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Flibanserin (Addyi) — Female HSDD

Flibanserin (Addyi) is FDA-approved for acquired, generalized hypoactive sexual desire disorder (HSDD) in women younger than 65, including postmenopausal women (December 2025 label expansion), characterized by low sexual desire causing marked distress or interpersonal difficulty, not attributable to a coexisting medical or psychiatric condition, relationship problems, or medication effects.[1][2] It was the first FDA-approved pharmacotherapy for female HSDD (2015), after two prior FDA rejections, and its approval was accompanied by significant debate about the medicalization of women's sexuality, whether the modest benefits justified the risks, and concerns about pharmaceutical-industry influence on FDA decision-making.[1][5]

For the clinical-conditions framework on female sexual dysfunction see Sexual Dysfunction (Women's Health). For the FDA-approved alternative on-demand option see Bremelanotide. For postmenopausal HSDD off-label transdermal testosterone see Female Testosterone for HSDD.

Mechanism of Action​

The precise mechanism of action in HSDD is not fully established. In vitro, flibanserin is a 5-HT₁A receptor agonist and 5-HT₂A receptor antagonist, with moderate antagonist activity at 5-HT₂B, 5-HT₂C, and dopamine D₄ receptors.[2] Stahl et al. judged the weaker 5-HT₂B and 5-HT₂C actions unlikely to be clinically relevant and D₄ activity less defined.[3] In preclinical work reviewed by Stahl et al., chronic flibanserin appeared to act preferentially at postsynaptic serotonin receptors on prefrontal-cortex pyramidal neurons, with sustained dopamine and norepinephrine increases in the prefrontal cortex and transient serotonin decreases in the prefrontal cortex, nucleus accumbens, and hypothalamus; this pattern may disinhibit sexual-desire pathways.[3][4] Flibanserin was originally developed as an antidepressant but showed only mild antidepressant activity; it was subsequently repurposed for HSDD.[5]

Indication​

Women younger than 65 with acquired, generalized HSDD — distress about decreased sexual desire that is not due to:

  • Coexisting medical or psychiatric condition.
  • Problems with the relationship.
  • Effects of a medication or other drug substance.

Not indicated for men or to enhance sexual performance.[2]

Dosing and Administration​

  • 100 mg orally once daily at bedtime.[2]
  • Bedtime dosing required to reduce the risk of hypotension, syncope, and CNS depression.
  • Patients should avoid driving and other activities requiring full alertness for at least 6 hours after dosing and until they know how flibanserin affects them.[2]
  • Discontinue after 8 weeks if no improvement in symptoms.[2]
  • If a bedtime dose is missed, take the next dose the following bedtime; do not double the dose.[2]

Efficacy​

Flibanserin's efficacy is modest. Findings.

  • Jaspers 2016 JAMA Intern Med meta-analysis of 8 RCTs (5,914 trial completers; at least 7,914 women assigned): pooled regimens totaling 100 mg/day (including one 50-mg twice-daily trial) increased satisfying sexual events (SSEs) by +0.49 per month over placebo; a sensitivity analysis limited to the FDA-approved 100-mg once-daily regimen found +0.54 per month. eDiary desire improved in premenopausal women (the only group measured), and FSFI desire-domain scores improved in the pooled analysis.[6]
  • Simon 2019 pooled the three pivotal 24-week trials (VIOLET, DAISY, BEGONIA; n = 2,465 premenopausal women) in a post hoc analysis: mean change from baseline in satisfying sexual events was 2.1 versus 1.2 per 28 days (flibanserin versus placebo), with statistically significant pooled improvements in FSFI desire and reductions in distress.[7] In the FDA label's individual-trial results, Studies 1 and 2 did not meet the eDiary-desire co-primary endpoint, whereas Study 3 met the FSFI-desire co-primary endpoint.[2]
  • Kamrul-Hasan 2024 Medicine meta-analysis of 8 RCTs (n = 7,906 women) found flibanserin superior to placebo in both premenopausal (SSE mean difference +0.69 per month) and postmenopausal women, though adverse events were more frequent; the December 2025 label now includes postmenopausal women younger than 65.[2][8]
  • Toledo 2026 J Minim Invasive Gynecol systematic review and meta-analysis (36 studies of desire, arousal and orgasm disorders): flibanserin improved total FSFI and desire and reduced distress; no trial directly compared CBT with drug therapy.[12]
  • ACOG PB 213 notes the overall quality of efficacy and safety evidence is "very low," with an average improvement of less than one additional satisfying sexual event per month.[9]

