Levitra Low Dose With Alpha Blockers Doesn’t Allay Hypotension Concern-FDA

Using a 5 mg dose of Levitra does not eliminate FDA's concerns about hypotension from concomitant use with alpha blockers, the agency said in review documents for the erectile dysfunction agent.

"The results of [Bayer's] trial using 5 mg vardenafil do not support the safe use of this dose in patients taking alpha blockers," medical reviewer George Benson, MD, concluded. "Until further data with the two lowest doses of vardenafil are available, I believe that vardenafil should be contraindicated in patients taking alpha blockers."

Discussion over the 5 mg study came in the final days preceding Levitra's Aug. 19 approval. Bayer had been notified on Aug. 1 that FDA wanted a contraindication "for all alpha blockers based on hypotension seen in drug-drug interaction studies of 10 and 20 mg in healthy volunteers with terazosin and tamsulosin," Office of Drug Evaluation III Director Florence Houn, MD, noted in an ¹ Aug. 15 approval memo.

On Aug. 7, the firm notified FDA that it had a study of 5 mg vardenafil that would support changing the contraindication to a warning that patients on alpha blockers should start at 5 mg. The following day, however, Bayer and marketing partner GlaxoSmithKline changed their minds about submitting the 5 mg data and said they would accept a contraindication, possibly because of concerns that the user fee clock would be extended.

Although the contraindication was agreed to, FDA nevertheless asked Bayer to submit the 5 mg study to the NDA and informed the firm that the submission "would not trigger an extension" of the user fee goal. "Even if the 5 mg data did not affect contraindications," Houn explained, "the information is needed for labeling of effects and explaining why there is a contraindication."

A summary of the study results appears in an ² Aug. 18 memo from Benson. The study examined the "expected additive [blood pressure]-lowering effect" of 5 mg Levitra vs. placebo on a background of the alpha blockers terazosin (Abbott's Hytrin and generics) or tamsulosin (Boehringer Ingelheim's Flomax ). Levitra was dosed either simultaneously with one of the alpha blockers or with a six-hour separation. The study included two cohorts of 21 subjects.

"In patients on terazosin 5 mg, one patient had a [systolic] BP of 99 [mm Hg] when dosed simultaneously with 5 mg vardenafil and one patient had a BP of 98 when dosed at six hours," Benson reported. In patients receiving 10 mg terazosin at the same time as Levitra, one of nine had BP under 85; at six hours, one of nine had BP of 93. With tamsulosin, two of 20 patients dosed simultaneously as well as with six-hour separation had SBP <85.

Two of Levitra's four postmarketing commitments relate to alpha blockers. FDA is asking Bayer to study "Levitra 2.5 mg and alpha blockers used for [benign prostatic hyperplasia]." The 2.5 mg dose is the lowest recommended dose; it is suggested for patients receiving certain CYP3A4 inhibitors.

FDA also asked for a study evaluating the drug-drug interactions between Levitra and Sanofi-Synthelabo's alpha blocker UroXatral (alfuzosin). UroXatral was approved in June 2003 and thus was not evaluated in Bayer's earlier studies.

Levitra labeling includes results from the 10 mg and 20 mg studies with alpha blockers, and instructs physicians that "the administration of lower doses of Levitra with alpha blockers has not been completely evaluated to determine if they can be safely administered together." The statement was included "to address the potential that healthcare providers might try reducing the dose of vardenafil to enable co-administration," Division of Reproductive & Urologic Drug Products Deputy Director Donna Griebel, MD, noted in an ³ Aug. 19 memo.

Studies evaluating 10 mg and 20 mg Levitra in combination with alpha blockers were submitted in response to a request in FDA's July 23, 2002 ⁴ 'approvable' letter. The agency noted that "it is expected that many men who seek treatment with Levitra for ED will require concomitant treatment for…BPH, and vice versa."

In its Feb. 19 response, Bayer submitted two studies: one with terazosin 10 mg and one with tamsulosin 0.4 mg. Patients received Levitra six hours after the alpha blockers in the first phase of the study and simultaneously in the second phase.

