Addyi (Flibanserin) in Adults 65 and Older: What Geriatric Off-Label Use Actually Means

What Is Flibanserin and Why Is Geriatric Use Considered Off-Label?

Flibanserin (brand name Addyi) received FDA approval on August 18, 2015, specifically for premenopausal women diagnosed with acquired, generalized hypoactive sexual desire disorder (HSDD). The FDA label states this indication explicitly and excludes postmenopausal women and men from the approved population. [1] Any prescribing to a patient aged 65 or older therefore falls outside the approved labeling and constitutes off-label use.

Off-label prescribing is legal and common in clinical medicine, but it transfers additional responsibility to the prescriber. The FDA requires flibanserin to be dispensed only through the Addyi REMS (Risk Evaluation and Mitigation Strategy) program, which mandates prescriber certification, patient counseling on alcohol avoidance, and pharmacy enrollment. [1] This REMS requirement applies regardless of age or menopausal status.

How Flibanserin Works

Flibanserin acts as a serotonin 1A receptor agonist and serotonin 2A receptor antagonist in the central nervous system. Unlike sildenafil or testosterone, it targets neurotransmitter pathways rather than vascular or hormonal ones. [2] The proposed mechanism is modulation of excitatory dopamine and norepinephrine signaling alongside inhibition of serotonin, shifting the balance toward desire-facilitating pathways.

Why the Geriatric Population Was Not Studied

The three key Phase 3 trials that supported FDA approval (BEGONIA, DAISY, and VIOLET) enrolled premenopausal women between approximately 22 and 50 years of age. [3] None included a dedicated geriatric cohort. FDA reviewers noted the absence of pharmacokinetic or efficacy data in adults 65 and older during the 2015 advisory committee review. The FDA label includes no dose adjustment recommendation for older adults simply because no geriatric trial data exist on which to base one.

Pharmacokinetics in Older Adults: What Changes With Age

Age-related physiological changes alter how nearly every drug behaves in the body. Flibanserin's pharmacokinetic profile raises specific concerns in this population.

Hepatic Metabolism and CYP3A4

Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, CYP2C19. [4] Hepatic blood flow and CYP enzyme activity both decline with age, typically by 20 to 40 percent between ages 20 and 70. [5] Because flibanserin is already contraindicated in patients with any degree of hepatic impairment, age-related reductions in hepatic clearance compound this concern even in patients without diagnosed liver disease.

Co-administration with moderate or strong CYP3A4 inhibitors (including fluconazole, ketoconazole, and many macrolide antibiotics) is contraindicated in the FDA label due to an up to 7-fold increase in flibanserin plasma exposure. [1] Adults 65 and older are more likely to be taking one or more of these inhibitors as part of existing regimens.

Volume of Distribution and Protein Binding

Older adults typically carry a higher proportion of body fat relative to lean mass, which can increase the volume of distribution for lipophilic drugs. Flibanserin is approximately 98 percent protein-bound, primarily to albumin. [4] Age-associated hypoalbuminemia, which occurs in roughly 20 percent of community-dwelling adults over 70, [6] may increase the fraction of unbound drug, potentially intensifying both therapeutic and adverse effects.

CNS Sensitivity

Age-related changes in blood-brain barrier permeability and receptor density amplify CNS drug effects in older patients. Flibanserin carries a boxed warning for somnolence and sedation even in the approved premenopausal population. [1] In geriatric patients, this risk compounds with other CNS-active agents common in this age group, including benzodiazepines, opioids, antiepileptics, and first-generation antihistamines.

Hypotension and Syncope Risk: The Most Serious Geriatric Concern

Orthostatic hypotension is one of the most consequential drug-related harms in adults 65 and older. Falls from syncope or near-syncope account for significant morbidity in this group. The CDC estimates that falls are the leading cause of injury-related death in adults 65 and older, with approximately 36 million falls reported annually in the United States. [7]

Flibanserin carries a boxed warning for severe hypotension and syncope. [1] In the key trials, hypotension occurred in 0.2 percent of flibanserin-treated premenopausal patients versus 0.0 percent of placebo recipients when alcohol was avoided. With alcohol co-ingestion, rates rose sharply. In a dedicated alcohol interaction study, 4 of 23 participants (17 percent) experienced hypotension and 2 experienced syncope after consuming approximately 2 to 3 standard drinks while taking flibanserin. [1]

Polypharmacy and Additive Hypotension

Older adults frequently take antihypertensives, alpha-blockers for benign prostatic hyperplasia, or nitrates for cardiovascular disease. Each of these can compound flibanserin's hypotensive effect. The 2023 American Geriatrics Society Beers Criteria do not currently list flibanserin specifically, but the general principle of avoiding CNS-active agents with hypotension potential in older adults applies. [8] A prescriber adding flibanserin to a regimen that already includes an ACE inhibitor, a diuretic, and a calcium channel blocker faces an interaction profile that has not been studied in any clinical trial.