"The efficacy of flibanserin is modest. In a meta-analysis of eight trials including 5,914 participants, flibanserin was shown to have increased the number of satisfying sexual experiences per month by 0.5 but with considerable side effects." — Davis SR, Sexual Dysfunction in Women, N Engl J Med 2024[4]

Boxed Warning and Contraindications​

Flibanserin carries a boxed warning for hypotension and syncope in specific settings.[2] Known hypersensitivity to Addyi or its components is also a contraindication; reported reactions include anaphylaxis and angioedema.[2]

Alcohol interaction (boxed warning)​

  • Taking flibanserin within 2 hours of alcohol consumption increases the risk of severe hypotension and syncope.
  • Patients should wait ≥ 2 hours after 1–2 standard drinks before taking the dose, or skip that evening’s dose if ≥ 3 drinks were consumed. After dosing, avoid alcohol until the following day.[2]

CYP3A4 inhibitors (contraindicated)​

  • Contraindicated with moderate or strong CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, certain HIV protease inhibitors, and grapefruit juice) because they increase flibanserin exposure and the risk of severe hypotension or syncope.[2]
  • Wait 2 weeks after the last CYP3A4-inhibitor dose before restarting flibanserin; stop flibanserin at least 2 days before starting a moderate/strong CYP3A4 inhibitor.[2]
  • Multiple concomitant weak CYP3A4 inhibitors (e.g., ginkgo, resveratrol, cimetidine, oral contraceptives, fluoxetine) may also increase concentrations.[2]

Hepatic impairment (contraindicated)​

  • Contraindicated in hepatic impairment of any degree — in a single-dose study, flibanserin AUC increased 4.5-fold in mild hepatic impairment versus matched controls; the increase for moderate impairment could not be quantified.[2]

Other drug interactions​

  • Other CNS depressants, including diphenhydramine, opioids, hypnotics, and benzodiazepines, may increase CNS depression; discuss concomitant use when prescribing flibanserin.[2]
  • CYP3A4 inducers, including carbamazepine, rifampin, and St. John's wort, substantially reduce flibanserin exposure; concomitant use is not recommended.[2]
  • In a study of 24 healthy volunteers, flibanserin doubled digoxin AUC; monitor digoxin concentrations during concomitant use because toxicity may occur.[2]

Adverse Effects​

Most common adverse reactions in the premenopausal label trials (100 mg at bedtime vs placebo).[2] Dizziness, somnolence and nausea each occurred in about 10% or more of treated women.[2][6][7]

EventFlibanserinPlacebo
Dizziness11.4%2.2%
Somnolence11.2%2.9%
Nausea10.4%3.9%
Fatigue9.2%5.5%
Insomnia4.9%2.8%

Somnolence, sedation or fatigue combined occurred in about 21% vs 8% (premenopausal trials) and 10% vs 6% (postmenopausal women younger than 65).[2]

Risk ratio for study discontinuation due to adverse events compared with placebo: 2.19 (95% CI 1.50–3.20).[6]

In 100-mg comparisons, the meta-analysis did not detect a statistically significant difference in serious adverse events (7 RCTs; n = 5,476; RR 1.23, 95% CI 0.77–1.95) or severe adverse events (4 RCTs; n = 3,112; RR 1.36, 95% CI 0.87–2.12).[8] Hypotension occurred in 0.2% and syncope in 0.4% of flibanserin-treated premenopausal patients in five 24-week trials, even without other concomitant medications known to cause hypotension or syncope.[2]

