Taking Sides: Should ob/gyns prescribe flibanserin for their patients?

Yes. It is effective for many women with hypoactive sexual desire.

By Holly L Thacker, MD

Dr Thacker is Professor and Director, Center for Specialized Women’s Health at Cleveland Clinic, Ohio, and Executive Director of Speaking of Women’s Health.

Sexual concerns are common in women and ob/gyns are in the best position to advise them about these problems. Until recently, physicians and their female patients have had only unregulated or unapproved and/or off-label treatment options with unclear benefit/risks ratios for sexual concerns. In 2015, the Food and Drug Administration (FDA) approved flibanserin as a first-in-class medication for hypoactive sexual desire disorder (HSDD), based on results from 3 pivotal trials.

When your patients have symptoms of HSDD, what do you do? Are you “certified” to prescribe flibanserin? If you are not yet certified, I believe you should be. After excluding medical, psychological and relationship problems, and medication side effects, I do not hesitate to prescribe flibanserin 100 mg at bedtime to appropriate patients in my practice. It has been studied in and proven to work in both premenopausal and postmenopausal women² although it is currently only FDA-approved for pre-menopausal women. It works for a good number of patients, that is, at least 50% have a meaningful response.

Flibanserin was initially studied as an antidepressant (with effects on depression similar to paroxetine) and the finding that it improved sexual desire was serendipitous. It is a 5-hydroxytryptophan (1A) receptor agonist and 5-hydroxytryptophan (2A) receptor antagonist that restores sexual desire by rebalancing brain chemistry. It is not an aphrodisiac and must be taken over time to be effective.

Many FDA-approved medications such as sildenafil approved for male erectile dysfunction, ospemifene approved for vulvovaginal atrophy and dyspareunia, and flibanserin approved for HSDD were initially studied for other conditions (cardiac indications, osteoporosis, and depression, respectively) and found to have advantageous sexual side effects.

In cases in which flibanserin (Addyi) fails to improve sex drive after 2 months, it can be abruptly discontinued without harm. The discontinuation rate of 12%–13% based on central nervous system (CNS) side effects is in line with that of other drugs affecting the CNS. Data from the pivotal trials with bedtime dosing showed that approximately 11% of flibanserin-treated women experienced somnolence and/or dizziness compared to the 2%–3% of placebo controls.¹

Flibanserin’s side effects-dizziness, hypotension, and somnolence-are also in line with many CNS antidepressants that we prescribe to women for conditions that include depression, anxiety, and premenstrual dysphoric disorder, with which ob/gyn physicians are already familiar. These risks can be reduced by taking the medicine at night and avoiding alcohol, which can raise flibanserin blood levels.

A recent article in JAMA Internal Medicine may cause some physicians to think twice about prescribing this drug, which is the only FDA-approved medication for women with HSDD. I find fault with both the biased meta-analysis³ and the biased editorial⁴ by an anti-pharma husband-and-wife couple, who took the FDA to task for approving the medication after its third submission.

I question the JAMA editorial staff as to why the meta-analysis³ was not more carefully vetted before being accepted for publication, particularly when a 2015 meta-analysis of all randomized, double-blind, placebo-controlled studies of flibanserin showed it to be effective in the treatment of HSDD.¹ In all 4 trials, flibanserin was superior to placebo in increasing satisfying sexual events (SSEs), sexual desire scores, and ratings on the Female Sexual Function Index. The proportion of women who experienced an adverse event, nervous system disorder, or fatigue indicated that flibanserin was well tolerated.

The JAMA analysis misleadingly concluded that flibanserin increased SSEs by an average of only 0.49 per month, therefore concluding that its effects were weak and outweighed by adverse effects of dizziness and somnolence. Their meta-analysis included dosing studies using the ineffective lower doses of 25 mg and 50 mg, diluting the results.

Using the FDA-required tool of SSE for women is an issue and important for women’s health clinicians to understand when reviewing the clinical trials and the history of delayed approval of flibanserin.⁵

Using SSE is a carryover from the FDA’s approval process for PDE5 inhibitors (like sildenafil), which specified that a man with significant erectile dysfunction cannot have an SSE without an erection. Clearly, women can and do have sexual events whether interested or not. (Some women have referred to this as “duty sex.”) These events were reported to happen 2.5 times a month in the flibanserin trials. This raises the baseline creating a ceiling effect on SSEs (2.5 at baseline + placebo effect +flibanserin effect = about 6 times per month.)

Interestingly and importantly, women who responded to flibanserin had on average 2.5 to 4 additional SSEs per month when compared to placebo and one quarter of the responders had more than 4 additional SSEs per month.

