The FDA’s Cardiovascular and Renal Drugs Advisory Committee voted 6-4 to recommend against approval of a fixed-dose combination of nebivolol and valsartan for treatment of hypertension.  

In February, Forest Laboratories Inc. submitted a new drug application (NDA) for fixed-dose nebivolol and valsartan combination tablets in doses of 5 mg/80 mg, 10 mg/160 mg, 10 mg/320 mg and 20 mg/320 mg as add-on therapy, replacement therapy or initial therapy for hypertension.

The advisory panel met Sept. 9 to weigh the treatment’s benefits and risks for the proposed indication.

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Available Evidence

Fixed-dose combination nebivolol and valsartan was evaluated in a factorial, placebo-controlled, 8-week trial in patients with stage I or stage II hypertension and a 52-week, single-arm, open-label trial.

Results from the factorial trial showed that statistically significant greater mean reductions in seated diastolic and systolic blood pressure (BP) were achieved with the fixed-dose combination drug, as compared with the highest available doses of nebivolol and valsartan alone.

Specifically, diastolic BP decreased by an additional ~3.6 mm Hg with the 10-mg/320-mg dose and 4.4 mm Hg with the 20-mg/320-mg dose of the fixed-dose combination drug vs. the highest marketed dose of valsartan alone.

Systolic BP also decreased by an additional ~3.3 mm Hg with the 10-mg/160-mg, 10-mg/320-mg and 20-mg/320-mg doses of the fixed-dose combination drug vs. the highest marketed dose of valsartan alone, according to briefing documents provided by the FDA in advance of the meeting.

The fixed-dose combination drug was also more effective when compared with nebivolol 40 mg alone, the highest dose available. However, the treatment difference between the 20-mg/320-mg fixed-dose combination drug and nebivolol 40 mg was only –1.2 mm Hg for diastolic BP, leading the FDA reviewers to question whether this difference is clinically meaningful.

Points of Discussion

In light of the study data, several committee members took issue with the effect size of fixed-dose combination nebivolol and valsartan in comparison with both its individual components and with other combination therapies.

Panel member Julia B. Lewis, MD, professor of medicine in the department of nephrology at Vanderbilt University School of Medicine in Nashville, said the decision was difficult but ultimately voted against approval.

“One final thing that swayed me is that other existing combination drugs’ effect sizes are significantly clinically and numerically higher,” she said during the meeting, noting her concern about clinicians selecting this drug when other drugs that may be more beneficial are available.

Committee member Philip Sager, MD, consulting professor of medicine at Stanford University School of Medicine and chair of the Scientific Programs Committee for the Cardiac Safety Research Consortium, echoed Dr. Lewis’s opinion.