Timing of Peak Exposure

Flibanserin is taken at bedtime specifically because peak plasma concentrations coincide with sleep, reducing the window of active hypotension and sedation risk. However, nocturia is common in older adults, and rising from bed during peak drug effect could precipitate a fall. Patients 65 and older who void once or more nightly represent a clinically distinct risk group for this reason.

The Small Evidence Base for Postmenopausal and Older Women

No randomized controlled trial has evaluated flibanserin specifically in women 65 and older. One small open-label pilot study examined flibanserin in postmenopausal women with HSDD and reported modest improvements in desire scores on the Female Sexual Function Index (FSFI), but the study was underpowered, lacked a placebo arm, and has not been replicated in a larger trial. [9]

The key BEGONIA trial (N=949) demonstrated that flibanserin 100 mg at bedtime increased satisfying sexual events by approximately 0.5 events per month over placebo at 24 weeks in premenopausal women (P<0.001). [3] DAISY and VIOLET produced similar effect sizes. None enrolled postmenopausal participants, and no subgroup analysis stratified patients by proximity to age 65.

The table below summarizes the evidence gap across age groups.

| Population | Randomized Trial Data | Regulatory Approval | |---|---|---| | Premenopausal women (approx. 22-50) | Yes (BEGONIA, DAISY, VIOLET, N>2,000 total) | Yes (FDA 2015) | | Postmenopausal women (51-64) | One small open-label pilot [9] | No | | Adults 65 and older | None | No | | Men (any age) | None | No |

A 2016 systematic review published in the Journal of Sexual Medicine examined all available flibanserin data and concluded that evidence for use outside the approved indication "remains insufficient to support clinical recommendations." [10]

HSDD in Older Women: The Condition Itself

HSDD is defined as persistently low sexual desire that causes personal distress, not explained by another medical condition, relationship factor, or medication effect. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) uses the broader category of Female Sexual Interest/Arousal Disorder (FSIAD). [11]

Prevalence in Older Adults

A nationally representative survey found that 43 percent of women aged 57 to 85 reported at least one sexual problem, with low desire being the most common, reported by 39 percent of sexually active women in that age range. [12] Distress about low desire, required for an HSDD diagnosis, was reported less frequently, particularly in older age groups. Clinicians should confirm that distress is present before considering any pharmacological treatment.

Differential Diagnosis Before Prescribing

Multiple conditions common in adults 65 and older mimic or contribute to HSDD. These include genitourinary syndrome of menopause (GSM), depression, hypothyroidism, diabetes-related neuropathy, cardiovascular disease, partner dysfunction, and medication side effects from SSRIs, antihypertensives, or opioids. [13] Treating an underlying cause often resolves low desire without adding another drug.

The Endocrine Society's 2019 clinical practice guideline on female sexual dysfunction states: "We recommend evaluating for and treating contributing medical, psychiatric, and relationship factors before initiating pharmacological therapy for HSDD." [14]

Non-Pharmacological Options

Cognitive behavioral therapy (CBT) and mindfulness-based sex therapy have demonstrated efficacy in multiple randomized trials for low sexual desire in women across age groups. A 2020 Cochrane review of psychological interventions for female sexual dysfunction found moderate-quality evidence supporting CBT for desire concerns. [15] For older adults where drug interactions and fall risk are real concerns, non-pharmacological approaches merit prioritization.

Drug Interactions Particularly Relevant in Patients 65 and Older

Flibanserin's interaction profile is extensive. The FDA label lists contraindications with moderate and strong CYP3A4 inhibitors and strong CYP2C19 inhibitors, and warns against co-use with alcohol, CNS depressants, and drugs that lower blood pressure. [1]

Common Geriatric Medications That Interact

The following drug classes appear frequently in geriatric polypharmacy and carry interaction signals with flibanserin:

• Azole antifungals (fluconazole, itraconazole): strong CYP3A4 inhibitors, contraindicated with flibanserin; fluconazole for recurrent vulvovaginal candidiasis is common in older women.
• Macrolide antibiotics (clarithromycin, erythromycin): moderate-to-strong CYP3A4 inhibitors, contraindicated during flibanserin use.
• SSRIs and SNRIs: not contraindicated but may add CNS depressant effect and complicate interpretation of desire symptoms.
• Alpha-1 blockers (tamsulosin, doxazosin, terazosin): used for urinary symptoms in older men and women; additive hypotension risk is clinically significant.
• Benzodiazepines and Z-drugs: additive sedation; both flibanserin and these agents increase fall risk independently.
• Grapefruit juice: inhibits CYP3A4 intestinally; patients should be counseled to avoid grapefruit during flibanserin use.

A 2022 analysis of Medicare Part D claims found that 68 percent of women aged 65 to 74 filled prescriptions for at least one drug that is a moderate or strong CYP3A4 inhibitor or inducer during a given year. [16] This statistic underscores the practical complexity of prescribing flibanserin in this age group.

