MARION's CARDIZEM SR IS APPROVABLE FOR HYPERTENSION, FDA SAYS; ADVISORY COMMITTEE SUPPORTS FDA DECISION TO DEFER IMMEDIATE RELEASE HYPERTENSION CLAIM
Marion's Cardizem SR (sustained release diltiazem) is approvable for the treatment of hypertension, FDA Cardio-Renal Drug Products Division Raymond Lipicky, MD, announced at the opening of the Nov. 3 Cardio-Renal Drugs Advisory Committee meeting. Noting that the committee would not be asked to vote on approval of the twice-daily capsule product but to help resolve issues pertaining to labeling, Lipicky told the panel that "the division has already recommended . . . that the sustained release formulation of diltiazem is approvable for hypertension." The sustained release version of the calcium channel blocker was developed for Marion by Elan. Marion is also seeking a hypertension claim for immediate release Cardizem, which is currently approved for angina. The advisory committee concurred with FDA's determination that existing data are not sufficient to support expansion of labeling for the immediate release product. In recommending labeling for the sustained release product, the committee dealt primarily with dosing information. Based on five presented studies, the committee suggested that labeling recommend a starting dose of 60 mg b.i.d., the lowest dose studied, despite agreement that the dose produced a minimal effect at trough (the end of the twelve hour dosing period). Explaining his rationale for recommending a 60 mg b.i.d. starting dose, committee reviewer Franz Messerli, MD, Tulane University, said: "The best studied dose is 180 mg b.i.d., but this seems to be a somewhat inappropriately high dose to start with. ]Efficacy is[ borderline at 60 mg ]b.i.d.[, but looking at a lot of elderly patients who will probably receive diltiazem, I think we should start with the borderline effect as the lowest dose." In titrated dose trials, most patients moved up to the 180 mg b.i.d. dose. In one of the trials, for example, of the 51 patients randomized to receive either 60 mg, 120 mg. or 180 mg Cardizem SR b.i.d., three patients completed the 12 week trial on the 60 mg b.i.d. dose, compared to nine on the 120 mg b.i.d. dose and 39 on the 180 mg b.i.d. regimen. Overall, 55% of the diltiazem-treated patients reached the goal of achieving at least a 10% reduction in blood pressure, while 12% of placebo patients achieved that goal. At the end of the study, the average reduction in trough systolic drug pressure for all diltiazem-treated patients was 12.3 mm hg and the average reduction in diastolic blood pressure was 11.4 mm hg. The committee did not make any formal recommendations about the upper dosing levels for sustained release diltiazem. Noting that only six patients in one study received a dose above 180 mg b.i.d. (240 mg b.i.d.), Messerli said that the data "is not sufficient to establish an upper dose limit." In the study that used 240 mg b.i.d. "there was the suggestion when looking at diastolic pressure that indeed the pressure curve did reach a plateau. However, when you look at systolic pressure this was not the case," Messerli explained. The committee agreed that edema and ECG abnormalities should be included in labeling as adverse reactions in addition to the reactions discussed in labeling for the immediate release product. Marion submitted the NDA for Cardizem SR in May 1985 and the firm has been on alert for the approval of the product for about a year. In fact, Marion began stocking inventory of the product at the end of 1987. Marion recently reworked its inventory to extend the expiration period of the product. Last April, when approval appeared in sight, Marion noted at a meeting with wholesalers that shipments of the product would be short-dated (about six months) because of the premature build-up of inventory ("The Pink Sheet" April 18, p. 4). With the reworking, however, short-dating will not be necessary; assuming a fairly quick approval, existing inventory will not expire for 18 months to two years. Marion has predicted that the sustained release product will pick up about 50% of Cardizem tablet sales -- now about $ 500 mil. annually -- within two years of marketing. A relatively quick approval will allow Marion to establish Cardizem SR before exclusivity for the immediate release product expires November 1992. Bolar is working on a generic version of Cardizem via a full NDA. Currently, only one calcium channel blocker is approved in a sustained release formulation -- verapamil (Searle's Calan SR and Knoll's Isoptin SR). Verapamil is also the only calcium channel blocker approved for hypertension. A second calcium channel blocker, Syntex' Cardene (nicardipine) is close to approval for hypertension; FDA announced at the same advisory committee meeting that Cardene also is approvable (see following story). The hypertension supplemental NDA for immediate release Cardizem was submitted simultaneously with the application for Cardizem SR. The committee recommended against approval, in part, because one of the two pivotal studies did not find a statistically significant difference between the drug and placebo. The committee was also concerned that the drug, which was studied primarily in b.i.d. dosing regimens, appeared to lose effect before the end of the 12-hour dosing interval and did not meet FDA's guideline criteria that blood pressure levels at trough be at least half those at peak. In its questions to the committee, the Cardio-Renal Division said it does not believe diltiazem "is a reasonable antihypertensive therapy when administered b.i.d." but asked the committee for advice about the approvability of a t.i.d. regimen. The drug was studied t.i.d. in one group of patients in one of the trials. Supporting his disapproval recommendation, Messerli said: "I concur with the opinion of the division that the immediate formulation of diltiazem is not a reasonable antihypertensive therapy when administered b.i.d. For the t.i.d. ]regimen[ we only have 24 patients, and it is clear that this subset of patients per se is not sufficient to make this dose approvable. if the sponsor wants to pursue this t.i.d. for approval, I think more data are needed." Explaining the division's rationale, Lipicky said there are "two reasons for the division's decision: there was ]only[ one trial that had a statistically significant effect . . . so there wouldn't be two adequate and well controlled trials; and . . . it was reasonably clear that duration of action of the immediate release was significantly less than 12 hours and, therefore, ]the dosing regimen[ was not supportable." Lipicky noted that the dissaproval decision has only been made at the division level and that Office of Drug Evaluation Director I Robert Temple, MD, has not yet made a final decision on the application. Temple indicated, however, that he would not be inclined to approve a t.i.d. regimen based on the submitted data. "I think we'd be very reluctant to recommend a dosing interval that's hardly been studied even if it . . . seemed probable that it would work out. It seems a sort of bad precedent to me," Temple remarked. Temple also indicated that a second study would be needed to support approval of a b.i.d. regimen and that FDA might take a somewhat more flexible attitude about the 50% trough to peak ratio requirement. "I think the conversation that's gone on here has, I guess, slightly caused me to be less certain of the rigid 50% rule," Temple said. "If the immediate release product was pursued and a second study showed that you did indeed have effect at the end of the interval, I'm not sure it couldn't make it."
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