Also when interpreting a mean increase of “one extra sexually satisfying event per month,” perspective is vital and a woman will be able to assess that herself. For the most part, the women enrolled in the trials were very healthy and in long-standing committed relationships with higher-than-average rates of SSEs at baseline.

At least 50% of women have a self-reported meaningful response to flibanserin and those who do not respond can stop therapy. Furthermore, the adverse effects of dizziness, hypotension, and somnolence can be reduced by taking the medicine at night and avoiding alcohol, which can raise flibanserin blood levels.

The JAMA editorial incorrectly stated that flibanserin carries a “black box warning.” Rather, it carries a boxed warning that using the drug with alcohol increases the risk of hypotension and syncope because it is processed through the cytochrome CYP3A4 pathway, as are antifungal medications taken for vaginal yeast infections.

In contrast to the alcohol challenge study, in the pivotal clinical trials on flibanserin, approximately 60% of women studied admitted to social alcohol use. Therefore, the FDA required a somewhat contrived additional alcohol challenge study that led to the development of a Risk Evaluation and Mitigation Strategy (REMS) program in order for certified physicians to prescribe and for certified pharmacists to dispense the drug.

To prescribe flibanserin, a physician must answer 4 simple questions online. The site with training and materials is: https://www.addyirems.com/AddyiUI/rems/home.action. As in the case of any drug, flibanserin must be used wisely.⁶ Its use with multiple weak CYP3A4 inhibitors (for example, oral contraceptives, cimetidine, fluoxetine, ginkgo, and ranitidine) may increase flibanserin exposure. Its use with strong CYP2C19 inhibitors (including proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals) may increase flibanserin levels.

On the other hand, using flibanserin with CYP3A4 inducers (carbamazepine, phenobarbital, phenytoin, rifabutin and rifampin) will decrease flibanserin levels. Digoxin levels may be increased if used concomitantly. Watch closely for excessive sedation when flibanserin is used with CNS depressants such as diphenhydramine, opioids, hypnotics, and benzodiazepines. Simvastatin levels may be increased by a factor of 1.5.

During a woman’s annual visit, clinicians may want to use a simple office screener, the Decreased Sexual Desire Screener,⁷ in practice or simply inquire about sexual function and sexual concerns. Not all women with sexual dysfunction are candidates for flibanserin; however many are and with shared decision-making, it is an excellent option for otherwise healthy women with HSDD. The bottom line is that flibanserin 100 mg daily taken orally at bedtime is an effective therapeutic option for women with HSDD.

Dr Thacker has no conflicts of interest to report in respect to the content of this article.

References

1. Gao Z, Yang D, Yu L, Cui Y. The efficacy and safety of flibanserin in women with HSDD: A systemic review and meta-anaylsis. J Sex Med. 2015;12:2095–2104.

2. Simon JA, Kingsberg SA, Shumel B, et al. Efficacy and safety of flibanserin in postmenopausal women with HSDD: results of the SNOWDROP trial. Menopause. 2014;21(6):633–640.

3. Jaspers L, Feys F, Bramer W, et al. Efficacy and safety of Flibanserin for the treatment of HSDD in women. A systemic review and meta-analysis. JAMA Intern Med. 2016;176(4):453–462.

4. Woloshin S, Schwartz LM. US FDA Approval of Flibanserin: Even the Score does not add up. JAMA Intern Med. 2016;176(4):439–442.

5. Joff JV, Chang C, Sewell C, et al. FDA Approval of Flibanserin-Treating HSDD. NEJM. 2016:374;2:101–104.

6. Flibanserin (Addyi) for HSDD. Med Lett Drugs Ther. Sept 28, 2015:1478;133–135.

7. Clayton AH, Goldfischer ER, Goldstein I, et al. Validation of the decreased sexual desire screener (DSDS): a brief diagnostic instrument for generalized acquired female HSDD. J Sex Med. 2009;6:730–738.

No. It is neither effective nor safe.

By Adriane Fugh-Berman, MD, and Alessandra Hirsch, MS

Dr Fugh-Berman is Associate Professor, Dept. of Pharmacology and Physiology, Georgetown University Medical Center, Washington, DC.

Ms Hirsch is a medical student at the University of Illinois Medical School, Chicago.

The world of women’s health saw a contentious, controversial, and politically charged drug approval process last year: that of flibanserin, a drug to treat low libido in premenopausal women. Is this pill “a milestone … a breakthrough,” as important as the birth control pill, as stated by Sally Greenberg, the executive director of the National Consumers League?¹ Or is it rather “a mediocre aphrodisiac with scary side effects?”² Women have voted on this question with their feet. In the first 10 weeks the drug was on the market, only 1841 prescriptions were sold.³

Physicians who care about data should join the many women who have stayed away from the drug despite the hype. In our opinion, flibanserin is not very effective, not very safe, and should not be prescribed.

