OTTAWA — A new, nonhormonal drug was safe and effective for reducing the incidence and severity of vasomotor symptoms of menopause in a series of three pivotal trials with a total of about 1,700 women.
If the drug, desvenlafaxine succinate, a serotonin-norepinephrine reuptake inhibitor (SNRI), is approved by the Food and Drug Administration, “it will be the first nonhormonal drug approved for treating hot flashes and nighttime awakenings,” Dr. Margery Gass said at the annual clinical meeting of the Society of Obstetricians and Gynaecologists of Canada. She and her colleague, Dr. Sophie Olivier, presented the data in five separate reports at the meeting.
“Women and their physicians are seeking an alternative to estrogen. What's exciting is that this drug seems effective against hot flashes and mood, the things that trouble women during menopause,” commented meeting attendee Dr. Jennifer Blake, chief of ob.gyn. at Sunnybrook Health Sciences Centre, Toronto.
Data from these studies were submitted by the drug's developer, Wyeth, to the FDA in June 2006, and—as of late June of this year—action by the FDA for the indication of moderate to severe menopausal vasomotor symptoms was still pending. Last January, the FDA told Wyeth that desvenlafaxine was approvable for the indication of major depressive disorder, but final approval for that use is also still pending. As of late June, a Wyeth spokeswoman said that the company plans to market the drug with the trade name Pristiq for both indications.
The largest of the three pivotal trials enrolled 689 women who reported having 50 or more moderate or severe hot flash episodes a week. Patients were randomized to daily desvenlafaxine dosages of 50, 100, 150, or 200 mg, or placebo, and were scheduled to receive 52 weeks of treatment. The primary efficacy end point was the number and severity of hot flashes after 12 weeks of treatment, and the number of nighttime awakenings. Hot flash episodes and nighttime awakenings were recorded in daily diaries. Efficacy data were available for 620 of the enrolled women.
At baseline, these women had an average of about 11 hot flash episodes daily, with an average severity of 2.4 points (with measurements defined as severe [3 points], moderate [2 points], and mild [1 point]). They also reported an average of 3.7 awakenings a night.
Treatment with desvenlafaxine was most effective in this study at the 100-mg/day level. The 145 women on that dosage reported an average daily reduction of 1.76 hot flash episodes, compared with placebo, and an average drop in episode severity of 0.33 points, compared with the placebo effect. The frequency of nighttime awakenings fell by 0.56 episodes a night, compared with the placebo group. All of these changes were statistically significant compared with placebo, reported Dr. Gass, of the department of ob.gyn. at the University of Cincinnati. Dr. Gass disclosed that she receives compensation as a consultant to Wyeth. In Wyeth's submissions to the FDA, it has proposed 100 mg/day as the recommended dosage, she said.
The placebo effect was substantial. The 77 women in the placebo group reported an average reduction of 6.3 hot flash episodes a day compared with their baseline number, an average drop in hot flash severity of 0.5 points, and an average drop in awakenings of 2.2 episodes a night.
Significantly more women were satisfied with treatment when taking 100 mg desvenlafaxine daily, compared with those in the placebo group. (See box, p. 26)
The researchers also evaluated the difference in treatment responses based on whether the women rated themselves as dissatisfied, neutral, or satisfied with their treatment response. The average increment in response between the women who self-rated themselves as neutral to the treatment, and those who were satisfied, was an additional reduction in hot flash episodes of 1.64 per day. Dr. Gass and her associates called this the “treatment satisfaction threshold.” The difference between neutral and satisfied was an average drop in hot flash severity of 0.2 points, and an average decrease in awakenings of 0.42 episodes per night.
Notably, the 100-mg/day dosage of desvenlafaxine produced a drop in all three measures, compared with placebo, that exceeded all three of these treatment satisfaction thresholds, said Dr. Gass, who is also director of the Menopause and Osteoporosis Center at the University of Cincinnati Medical Center.
“They looked at patient satisfaction levels and showed a clinically meaningful difference from the drug compared with placebo,” commented Dr. Blake, who is also a professor and associate chair of medicine at the University of Toronto.
The efficacy of the 100-mg dosage was confirmed in a second study that included 484 women who were randomized to either 100 mg or 150 mg desvenlafaxine daily or placebo, and were treated for 26 weeks. Again, the primary efficacy end points were measured after 12 weeks of treatment. The data from this second study were presented in a combined analysis with data from the first study, so that the total group included 843 women: 307 who received 100 mg/day desvenlafaxine, 281 who received 150 mg/day, and 255 who received placebo.