Table 2.
Studies of flibanserin in the clinical development program for HSDD
| Study | Type of study | Patients and study medication | Key findings |
|---|---|---|---|
| Phase 3 studies | |||
| VIOLET53 | R, DB, PC; 24 wk | Premenopausal women with HSDD (n = 295 placebo, n = 295 flibanserin 50 mg qhs, n = 290 flibanserin 100 mg qhs) | Significant improvement in FSFI desire score, FSFI total score, FSDS-R-13 score, and number of SSEs for flibanserin 100 mg/d vs placebo; most common AEs with flibanserin 100 mg (≥5% and 2 × placebo): nausea (11.4%), somnolence (11.0%), dizziness (9.0%), fatigue (6.2%) |
| DAISY54 | R, DB, PC; 24 wk | Premenopausal women with HSDD (n = 398 placebo, n = 396 flibanserin 25 mg bid, n = 392 flibanserin 50 mg bid, n = 395 flibanserin 100 mg qhs) | Significant improvement in FSFI desire score, FSFI total score, FSDS-R-13 score, and number of SSEs for flibanserin 100 mg/d vs placebo; most common AEs with flibanserin 100 mg (≥5% and 2 × placebo): dizziness (12.2%), nausea (11.9%), somnolence (11.9%); discontinuation due to AEs: 15.7% of patients treated with flibanserin 100 mg |
| BEGONIA55 | R, DB, PC; 24 wk | Premenopausal women with HSDD (n = 545 placebo, n = 542 flibanserin 100 mg qhs) | Significant improvement in FSFI desire score, FSFI total score, FSDS-R-13 score, and number of SSEs for flibanserin 100 mg/d vs placebo; most common AEs with flibanserin 100 mg (≥5% and 2 × placebo): somnolence (14.4%), dizziness (10.3%), nausea (7.6%), URI (5.2%); discontinuation due to AEs: 9.6% of flibanserin-treated patients |
| SNOWDROP56 | R, DB, PC; 24 wk | Naturally postmenopausal women with HSDD (n = 480 placebo, n = 467 flibanserin 100 mg qhs) | Significant improvement in FSFI desire score, FSFI total score, FSDS-R-13 score, and number of SSEs for flibanserin 100 mg/d vs placebo; most common AEs with flibanserin 100 mg (≥5% and 2 × placebo): dizziness (9.9%), somnolence (8.8%), nausea (7.5%); discontinuation due to AEs: 8.1% of flibanserin-treated patients |
| PLUMERIA57 | R, DB, PC | Naturally postmenopausal women with HSDD (n = 369 placebo, n = 376 flibanserin 100 mg qhs) | Study discontinued for administrative reasons∗; week 16 used as study end point; most common AEs with flibanserin 100 mg (≥5% in either treatment group): insomnia (7.7%), somnolence (6.9%); discontinuation due to AEs: 10.4% of flibanserin-treated patients; at week 16, significant improvement in FSFI desire score for flibanserin vs placebo; between-group comparison for SSE did not reach statistical significance |
| ROSE58 | R, DB, PC, withdrawal study | Premenopausal women with HSDD (n = 738 received OL flibanserin, flexibly dosed); treatment responders at OL week 24 were randomly assigned (n = 170 placebo, n = 163 flibanserin) | Sustained efficacy with continued flibanserin (ie, significantly better outcomes with flibanserin vs placebo in FSFI desire score, FSFI total score, FSDS-R-13 score, and number of SSEs at DB end point); most common AEs with OL flibanserin (≥10%): somnolence (14.1%), fatigue (10.3%); discontinuation due to AEs: 2.5% of flibanserin-treated patients in DB phase and 15.2% of flibanserin-treated patients in OL phase; no withdrawal reactions reported after abrupt discontinuation of flibanserin |
| SUNFLOWER59 | OL extension study; 52 wk | Premenopausal women with HSDD (n = 1723 OL flibanserin, flexibly dosed) | Incidence of prespecified AEs of interest: somnolence (15.8%), fatigue (7.6%), dizziness (6.9%), nausea (6.3%), sedation (1.6%), vomiting (1.4%); discontinuation due to AEs: 10.7% of patients; serious AEs reported in 1.2% of patients; none considered drug-related by the investigator; improvement in measurements of sexual desire (FSFI desire score, FSFI total score, FSDS R-13 score) |
| SSRI/SNRI study60 | R, DB, PC; 12 wk; study designed and powered to assess safety | Premenopausal women with remitted or mild depressive disorder and decreased sexual desire with related distress taking SSRI or SNRI (n = 38 placebo, n = 73 flibanserin 100 mg qhs [including n = 45 up-titrated after 2 wk of 50 mg qhs]) | Study discontinued for administrative reasons∗; most common AEs with flibanserin (≥3% and > placebo): dry mouth (5.5%), insomnia (5.5%), back pain (4.1%), dizziness (4.1%); no increased risk of depression, anxiety, or suicidal ideation when flibanserin added to stable SSRI or SNRI treatment regimen; no significant differences between flibanserin and placebo on exploratory outcome measures |