A mixed serotonin receptor agonist/antagonist that also has weak partial agonist effects on dopamine levels, flibanserin’s precise mechanism of action is unknown. What is known is that flibanserin is, at best, minimally effective. A recent meta-analysis and systematic review of 8 trials of flibanserin in 5914 women indicates that “sexually satisfying events” (which need include neither partner nor orgasm) increased by less than one-half event per month over placebo.⁴ While half an event a month might be worthwhile for a woman having no events, women in the clinical trials were not starting at zero; they were already having 2–3 sexually satisfying events per month at baseline.⁵ One trial participant was having 34 sexually satisfying events per month.⁶

Company-sponsored key opinion leaders downplay the importance of sexually satisfying events, suggesting that even if women are enjoying sex, they still “want to want.” This shows a misunderstanding of women’s sexuality. Many women have responsive rather than spontaneous desire; ie, desire follows arousal. Recognition of this entirely normal state is why hypoactive sexual desire disorder (HSDD), the condition flibanserin was approved to treat, is no longer in the Diagnostic and Statistical Manual of Mental Disorders (DSM), published by the American Psychiatric Association; it’s been replaced with female sexual interest/arousal disorder (FSI/AD). Lack of receptivity to sexual initiation or arousal in response to appropriate stimuli is necessary for diagnosis.⁷

Compared to placebo groups, only 9%–15% more subjects in the flibanserin group experienced any improvement in libido at all.⁸ It is unclear whether flibanserin actually has any specific effect on libido. The drug is highly sedating and sedation may increase receptivity, not to mention alter recall of events. Also, sleeping better can improve one’s sex life. While such paltry benefits might be acceptable in a risk-free drug, flibanserin can cause serious adverse effects, including unpredictable hypotension and sudden, prolonged unconsciousness. These events are not limited to the first dose-or even the first few weeks⁸-and there is no evidence that women become tolerant to the drug’s adverse effects. 

Besides sudden prolonged unconsciousness and severe hypotension, flibanserin causes dizziness, somnolence, nausea, and fatigue. One in 5 subjects (21%) in clinical trials experienced symptoms consistent with CNS depression. Accidental injuries associated with CNS depression occurred more than twice as often in flibanserin-treated patients as in placebo-treated patients.⁸

When flibanserin is combined with alcohol or many common drugs, the risk/benefit ratio gets worse. Concerned about evidence that alcohol increases adverse events, the FDA requested that the manufacturer perform an alcohol interaction study.⁸ Stunningly, Sprout Pharmaceuticals performed the study in 25 subjects-only 2 of whom were women. Implausibly to us, Sprout representatives claimed that they could find no women eligible for the study, which required a baseline alcohol intake of 5 drinks per week.⁶ Men are less susceptible to alcohol than women, which makes these findings even more problematic. Four (17%) of the participants who mixed the currently approved 100-mg dose of flibanserin with the equivalent of 2 drinks experienced hypotension or syncope. Systolic blood pressure levels dropped by up to 46 mmHg. A quarter of the subjects (6 of 24) who took flibanserin 100 mg with the equivalent of 4 drinks experienced orthostatic hypotension.⁸

Many young women (the drug is approved for premenopausal women only) consume alcohol, and no level of alcohol has been deemed safe in combination with flibanserin. But even in nondrinkers the drug may not always be safe, as other drug interactions can occur. Flibanserin’s boxed warning cautions not only against consuming the drug with alcohol, but also consuming it with CYP3A4 inhibitors, or in the context of hepatic impairment.⁵

Adverse effects are exacerbated by oral contraceptives (OCs), antifungals, triptans, and many other drugs. The maximum tolerated dose of flibanserin is 250 mg-quite close to the 100 mg/day recommended dose,⁸ and especially problematic when one considers that many common drugs increase flibanserin levels. Oral contraceptives increase flibanserin levels 42%. Triptans increase flibanserin 4.5-fold. An interaction study that combined fluconazole with flibanserin had to be stopped after every one of the first 15 subjects experienced adverse effects. Three subjects in this study experienced syncope or drastic drops in blood pressure, with diastolic readings in the 40s.⁸

Many other potentially dangerous interactions are to be expected. Flibanserin is metabolized by cytochrome P450 enzyme CYP3A4. Besides ketoconazole and fluconazole, inhibitors include clarithromycin, telithromycin, many antivirals, and grapefruit juice. Flibanserin is also metabolized by CYP2C19, which is inhibited by many common antidepressants, anticonvulsants, and proton pump inhibitors. Also, up to 15% of Asians and up to 5% of Caucasians have low levels of this enzyme, and so may be exposed to double the levels of flibanserin even without the addition of an interacting drug.⁸