Flibanserin does not prolong the QT interval to a clinically relevant extent.[2]

Special Populations​

  • Strong CYP2C19 inhibitors (e.g., proton-pump inhibitors, SSRIs, benzodiazepines, some antifungals) may raise flibanserin exposure; discuss before prescribing.[2]
  • CYP2C19 poor metabolizers (2–15% of Asians, 2–5% of Caucasians / Africans): increased flibanserin exposure; increased monitoring for hypotension is recommended.[2]
  • Postmenopausal women. The December 2025 label includes women younger than 65.[2] Earlier reviews described modest benefit in women studied before the label expansion.[4][8] In the label's under-65 analysis of the completed 24-week trial, 447 naturally postmenopausal women received flibanserin and 455 received placebo (efficacy set, 430 and 451; completion, 79% and 83%); the week-24 between-group difference was 0.4 satisfying sexual events per 28 days.[2] Women with substantial medical or psychiatric comorbidities were excluded.[2] PLUMERIA ended early: 45.3% completed week 16, and its satisfying-event comparison was not statistically significant.[13]
  • Pregnancy. The label reports no studies in pregnant women; animal studies found fetal toxicity with substantial maternal toxicity.[2]
  • Breastfeeding. Addyi is not recommended because of potential infant sedation; whether flibanserin enters human milk is unknown.[2]
  • Not indicated in men or to enhance sexual performance.[2]
  • Safety and effectiveness have not been established in geriatric patients (≥ 65 yr).[2]

REMS Program and Prescribing Requirements​

Both the prescribing physician and the dispensing pharmacist were originally required to complete a Risk Evaluation and Mitigation Strategy (REMS) certification. FDA removed the prescriber/pharmacy certification elements on October 9, 2019; the modified REMS retained a Medication Guide. Counseling must follow the current alcohol-timing and interaction instructions above.[11]

Guideline Recommendations​

GuidelinePosition
ACOG 2019 (Practice Bulletin 213)[9]Level B (limited or inconsistent scientific evidence): flibanserin can be considered for HSDD in premenopausal women without depression after counseling about alcohol risks. The bulletin separately rates the overall efficacy and safety evidence as very low quality and describes the mean benefit as fewer than one additional satisfying sexual event per month.
AAFP 2025 (Dalrymple)[10]Cognitive behavior therapy is described as first-line for disorders of sexual desire and arousal; mindfulness-based interventions may also help these disorders, and sex therapy is discussed for orgasmic disorders. Flibanserin is noted as having modest benefits and being relatively expensive.
Davis 2024 NEJM review[4]Characterizes flibanserin's efficacy as modest; notes that bremelanotide (Vyleesi) is the alternative FDA-approved pharmacologic option for premenopausal HSDD, administered as a subcutaneous injection on an as-needed basis.
VA/DoD 2026 menopause guideline[14]Suggests flibanserin for HSDD in perimenopause and menopause (Weak for).
5th ICSM HSDD consensus (2026)[15]Rates evidence for flibanserin in premenopausal HSDD as Strong and in postmenopausal HSDD as Moderate.

Counseling and Prescribing Pearls​

  • Bedtime dosing minimizes daytime sedation and hypotension exposure.
  • Patients must be counseled explicitly on alcohol avoidance — wait ≥ 2 hours after 1–2 drinks before the dose, skip the dose if ≥ 3 drinks, avoid alcohol until the following day after dosing.
  • Onset of action is gradual — allow 8 weeks of daily use before assessing response.
  • Set expectations from Jaspers et al.'s meta-analysis of trials in premenopausal and postmenopausal women: 100-mg flibanserin added 0.49 satisfying sexual events per month versus placebo (95% CI 0.32–0.67).[6]
  • Re-screen for medical, psychiatric or relational causes if no response by 8 weeks; discontinue if no benefit at 8 weeks per the FDA label.
  • Check for moderate or strong CYP3A4 inhibitors and hepatic impairment before prescribing and when medications or health status change; both are contraindications.[2]
  • In patients predisposed to hypotension, weigh the risk of syncope before prescribing; advise patients with presyncope to lie supine immediately and seek prompt care if symptoms persist, and to seek prompt care after syncope.[2]
  • Discuss cognitive behavior therapy as a first-line option for desire/arousal disorders; consider mindfulness, sex therapy, or couples therapy as appropriate before or alongside pharmacotherapy.[9][10]
  • Consider bremelanotide for patients who prefer on-demand dosing or cannot tolerate daily bedtime sedation, and transdermal testosterone for postmenopausal patients (off-label).

