快樂小藥師 Im pharmacist nichts glücklich

Objective: This study aimed to assess the efficacy and safety of flibanserin, a serotonin receptor 1A agonist/serotonin receptor 2A antagonist, in postmenopausal women with hypoactive sexual desire disorder (HSDD).

Methods: Naturally postmenopausal women with HSDD received flibanserin 100 mg once daily at bedtime (n = 468) or placebo (n = 481) for 24 weeks. Co–primary endpoints were changes from baseline to week 24 in the number of satisfying sexual events (SSEs) across 28 days and in the Female Sexual Function Index (FSFI) desire domain score. Secondary endpoints included change from baseline in Female Sexual Distress Scale—Revised (FSDS-R) Item 13 score (which assesses distress due to low sexual desire), FSDS-R total score, and FSFI total score. The Patient Benefit Evaluation was asked on treatment discontinuation.

Results: There were significant improvements with flibanserin versus placebo in the mean (SE) changes in the number of SSEs (1.0 [0.1] vs 0.6 [0.1]), FSFI desire domain score (0.7 [0.1] vs 0.4 [0.1]), FSDS-R Item 13 score (-0.8 [0.1] vs -0.6 [0.1]), FSDS-R total score (-8.3 [0.6] vs -6.3 [0.6]), and FSFI total score (4.2 [0.4] vs 2.7 [0.4]; all P < 0.01). More women on flibanserin (37.6%) than women on placebo (28.0%) reported experiencing meaningful benefits from the study medication on treatment discontinuation. The most frequent adverse events associated with flibanserin were dizziness, somnolence, nausea, and headache.

Conclusions: In naturally postmenopausal women with HSDD, flibanserin, compared with placebo, has been associated with improvement in sexual desire, improvement in the number of SSEs, and reduced distress associated with low sexual desire, and is well tolerated.

Hypoactive sexual desire disorder (HSDD) is defined by the American Psychiatric Association as a persistent or recurrent deficiency in or absence of sexual fantasies and desire for sexual activity that causes marked distress or interpersonal difficulty. For a diagnosis of HSDD to be assigned, the desire problem must not be better accounted for by another psychiatric disorder (eg, depression), substance (eg, a medication), or medical condition.1

Although the most commonly reported sexual problem among older women is loss of desire,2-4 estimates of the prevalence of HSDD vary depending on the methodology used and the population studied.5 The prevalence of low sexual desire associated with distress among naturally postmenopausal women was 6.6% in a US survey of 541 naturally postmenopausal women conducted in 2004-2005 6 and 9.3% in a US survey of 10,429 women conducted in 2006.7

HSDD is a multifactorial condition.8 It has been hypothesized that HSDD is caused by dysregulation of the excitatory and inhibitory signals in the central nervous system that regulate sexual response.9,10 Dopamine, norepinephrine, and testosterone seem to play roles in the stimulation of sexual desire, whereas serotonin inhibits sexual desire.9,11 Treatment with testosterone has been shown to improve sexual desire in both naturally and surgically postmenopausal women with HSDD 12-14; however, that women with HSDD are, in general, deficient in testosterone has not been established.15

Currently, there are no Food and Drug Administration (FDA)–approved pharmacological treatments for HSDD. In 2004, a testosterone patch (Intrinsa; Procter and Gamble Pharmaceuticals, Cincinnati, OH) was reviewed by an FDA advisory committee, which, based on safety concerns, recommended against approval. The application for FDA approval was subsequently withdrawn, but the patch was approved in Europe in 2006 for the treatment of HSDD in surgically postmenopausal women who are receiving estrogen therapy.16 Few agents are undergoing clinical development for the treatment of HSDD. Although draft guidance on the development of drugs for female sexual dysfunction was issued by the FDA in 2000,17 it was never finalized and has now been withdrawn.

Flibanserin is a postsynaptic agonist of serotonin (5-HT) receptor 1A and an antagonist of serotonin receptor 2A 18 that has been shown to induce transient decreases in serotonin and increases in dopamine and norepinephrine in certain regions of the brain.19-21 By modulating these neurotransmitters in specific brain areas, flibanserin is believed to improve the balance of systems that regulate sexual desire in women with HSDD.20 The efficacy and safety of flibanserin 100 mg once daily at bedtime (qhs) as HSDD treatment are supported by results from three randomized placebo-controlled trials in North American premenopausal women with HSDD (BEGONIA, DAISY, and VIOLET) and an extension trial.22-25 In these studies, flibanserin was associated with an increase in satisfying sexual events (SSEs), an improvement in sexual desire (measured using the Female Sexual Function Index desire domain [FSFI-d]26), and a decrease in sexual distress, and was well tolerated.

