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KNOLL's ISOPTIN IS COMPARABLE TO INDERAL IN HYPERTENSION TREATMENT, FDA CMTE. SAYS; ARRHYTHMIA INDICATION, LONG-ACTING FORM IN HYPERTENSION OKAY

Executive Summary

Knoll's Isoptin (verapamil) is as effective as the beta blockers propranolol (Ayerst's Inderal) and metoprolol (Ciba-Geigy's Lopressor) for the treatment of hypertension, FDA's Cardio-Renal Drugs Advisory Cmte. concluded at its April 11 meeting. Verapamil is comarketed by Searle (Calan). Cmte. reviewer Philip Reid, MD, Sinai Hospital, declared that Knoll "convincingly demonstrated that [verapamil] is as effective as currently existing antihypertensives, specifically demonstrated [in the] beta blockers [propranolol and metoprolol]." He said the safety data also show "relatively convincingly" that verapamil "is as safe as other drugs" for the treatment of hypertension "and, in fact, in some cases might be better." Knoll VP-Medical Research Juan Guerrero, MD, reported the results of controlled trials of verapamil versus propranolol and verapamil versus metoprolol. In one trial, 18 patients were randomized to receive either verapamil 185 mg b.i.d. or propranolol 120 mg b.i.d. for four weeks or longer. Guerrero said both drugs "induced significant blood pressure reduction throughout [the] day and night. Verapamil did it for 21 of the 24 hours and propranolol for all 24 hours." He added that "propranolol caused a greater reduction in heart rate than verapamil." In the metoprolol trial of 20 patients, Guerrero said, "verapamil given as a standard 120 mg three times daily was as efficacious as metoprolol 100 mg twice a day in reducing supine, systolic and diastolic, as well as standing blood pressure." He noted that "verapamil induced significantly greater reduction than metoprolol in standing blood pressure" while metoprolol decreased heart rate by three or four-fold in comparison to verapamil. The cmte. unanimously recommended that verapamil be approved for use in the management of hypertension with the provision that Knoll conduct certain post-marketing studies. The post-marketing studies recommended by the cmte. are: (1) a formal dose response study; (2) a withdrawal trial after a protracted period of use, such as a year, to determine if the effect of the drug is maintained; (3) a head-to-head study against diuretics and angiotensin converting enzyme inhibitors; and (4) a study to define the relationship of verapamil blood levels to antihypertensive effect. Cmte. chairman Jeffrey Borer, MD, New York Hospital-Cornell Medical Center, commented that "there is sufficient information so that an acceptably safe and effective set of administration instructions can be given." However, he said, the recommendations "cannot be considered optimal" and "should be improved upon with an appropriate dose-response curve generating study, particularly at the low end." FDA Office of Drug Research & Review Director Robert Temple, MD, remarked that one of the flaws with a hypertension study "is that it's always possible that in some of the people their hypertension wasn't real at baseline, or something like that, and you have no control group." He said if patients are still available, one "could do a randomized withdrawal trial to show that they returned toward hypertensive levels." Verapamil is apparently already being widely used by the medical community for hypertension. In a survey of drug utilization in the U.S. during 1983, FDA found that, based on Natl. Disease and Therapeutic Index data, in nonhospital settings 28% of verapamil uses were for approved indications of the drug ("The Pink Sheet" Feb. 18, p. 6). Also recommended by the cmte. for approval was a verapamil indication for prevention of paroxysmal supraventricular tachycardia and a sustained release dosage form for use in hypertension. The cmte. agreed there is sufficient information on blood levels to approve the sustained release form for hypertension, but concluded there was not enough data to approve the formulation for angina. The cmte. also recommended that a post-approval study be conducted to determine the minimum effective dose of the long-acting dosage form. In a list of questions presented to the cmte., FDA explained that "approval of a sustained release formulation, from a regulatory point of view, hinges upon proving dose equivalence. That is, what dose of sustained release is appropriate and will the unit dose strength allow appropriate titration using the sustained release?" The Cardio-Renal Div. said its position is that "the dosing information and blood level information for verapamil rests almost entirely upon trials of titrated dose design." In the division's judgment, "none of the trials submitted by the sponsor reasonably establish a dose that one should begin titrating for either hypertension, angina, or supraventricular arrhythmias." Cardio-Renal Div. Acting Director Raymond Lipicky, MD, explained that Knoll initially asked FDA to approve the sustained release formulation of verapamil "on the basis of blood level data alone, with the idea being that if you simply split the peaks and valleys of immediate release with an equivalent dose in the sustained release, that that should be sufficient." He said Knoll's current studies "show that the sustained release is safe and effective at some dose." However, he asserted, "one can't demonstrate a relationship between blood level and effect." Cmte. member Raymond Woosley, MD, Vanderbilt University, responded that it is "asking too much of science to have everything fall into nice baskets and dose response curves when you've got so many variables coming into play." He said "physicians, in general, recognize that diseases are variable, responses to drugs are variable, and they will titrate a patient's response." Lipicky stated: "One would like to know what dose one should start titrating [the drug] from, given that the dose one is titrating from is 10 to 100 times smaller than the dose that one has available to start titrating with. That seems crazy to me, even though it may be totally safe." Regarding verapamil's use in supraventricular arrhythmias, the cmte. recommended that the package insert be written to advise physicians to "exercise caution in patients who manifest documented accessory pathway conduction." In support of the arrhythmia indication, Knoll presented studies comparing the effect of verapamil used concomitantly with digoxin. Elieser Kaplinsky, MD, Rambam Medical Center (Haifa, Israel), reported the results of a five-phase study of 24 patients who received either no treatment, 25 mg digoxin, .5 mg digoxin, 240 mg verapamil with .25 mg digoxin, or 240 mg verapamil. Kaplinsky said the addition of verapamil to digoxin allowed for better control of heart rate. He concluded that verapamil acts directly on the heart rather than simply enhancing digoxin's activity. "By increasing the digoxin level, we get progressive control of the resting heart rate," Kaplinsky said. However, he added, during exercise, there is "only a very small change in significance and the exercise heart rate response is very excessive." He said the addition of verapamil "produces immediate control at rest and during exercise this change is not due to the increase in digoxin."
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