See Also​

References​

1. Joffe HV, Chang C, Sewell C, et al. FDA approval of flibanserin — treating hypoactive sexual desire disorder. N Engl J Med. 2016;374(2):101–104. doi:10.1056/NEJMp1513686

2. Sprout Pharmaceuticals. Addyi (flibanserin) prescribing information, revised December 2025. DailyMed. Accessed September 11, 2026.

3. Stahl SM, Sommer B, Allers KA. Multifunctional pharmacology of flibanserin: possible mechanism of therapeutic action in hypoactive sexual desire disorder. J Sex Med. 2011;8(1):15–27. doi:10.1111/j.1743-6109.2010.02032.x

4. Davis SR. Sexual dysfunction in women. N Engl J Med. 2024;391(8):736–745. doi:10.1056/NEJMcp2313307

5. Deeks ED. Flibanserin: first global approval. Drugs. 2015;75(15):1815–1822. doi:10.1007/s40265-015-0474-y

6. Jaspers L, Feys F, Bramer WM, Franco OH, Leusink P, Laan ETM. Efficacy and safety of flibanserin for the treatment of hypoactive sexual desire disorder in women: a systematic review and meta-analysis. JAMA Intern Med. 2016;176(4):453–462. doi:10.1001/jamainternmed.2015.8565

7. Simon JA, Thorp J, Millheiser L. Flibanserin for premenopausal hypoactive sexual desire disorder: pooled analysis of clinical trials. J Womens Health. 2019;28(6):769–777. doi:10.1089/jwh.2018.7516

8. Kamrul-Hasan ABM, Hannan MA, Alam MS, et al. Role of flibanserin in managing hypoactive sexual desire disorder in women: a systematic review and meta-analysis. Medicine (Baltimore). 2024;103(25):e38592. doi:10.1097/MD.0000000000038592

9. American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Gynecology. Female sexual dysfunction: ACOG Practice Bulletin Number 213. Obstet Gynecol. 2019;134(1):e1–e18. doi:10.1097/AOG.0000000000003324

10. Dalrymple SN, Hoeg L, Thacker H. Female sexual dysfunction: common questions and answers. Am Fam Physician. 2025;111(5):433–442. PMID 40378324

11. US Food and Drug Administration. Addyi supplemental approval review: October 2019 REMS modification. Certification elements removed; Medication Guide retained.

12. Toledo RG, Winkelman WD, Reyes-Gonzalez D, et al. Female sexual desire, arousal, and orgasmic dysfunctions: a systematic review and meta-analysis of treatment options. J Minim Invasive Gynecol. 2026;33(1):16–33.e3. doi:10.1016/j.jmig.2025.06.004

13. Portman DJ, Brown L, Yuan J, Kissling R, Kingsberg SA. "Flibanserin in Postmenopausal Women with Hypoactive Sexual Desire Disorder: Results of the PLUMERIA Study." J Sex Med. 2017;14(6):834–842. doi:10.1016/j.jsxm.2017.03.258

14. Department of Veterans Affairs, Department of Defense. VA/DoD Clinical Practice Guideline for Menopause: Provider Summary. Version 1.0. 2026. Provider summary.

15. Rowen TS, Abdo C, el Kak F, et al. "Evaluation and management of hypoactive sexual desire disorder in women. Recommendations from the 5th International Consultation on Sexual Medicine (ICSM 2024)." Sex Med Rev. 2026;14(1):qeaf057. doi:10.1093/sxmrev/qeaf057