The SNOWDROP trial was designed to investigate the efficacy and safety of flibanserin 100 mg qhs across 24 weeks of treatment in naturally postmenopausal women with HSDD. This was the first clinical trial to investigate flibanserin as a treatment for HSDD in postmenopausal women.

A total of 1,997 women were screened, and 949 women were randomized to receive flibanserin (n = 468) or placebo (n = 481; Fig. 1). The most frequent reasons for screen failure were as follows: endometrial thickness of more than 4 mm, depression (history of major depressive disorder within 6 mo before screening or a score of >=14 on the Beck Depression Inventory-II),29 and use of medication prohibited by the study protocol. Among the randomized women, 2 were not treated, and 185 (19.5%) discontinued the trial prematurely (102 [21.8%] in the flibanserin group and 83 [17.3%] in the placebo group). Baseline characteristics were similar between groups (Table 1). At baseline, there were 2.0 SSEs in the placebo group and 2.1 SSEs in the flibanserin group (standardized to 28 d).

At week 24, improvements in both co–primary endpoints were observed with flibanserin versus placebo. Mean (SE) SSEs increased by 1.0 (0.1) with flibanserin versus 0.6 (0.1) with placebo (P = 0.004; Fig. 2, Table 2). Adjusted mean (SE) FSFI-d score increased by 0.7 (0.1) with flibanserin versus 0.4 (0.1) with placebo (P < 0.001; Fig. 3, Table 2). Similar results were achieved using mixed-model repeated-measures analyses: the adjusted mean (SE) change in SSEs was 1.1 (0.2) with flibanserin versus 0.5 (0.2) with placebo (P = 0.002), and the adjusted mean (SE) change in FSFI-d score was 0.7 (0.1) with flibanserin versus 0.4 (0.1) with placebo (P < 0.001).

Improvements in sexual distress (FSDS-R total score) and distress associated with low sexual desire (FSDS-R Item 13 score) were observed with flibanserin versus placebo. The adjusted mean (SE) change in FSDS-R Item 13 score was -0.8 (0.1) with flibanserin versus -0.6 (0.1) with placebo (P = 0.008; Fig. 4, Table 2), whereas the adjusted mean (SE) change in FSDS-R total score was -8.3 (0.6) with flibanserin versus -6.3 (0.6) with placebo (P = 0.006; Fig. 5, Table 2). The adjusted mean (SE) FSFI total score increased by 4.2 (0.4) with flibanserin versus 2.7 (0.4) with placebo (P = 0.003; Fig. 6, Table 2).

At week 24, the adjusted mean (SE) PGI-I score was lower with flibanserin (3.4 [0.1]) than with placebo (3.7 [0.1]; P < 0.001), indicating greater improvement. The number of women who responded “yes” when asked whether they had experienced a meaningful benefit from the study medication (PBE) was higher in the flibanserin group (163 [37.6%]) than in the placebo group (127 [28.0%]; P = 0.003).

AEs were experienced by 296 (63.4%) women in the flibanserin group versus 248 (51.7%) women in the placebo group (Table 3). Almost all AEs reported were mild or moderate in intensity (96.5% in the placebo group and 94.0% in the flibanserin group). The most frequently reported AEs were dizziness, somnolence, nausea, and headache (Table 3). AEs were considered by the investigator to be drug-related in 139 (29.8%) women on flibanserin versus 61 (12.7%) women on placebo. Thirty-eight (8.1%) women on flibanserin and 17 (3.5%) women on placebo discontinued treatment because of an AE. The most common AEs leading to discontinuation of flibanserin were dizziness (1.3%) and insomnia (0.9%).

Twelve women experienced one or more serious AEs: four (0.8%) women on placebo (5 events) and eight (1.7%) women on flibanserin (12 events). Two AEs in the flibanserin group were considered life-threatening, and one AE (alcohol poisoning) was fatal. No serious AEs were considered by the investigator to be related to treatment. There was no evidence of increased suicide ideation in the flibanserin group. The incidence of AEs in the posttreatment period was similar in the placebo (8.3%) and flibanserin (11.1%) groups.

