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

     

    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

    1. 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.

    2. 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-increas....

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

    4. 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.

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

    6. 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.

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

    8. 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.

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

    1. 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-probl....

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

    3. 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.

     

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