Houn pointed out that "if the studies showed no effect on blood pressure, this drug would have advantages over [Pfizer's] Viagra (sildenafil)," which is not contraindicated for alpha blockers but does come with precautions recommending reduced dosing.

"However, the tests showed drops in blood pressure that were clinically meaningful," Houn said, citing "a decrease of between 7 and 23 mm Hg of blood pressure" across the two studies.

In addition, the terazosin plus Levitra study was halted early due to a significant number of patients with hypotension. "When 10 or 20 mg vardenafil was dosed simultaneously with terazosin 10 mg, a significant proportion of patients experienced significant hypotension and this portion [part 2] of the study was terminated," Benson explained.

"Although it can be argued that the design of this study resulted in patients who were on high doses of terazosin who were, therefore, prone to significant lowering of blood pressure, subsequent dosing with vardenafil resulted in further decreases of [BP] to unacceptable levels."

In the first part of the terazosin study, Benson noted, three of the 29 patients on 10 mg Levitra and seven of the 28 patients on 20 mg had standing systolic blood pressure under 85 mm Hg.

The tamsulosin study had an identical design and returned results that also were of concern. In the second phase, two of the 16 patients receiving 10 mg vardenafil had standing SBP under 85 and five patients receiving 20 mg had SBP under 100.

"Based on the results of these two studies, I believe that vardenafil (at least at doses of 10 and 20 mg) should be contraindicated in patients taking alpha blockers," Benson recommended. A summary of the two studies' results appears in the drug interactions section of labeling.

Although Bayer agreed to the contraindication by Aug. 8, FDA continued to explore the issue to determine if a contraindication would be a "realistic means to manage the risk," Houn noted.

"To critically examine the use of a contraindication to manage the risk of coadministration…the DRUDP requested that the applicant submit data on the projected number of patients that would have both conditions, [ED] and BPH," Griebel explained.

"Similarly, DRUDP requested information from the Office of Drug Safety evidence for co-prescription of sildenafil and alpha blockers. The postmarketing data from sildenafil was also examined for evidence of adverse event reporting related to concomitant use."

Bayer estimated that 19 mil. men have BPH, 1.6 mil. of whom are treated with alpha blockers. About 500,000 men with BPH also have ED, approximately 70,000 of whom are prescribed ED medications, FDA said.

Griebel cited a report from the Aug. 5, 2003 Annals of Internal Medicine in which "age-adjusted use of alpha blockers ranged from 3% in men less than 59 years of age, to as high as 7% in men aged 70-79….Use of oral therapy for [ED] in those two age categories was reported to be 4% and 8%, respectively."

To examine Viagra's co-prescription data, ODS performed a "unit evaluation of hypotension adverse events" reported in the Adverse Event Reporting System (AERS) database for Viagra. The evaluation found that 49 of 245 hypotension event reports cited concomitant alpha blockers.

"The members of the review team discussed these data with the office director and the division director, and reached concurrence that labeling vardenafil with a contraindication…would be appropriate," Griebel's memo states.

Of the three PDE-5 agents approved for ED, Levitra is the only one that is completely contraindicated for use with alpha blockers.

Viagra labeling recommends that the standard dose of 50 mg be halved with alpha blockers; the precautions section advises that "simultaneous administration…to patients taking alpha blocker therapy may lead to symptomatic hypotension in some patients." Following the introduction of Levitra, Pfizer appeared to be promoting the labeling distinction as an advantage.

Lilly Icos' Cialis (tadalafil), the latest PDE-5 ED agent to enter the market following approval Nov. 21, is contraindicated for use with alpha blockers other than tamsulosin at 0.4 mg once daily.

"When tadalafil 20 mg was administered to healthy subjects taking doxazosin (8 mg daily)…there was significant augmentation of the blood-pressure-lowering effect of doxazosin," Cialis' precautions section states.

chart: ⁵ Levitra FDA Reviewerschart: ⁶ Levitra Clinical Development