Hepatic Impairment: An Absolute Contraindication

The FDA label for flibanserin states clearly that the drug is contraindicated in patients with hepatic impairment of any severity. [1] In clinical pharmacology studies, mild hepatic impairment increased flibanserin AUC by approximately 4.5-fold. Hepatic impairment prevalence rises with age; nonalcoholic fatty liver disease (NAFLD) affects an estimated 20 to 40 percent of adults over 60 in the United States. [17]

Prescribers considering flibanserin in an older patient should obtain baseline liver function tests and review any history of alcohol use disorder, hepatitis B or C, or metabolic-associated steatotic liver disease. Abnormal transaminases at any level are a contraindication to prescribing.

The REMS Program: Requirements That Apply to All Patients

The Addyi REMS was established because FDA determined that the drug's benefits are outweighed by risks without specific safeguards. [1] Requirements include:

1. Prescribers must complete a certified training module and enroll in the program.
2. Patients must receive a medication guide and counseling about alcohol avoidance and hypotension risk before the first prescription is dispensed.
3. Pharmacies must be REMS-enrolled to dispense the drug.

These requirements do not change for older patients. A prescriber writing an off-label prescription for a 68-year-old patient must still complete REMS certification and provide the required counseling. The REMS program does not address geriatric-specific risks because it was designed for the approved population, which means the counseling content does not specifically mention fall risk, polypharmacy, or hepatic age-changes. Prescribers must supplement the standard REMS counseling with age-specific safety discussions.

Clinical Decision-Making Framework for Older Patients

When a patient 65 or older presents with concerns about low sexual desire, flibanserin should be one of the last options considered rather than an early intervention. A reasonable clinical sequence includes:

Step 1: Rule Out Reversible Causes

Screen for GSM, thyroid dysfunction, depression, uncontrolled diabetes, and desire-suppressing medications (particularly SSRIs, opioids, and antiandrogens). Treating these conditions first may fully resolve the complaint.

Step 2: Assess Baseline Cardiovascular and Hepatic Risk

Obtain a medication reconciliation covering all prescription, over-the-counter, and herbal products. Check liver function tests. Document baseline blood pressure and assess orthostatic changes. Patients on any moderate or strong CYP3A4 inhibitor cannot receive flibanserin.

Step 3: Offer Non-Pharmacological Therapy

Refer to a certified sex therapist or psychologist with experience in CBT for sexual dysfunction. A course of mindfulness-based sex therapy typically spans 8 to 12 weekly sessions. Evidence supports efficacy comparable to pharmacological approaches in some populations. [15]

Step 4: Consider Ospemifene or Low-Dose Vaginal Estrogen First

For older women where GSM contributes to desire problems, FDA-approved options for postmenopausal women include ospemifene (Osphena) 60 mg daily and low-dose vaginal estrogen (estradiol cream, ring, or tablet). These have established efficacy and safety data in older women and address a common contributing factor flibanserin does not touch.

Step 5: If Flibanserin Is Still Being Considered

The prescriber should document: confirmed HSDD diagnosis with personal distress, failure or contraindication of non-pharmacological and first-line pharmacological options, absence of CYP3A4 inhibitors from the medication list, normal liver function, confirmed ability of the patient to abstain from alcohol, and a fall-risk assessment. A shared decision-making discussion should cover the absence of clinical trial data in this age group.

What Prescribers and Patients Should Know About Absolute Alcohol Restriction

Alcohol restriction is non-negotiable with flibanserin. [1] In the alcohol interaction study, the combination produced severe hypotension in a young, otherwise healthy population. In older adults with reduced baroreflex sensitivity, the risk of losing consciousness after drinking while on flibanserin is likely higher, though this specific population was never studied.

Alcohol consumption is common in adults over 65. The National Institute on Alcohol Abuse and Alcoholism (NIAAA) reports that approximately 40 percent of adults 65 and older drink alcohol at least occasionally. [18] A prescriber must assess drinking habits directly and honestly before prescribing. Patients who drink socially, even occasionally, are not candidates for flibanserin.

Monitoring If Flibanserin Is Prescribed Off-Label in an Older Patient

A prescriber who proceeds with flibanserin in an older patient after exhausting the above alternatives should establish a monitoring plan:

• Blood pressure check at baseline and at the 4-week follow-up, both seated and standing (orthostatic protocol)
• Repeat liver function tests at 3 months
• Fall-risk reassessment at each visit using a validated tool such as the Timed Up and Go (TUG) test
• Medication reconciliation at every visit to catch newly added CYP3A4 inhibitors
• Documented patient re-counseling about alcohol avoidance at each prescription renewal

The FDA label states that flibanserin should be discontinued if no improvement in symptoms occurs within 8 weeks of initiating treatment. [1] This timeline applies to off-label use as well, and continued prescribing beyond 8 weeks without documented response is difficult to justify clinically in any population.