Flibanserin increased digoxin levels 81%; all 24 subjects in a flibanserin/digoxin interaction study experienced a drug-related adverse effect, 2 of which were serious.⁸ Digoxin is metabolized by p-glycoprotein, rather than CYP enzymes, so interactions can be expected with other drugs metabolized by p-glycoprotein, including loperamide, dabigatran, protease inhibitors, cyclosporine, calcium channel blockers, and many others.⁹ In fact, the drug label for Addyi lists more than 40 drugs causing clinically significant interactions with flibanserin, including diphenhydramine, opioids, erythromycin, benzodiazepines, antifungals, carbamazepine, phenobarbital, and rifampin.⁶

Flibanserin was tested on highly selected, healthy populations who were not taking most of the drugs listed above. Thus, in the general population, the adverse effects of flibanserin can be expected to be much worse. At a recent meeting of the American College of Obstetricians and Gynecologists (ACOG), flibanserin supporters emphasized that it was an effective drug for certain people under certain circumstances. But who exactly would that be? The ideal flibanserin patient would be premenopausal, non-Asian, perfectly healthy, and in a long-term, heterosexual, happy relationship with a sexually functional partner. She would have a mysteriously diminished sex drive that is not due to disease, medication, surgery, relationship problems, boredom, fatigue, or stress and that is unresponsive to psychosexual therapy; she would not be pregnant, intending to become pregnant, or nursing; and she would be willing to forgo alcohol, OCs, grapefruit juice, yeast medications, migraine medications, and most other drugs.

Even then, she may suddenly pass out. In the FDA’s words, “no risk management strategy will eliminate the risks of hypotension/syncope associated with flibanserin use alone ... .”⁸

Women are not lining up to take this dangerous drug. At the ACOG meeting this year, 55% of about 200 attendees at a debate on prescribing flibanserin stated that they’d never been asked about the drug. Physicians are not lining up to champion the drug either. Fewer than 1% of ob/gyns have taken the Risk Evaluation and Mitigation Strategy program to become certified prescribers.¹⁰

The narrow margin of safety of flibanserin is unacceptable in a drug given to healthy women, especially for a condition that is effectively treated by a safe, accepted therapy. The occurrence of adverse effects in premenopausal healthy women is disturbing enough, but the potential off-label use of this drug in postmenopausal women can only be expected to cause a higher rate of adverse events.

Luckily, women and many ob/gyns have seen through the hype. We believe flibanserin is a bad drug. Don’t prescribe it.

Neither Dr Fugh-Berman nor Ms Hirsch has a conflict of interest to report in respect to the content of this article.

References

Foshay K. Is the little pink pill pitting science against gender politics? America Tonight (Al-Jazeera). http://america.aljazeera.com/watch/shows/america-tonight/articles/2015/6/12/little-pink-pill-viagra-women-gender-politics-flibanserin.html.

Pollack A. ‘Viagra for women’ is backed by an FDA panel. The New York Times. http://www.nytimes.com/2015/06/05/business/panel-backs-a-drug-to-increase-womens-sex-drive.html.

McCullough M. Little desire for women's sex drug. Philly.com. http://articles.philly.com/2015-12-21/news/69189387_1_low-libido-intrinsa-libigel.

Jaspers L, Feys F, Bramer WM, Franco OH, Leusink P, Laan ET. 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.

Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals; 2015.

U.S. Food and Drug Association. June 4, 2015 Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee Meeting [Transcript]. 2015.

Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. American Psychiatric Association, Washington DC , 2013 Female Sexual Interest/Arousal Disorder 302.72 (F52.22)

U.S. Food and Drug Administration. 2015 June 4. Joint Meeting of the Bone, Reproductive and Urologic Drugs Advisory Committee (BRUDAC) and the Drug Safety and Risk Management (DSaRM) Advisory Committee Briefing Document.

Finch A, Pillans P. P-glycoprotein and its role in drug-drug interactions. Aust Prescr. 2014;37:137–139.

Edney A, Colby L. The female libido pill is no Viagra. Bloomberg News.. http://www.bloomberg.com/news/articles/2015-11-17/valeant-s-newest-problem-the-female-libido-pill-isn-t-selling.

Simon JA, Dhanuka I. Flibanserin for postmenopausal women-Are they really that different? Maturitas. 2015;82(4):325–327.

Simon JA, Kingsberg SA, Shumel B, Hanes V, Garcia M Jr, Sand M. Efficacy and safety of flibanserin in postmenopausal women with hypoactive sexual desire disorder: results of the SNOWDROP trial. Menopause. 2014;21(6):633–640.