| Other studies | |||
| Alcohol challenge study61 | R, DB, PC single-dose, crossover study | Healthy volunteers (n = 23 men, n = 2 women); flibanserin 100 mg or placebo with ethanol 0.4 or 0.8 g/kg or flibanserin alone, consumed within 10 min in the morning | Incidence of sedation-, hypotension-, and syncope-related AEs was increased when flibanserin was coadministered with either concentration of alcohol |
| Alcohol use analysis61 | Pooled post hoc analysis of 5 RCTs | Premenopausal women with HSDD (n = 1,905 placebo [64% self-reported alcohol users], n = 1,543 flibanserin 100 mg qhs [58% self-reported alcohol users]) | Rate of hypotension- and syncope-related AEs during treatment with flibanserin was slightly higher numerically in self-reported alcohol users vs non-users, although the incidence of such events was infrequent (0.7% vs 0.3%); rate of hypotension- and syncope-related AEs was similar (0.3%) for alcohol users vs non-users in placebo group |
| Driving study62 | R, DB, PC, crossover study | Healthy premenopausal women (n = 72 completed all 4 treatment periods); zopiclone 7.5 mg qhs on nights 1 and 7 with 5 d of placebo in between; flibanserin 100 mg qhs × 7 d; flibanserin 200 mg qhs (2 × approved dose) on night 7 after 6 nights of 100 mg; placebo × 7 d | Flibanserin 100 mg was significantly better than placebo in driving simulation and cognitive assessments after acute and steady-state night-time dosing; no significant difference for flibanserin 100 mg vs 200 mg; impairment with zopiclone (sedative) vs placebo supported sensitivity of outcome measures |
| Oral contraceptive PK study63 | Meta-analysis of 9 phase 1 studies (effect of oral HC use on flibanserin PK) | Healthy female volunteers and patients with HSDD; flibanserin (25 mg qd, 50 mg qd, 50 mg bid, 100 mg qd); single-dose flibanserin (n = 39 [HC users], n = 114 [HC non-users]) and multiple-dose (ie, steady-state) flibanserin (n = 17 [HC users], n = 91 [HC non-users]) | AUC0-∞ 1.42-fold higher (90% CI = 1.23–1.63) after single-dose flibanserin; AUC0-T 1.44-fold higher (90% CI = 1.19–1.73) at steady state in HC users vs non-users |
| Oral contraceptive PK study64 | R, OL, crossover study (effect of flibanserin on oral contraceptive PK) | Healthy premenopausal women (N = 24 [23 completed both treatment periods]); single doses of ethinyl estradiol 30 μg + levonorgestrel 150 μg alone (reference) or preceded by 14 d of flibanserin 100 mg qhs (test) | Pretreatment of flibanserin 100 mg once daily for 2 wk produced no clinically relevant change in single-dose PK of ethinyl estradiol or levonorgestrel; incidence of AEs was higher for flibanserin before oral contraceptive administration vs oral contraceptive alone but did not increase after coadministration |
| Population PK study65 | Single-dose PK study | Healthy volunteers (n = 14 men, n = 10 women); 1 dose of flibanserin 100 mg after overnight fast | In PK/PD model, rapid drug distribution was identified; relation of drug concentration with drowsiness (assessed by VAS) indicated minimal sedating effect of flibanserin at concentrations typically observed 4 h after administration |
AE = adverse event; AUC0-∞ = area under the dose-normalized concentration-time curve extrapolated to infinity; AUC0-T = area under the dose-normalized concentration-time curve over the dosing interval; bid = twice daily; DB = double-blinded; FSFI = Female Sexual Function Index; FSDS-R-13 = Female Sexual Distress Scale–Revised, Item 13; HC = hormonal contraceptive; HSDD = hypoactive sexual desire disorder; OL = open-label; PC = placebo-controlled; PD = pharmacodynamic(s); PK = pharmacokinetic(s); qd = daily; qhs = at bedtime; R = randomized; RCT = randomized controlled trial; SNRI = serotonin-norepinephrine reuptake inhibitor; SSE = satisfying sexual events; SSRI = selective serotonin reuptake inhibitor; URI = upper respiratory tract infection; VAS = visual analog scale.
∗
The development of flibanserin in this population was discontinued by the sponsor (Boehringer Ingelheim).