pink Sheet" Oct. 28, 1991, p. 17). "A combined analysis of placebo-controlled studies in patients with heart failure has shown a slightly higher incidence of death in patients randomized to receive Manoplax, with a relative risk of 1.17 for patients on treatment and 1.52 in an intent-to-treat analysis," labeling notes. "Neither figure reflects a statistically significant difference and in both analyses confidence intervals are wide and exclude neither possible benefit nor possible harm." Draft labeling warns: "Manoplax should not be substituted for an ACE inhibitor as its effects on patients' survival have not been evaluated in large-scale studies. It is not known to improve survival. Survival effects of Manoplax are being evaluated in an ongoing study." The study, called PROFILE, involves adding flosequinan or placebo to a diuretic, digoxin and an ACE inhibitor in 3,500 patients with NYHA Class III and Class IV heart failure. The patients will be followed for an average of two to three years. The "Information for patients" section of labeling states that "patients should be advised that although flosequinan has produced clinical benefits for patients with congestive heart failure, its effects on survival are unknown and may even be adverse." Manoplax is described in labeling as "the first of a new class of fluoroquinolone cardiovascular agents that produces systemic vasodilation by exerting direct relaxant effects on peripheral arteries and veins." Labeling notes that trials evaluated the effects of Manoplax on exercise tolerance and symptoms in patients on diuretics, digitalis and, in one study, on ACE inhibitors. "In three multicenter, placebo-controlled trials, Manoplax increased treadmill exercise tolerance time compared to placebo by about 45- 60 seconds," labeling states. "Favorable effects on NYHA classification and symptoms (individually or through use of a quality-of-life questionnaire) were seen in some studies." FACET (Flosequinan-ACE Inhibitor Trial), the first trial to evaluate the addition of flosequinan to a standard treatment regimen of a diuretic, digoxin and an ACE inhibitor, was presented at the American Heart Association's 65th Scientific Sessions in November ("The Pink Sheet" Nov. 23, 1992, T&G-5). The FACET trial involved 322 patients, mostly with Class II and Class III CHF, who received flosequinan 100 mg once-daily, 75 mg twice-daily or placebo added to their baseline therapy with furosemide, digoxin, and captopril or enalapril. The flosequinan 100 mg dosage showed an improvement in exercise tolerance that was statistically significant. The flosequinan 100 mg dose also showed a significant improvement in the quality-of-life assessment. The patient information section of labeling says "patients should be told that the beneficial effects of Manoplax, such as improvement of symptoms, may not be immediate, and they may need to wait 4-8 weeks for the onset of its effects." In addition, "patients with symptomatic improvement should be cautioned to increase their physical activity gradually." Manoplax can cause hypotension, labeling warns. "Patients with heart failure treated with Manoplax commonly have a small decrease in blood pressure, about 1-2 mmHg." Some patients "experienced symptoms probably related to blood pressure effects; these were more notable in patients receiving an ACE inhibitor." The labeling advises that "blood pressure should be monitored at frequent intervals for at least 2 to 4 hours after initial drug administration." The labeling also cautions that "some patients receiving Manoplax have experienced marked increases in heart rate. Although such events have not generally been accompanied by adverse symptoms, it is recommended that heart rate be monitored and the dosage of the drug be reduced if excessive increases in heart rate are observed." Because Manoplax and its active metabolite have anticoagulant activity, "patients receiving anticoagulants should have their coagulation status monitored during the course of treatment with flosequinan." The labeling also recommends that patients' liver transaminases be monitored since some patients experienced elevations in transaminases. Since renal and/or hepatic dysfunction could prevent elimination of Manoplax, the label recommends using a low dose of the drug in patients with such a condition. The patient information section says that "patients should be informed that Manoplax commonly produces headaches, but that these will generally disappear over 1-2 weeks with continued use of the drug." For patients not receiving ACE inhibitors, the labeling recommends a starting and maintenance dosage of "100 mg daily administered as a single dose in the morning." For patients who are also taking ACE inhibitors, "the initial dose of Manoplax should be 50 mg once daily, titrating upward at about weekly intervals to 100 mg once daily." Manoplax will be available in 50 mg, 75 mg and 100 mg tablets.