Increases in prolactin, progesterone, and sex hormone–binding globulin that were of possible clinical significance (cutoff: prolactin, >30 ng/dL; progesterone, >=3,750 ng/mL; sex hormone–binding globulin, >120 nmol/L) were reported in 5 (1.4%), 14 (3.8%), and 12 (3.3%) women on flibanserin versus 2 (0.5%), 10 (2.5%), and 15 (3.8%) women on placebo, respectively. Clinically relevant changes in blood pressure (defined as outside the reference range and ±15 mm Hg [diastolic] or ±20 mm Hg [systolic]) were observed in three (0.6%) women on flibanserin and four (0.8%) women on placebo. Clinically relevant decreases in pulse (by >=15 bpm and reaching below 50 bpm) were observed in three (0.6%) women on flibanserin and one (0.2%) woman on placebo.

In this randomized, placebo-controlled trial, 24-week treatment with flibanserin 100 mg qhs was associated with significant improvements in sexual desire and distress associated with low sexual desire in postmenopausal women with HSDD. This is the first time that a nonhormone pharmacological treatment has been shown to be effective for treating HSDD in postmenopausal women.

The FSFI-d score, chosen as a co–primary endpoint in this study, has been used extensively as a measure of sexual desire in women and has been validated in both premenopausal and postmenopausal women with HSDD.32,33 Change in SSEs was required by the FDA as a primary endpoint in this trial and has been shown to be responsive to treatment in previous trials on premenopausal women with HSDD.22-25 However, the frequency of SSEs is influenced by multiple factors and does not necessarily correlate with sexual desire or with the distress associated with low sexual desire.34 Distress associated with low sexual desire is a defining feature of HSDD, and relief of distress is recognized as a key aim of its treatment. The FSDS-R and its item 13 (distress due to low desire) have been validated to be of relevance to women with HSDD.27,31

The baseline characteristics of the women in this trial were broadly similar to those of the postmenopausal cohort of women who participated in a recent HSDD registry. The mean baseline FSFI total score in this trial population was 15.9 compared with 14.0 in postmenopausal women in the registry.35 Baseline measures of SSEs and FSFI total score were lower in postmenopausal women in this trial (2.0 and 15.9, respectively) than in studies of flibanserin in North American premenopausal women (2.5-2.8 and 19.0-20.1, respectively).22-25 However, baseline FSFI-d scores were similar in postmenopausal women in this trial (1.8) and in premenopausal women in similar trials (1.8-1.9).22-24 The magnitude of improvement in FSFI-d and total scores with flibanserin was similar in the trials in premenopausal and postmenopausal women, with FSFI-d score improvements of 0.9 to 1.0 point in the DAISY, VIOLET, and BEGONIA trials versus 0.7 point in this trial, and with FSFI total score improvements of 4.1 to 5.3 points in the DAISY, VIOLET, and BEGONIA trials versus 4.2 points in this trial. However, the increase in SSEs seemed to be somewhat smaller in this trial than in the trials of flibanserin conducted in premenopausal women (1.0 vs 1.6-2.5). This may have been because postmenopausal women with HSDD have a greater prevalence of arousal and sexual pain problems than premenopausal women with HSDD,35 partner issues, or other reasons.

Flibanserin was well tolerated by the postmenopausal women in this study, with the observed AEs being consistent with those reported in trials of flibanserin in premenopausal women 22-25,36 and with those associated with other serotonin receptor 2A antagonists.37,38 Nearly all AEs were mild or moderate, and only about 8% of women in the flibanserin group (vs 3.5% in the placebo group) discontinued from the investigation prematurely because of AEs. Although the active treatment group had double the number of discontinuations due to AEs as the placebo group, the percentage of women discontinuing from the trial overall was quite low and consistent with other trials of this type and duration.39-41 The AEs that most frequently resulted in discontinuation were dizziness (1.3%) and insomnia (0.9%) in the flibanserin group, and anxiety (0.8%) and fatigue (0.8%) in the placebo group.

The inclusion and exclusion criteria for this trial were less constrained than those used in previous phase III trials of flibanserin (eg, the list of prohibited medications was greatly reduced). However, a limitation of this study was its restriction to women in stable heterosexual relationships with a sexually functional partner, who, except for their sexual dysfunction, were not experiencing any other psychiatric disorder (including depression, which often occurs concomitantly with HSDD)42 and were not taking concomitant medications that could affect sexual function. Also excluded from this study population were women with induced menopause (ie, caused by radiation, chemotherapy, or surgical operation). Thus, the study population was not entirely reflective of women seeking treatment for distressing low sexual desire in clinical practice.

These results demonstrate that flibanserin 100 mg qhs improves sexual desire, improves sexual function, and reduces distress related to loss of desire in naturally postmenopausal women with HSDD, and is well tolerated.