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Flibanserin (Addyi) — Female HSDD

Flibanserin (Addyi) is FDA-approved for acquired, generalized hypoactive sexual desire disorder (HSDD) in premenopausal women only (under age 65) — characterized by low sexual desire causing marked distress or interpersonal difficulty, not attributable to a coexisting medical / 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.[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. 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] It acts postsynaptically, preferentially at prefrontal-cortex pyramidal neurons, resulting in sustained increases in dopamine and norepinephrine and transient decreases in serotonin in select brain regions (prefrontal cortex, nucleus accumbens, hypothalamus) — a profile thought to disinhibit pathways involved in sexual desire.[3][4] Notably, flibanserin was originally developed as an antidepressant but showed only mild antidepressant activity; it was subsequently repurposed for HSDD.[5]

Indication​

Premenopausal women 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 approved for postmenopausal women and not approved 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 activities requiring full alertness (e.g., driving) for at least 6 hours after dosing.[2]
  • Discontinue after 8 weeks if no improvement in symptoms.[2]

Efficacy​

Flibanserin's efficacy is modest. Key findings.

  • Jaspers 2016 JAMA Intern Med meta-analysis of 8 RCTs (n = 5,914 women): flibanserin 100 mg increased satisfying sexual events (SSEs) by +0.49 per month over placebo, with small improvements in eDiary desire and FSFI desire-domain scores.[6]
  • Simon 2019 pooled analysis of the three pivotal trials (VIOLET, DAISY, BEGONIA; n = 2,465 premenopausal women): mean increase 2.1 vs 1.2 SSEs / 28 days (flibanserin vs placebo), with statistically significant improvements in desire and reductions in sexual distress.[7]
  • Kamrul-Hasan 2024 Medicine meta-analysis of 8 RCTs (n = 7,906 women) confirmed efficacy in both premenopausal and postmenopausal women — but the drug remains FDA-approved for premenopausal use only.[8]
  • ACOG PB 213 notes the overall quality of efficacy / 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]

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 drinks before taking the dose, or skip the dose entirely if ≥ 3 drinks were consumed.

CYP3A4 inhibitors (contraindicated)​

  • Contraindicated with moderate or strong CYP3A4 inhibitors (e.g., ketoconazole, fluconazole, certain HIV protease inhibitors) — these increase flibanserin concentrations and the risk of severe hypotension / syncope.
  • Discontinue the CYP3A4 inhibitor for 2 weeks before restarting flibanserin.[2]
  • Multiple concomitant weak CYP3A4 inhibitors (e.g., ginkgo, resveratrol, cimetidine) may also increase concentrations.[2]

Hepatic impairment (contraindicated)​

  • Contraindicated in hepatic impairment of any degree — flibanserin exposure increases 4.5-fold.[2]

Adverse Effects​

The most common adverse events (≥ 10% of patients).[2][6][7]

EventFlibanserinPlacebo
Dizziness~ 11%~ 2%
Somnolence / sedation / fatigue~ 21% (premenopausal trials)~ 8%
NauseaCommon—
InsomniaCommon—

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

Serious adverse events and severe adverse events were comparable between flibanserin and placebo groups across the 8-RCT meta-analysis.[8] Hypotension occurred in 0.2% and syncope in 0.4% of flibanserin-treated premenopausal patients even without concomitant risk factors.[2]

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

Special Populations​

  • CYP2C19 poor metabolizers (2–15% of Asians, 2–5% of Caucasians / Africans) — increased flibanserin exposure; increased monitoring for hypotension is recommended.[2]
  • Postmenopausal women — studies show similar modest efficacy, but flibanserin is not FDA-approved for this population.[4][8][9]
  • 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. A patient–provider agreement form regarding alcohol use during treatment was also required. These requirements were modified in 2019 (the alcohol-related REMS shifted to contraindication-based labeling rather than mandatory prescriber certification), but along with the high cost of flibanserin remain noted barriers to patient use.[1][9]

Guideline Recommendations​

GuidelinePosition
ACOG 2019 (Practice Bulletin 213)[9]Flibanserin can be considered for HSDD in premenopausal women without depression who are appropriately counseled about alcohol risks; evidence quality is "very low" and benefits are minimal.
AAFP 2025 (Dalrymple)[10]Psychological interventions (CBT, mindfulness-based therapy, sex therapy) are recommended first-line for disorders of sexual desire and arousal; 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.

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, ideally avoid alcohol for the rest of the night after dosing.
  • Onset of action is gradual — allow 8 weeks of daily use before assessing response.
  • Set realistic expectations regarding the modest +0.49 SSE/month effect size vs placebo.
  • Re-screen for medical / psychiatric / relational causes if no response by 8 weeks; discontinue if no benefit at 8 weeks per the FDA label.
  • Screen for moderate / strong CYP3A4 inhibitors and hepatic impairment at every refill — both are contraindications.
  • Discuss first-line psychological interventions (CBT, mindfulness, sex therapy, couples therapy) before or alongside pharmacotherapy.
  • 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. US Food and Drug Administration; 2025.

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.