Flibanserin: A controversial drug for female hypoactive sexual desire disorder.

Sexual functioning is an integral part of human life. Female sexual dysfunction (FSD) adversely affects quality of life and general well-being. The Food and Drug Administration recently approved flibanserin, for treatment of female hypoactive sexual desire disorder (HSDD), regarded as the most common FSD, amid great controversy. A novel multifunctional serotonin agonist and antagonist, flibanserin, has been shown to be efficacious in treating HSDD but with a rather tenacious side effect profile. We review this interesting drug in its entirety. Data for the article were collected by reviewing articles on PubMed, the drug (Addyi) website, and related websites on the internet.

Sexual functioning is an integral part of human life and has been shown in research to be important to both men and women[1] In the Study of Women's Health across the Nation, more than 75% of women reported sex to be moderately to extremely important.[2]

Around 43% of women report sexual problems with 22.2% reporting sexually related personal distress.[3] Hypoactive sexual desire disorder (HSDD) has been regarded to be the most common female sexual dysfunction (FSD) and affects nearly 1 in 10 women.[45] It is a persistent or recurrent absence of deficiency of sexual desire or receptivity to sexual activity that causes marked distress or interpersonal difficulty.[6] For a diagnosis of HSDD, the desire problem must not be better accounted for by another psychiatric disorder such as depression, substance abuse, or medical condition.[7] Not only does FSD negatively affect health-related quality of life but also general well-being.[89]

HSDD was removed from the fifth edition of Diagnostic and Statistical Manual of Mental Disorder (DSM-V). Its symptoms were established as a criterion for female sexual interest/arousal disorder. However, ACOG recognizes HSDD as a separate entity.[6]

Originally developed as an antidepressant, with a potentially rapid onset of action, flibanserin was approved by the Food and Drug Administration (FDA) for HSDD in August 2015 despite the removal of HSDD from DSM-V.[1011] The approval came with the caveat that the drug be dispensed through a special risk management program. It is the first FDA-approved drug for treatment of premenopausal women with acquired, generalized HSDD. We review this drug in its entirety, controversies surrounding its approval, dosage, pharmacokinetics, indications, adverse effects, and contraindications.

MECHANISM OF ACTION

Flibanserin is a novel multifunctional serotonin agonist and antagonist.[12]

Libido is positively regulated by synaptic dopamine and also other microcircuits where norepinephrine, testosterone, and estrogen act. Libido is negatively modulated by microcircuits where prolactin and serotonin act.[121314] It implies relative deficiency of microcircuit dopamine and norepinephrine, or a relative excess of microcircuit serotonin can lead to disorder of sexual interest and desire.

Flibanserin has two principal pharmacological actions in neural microcircuits: it acts as a full agonist at postsynaptic 5HT1A receptors and an antagonist at postsynaptic 5HT2A receptors.[1215] Exclusive binding at these receptors differentiates flibanserin from buspirone and bupropion.[4] This action in the prefrontal cortex causes the downstream release of dopamine and norepinephrine and reduction of serotonin, consistent with sites of abnormal neuroimaging described in patients with reduced sexual interest and desire.[121617] Flibanserin acts selectively on pyramidal neurons that excite brainstem 5HT neurons yet also selectively on pyramidal neurons that inhibit brainstem Norepinephrine and Dopamine neurons.[15]

PHARMACOKINETICS

Flibanserin shows linear and dose proportional kinetics following a single oral dose (5–150 mg) and multiple oral doses (total daily dose ranging from 60 to 300 mg).[4] It is 90% absorbed and has mean half-life of ~ 11 h. With mild hepatic impairment, half-life increases to 26 h. Taking the drug with food increases its absorption. It has 98% protein binding, primarily to albumin. Its oral bioavailability is 33%.[18] Steady state of flibanserin is achieved only after 3 days of dosing and so it is incorrect to call it “female Viagra” because Viagra is used as needed.[19]

Flibanserin undergoes oxidative metabolism by CYP3A4 and to a lesser extent by CYP2D6 cytochrome P450 isoenzymes. Concomitant CYP3A4 inhibitors may increase flibanserin exposure and are contraindicated. Flibanserin may be used 2 weeks after the last dose of a moderate or strong CYP3A4 inhibitor. A moderate or strong CYP3A4 inhibitor may be initiated 2 days after the last dose of flibanserin. Strong CYP3A4 inhibitors include ketoconazole, itraconazole, clarithromycin, nefazodone, ritonavir, indinavir, and conivaptan. Moderate CYP3A4 inhibitors include atazanavir, ciprofloxacin, diltiazem, verapamil, erythromycin, fluconazole, and grapefruit juice. Weak CYP3A4 inhibitors such as oral contraceptive pills, cimetidine, fluoxetine, Ginkgo biloba, and ranitidine may be associated with increased risk for hypotension, syncope, and central nervous system (CNS) depression.[1819]

Furthermore, CYP3A4 inducers can substantially reduce flibanserin concentrations and are not recommended with it. These include etravirine, carbamazepine, phenobarbital, phenytoin, rifampin, and St. John's wort.[19]

The use of flibanserin in patients who are CYP2C19 poor metabolizers results in increased flibanserin concentrations and may increase the risk of hypotension and syncope. These patients should be closely monitored for adverse reactions. These include drugs such as proton-pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, and antifungals.[19]

Flibanserin inhibits P-glycoprotein. Increased monitoring of concentrations of drugs transported by P-glycoprotein that have a narrow therapeutic index such as digoxin and sirolimus is indicated.

Flibanserin is excreted mostly through bile and the kidneys as inactive metabolites.[20]

DOSING

100 mg PO once daily at bedtime.[20]

Administration during waking hours increases risk of hypotension, syncope, accidental injury, and depression. It is discontinued after 8 weeks if no improvement occurs.[181920]

In case of missed dose, the patient should take the next dose at bedtime the next day. Doses should not be doubled.

Currently, it is not indicated in postmenopausal women or in men. Neither is it indicated to enhance sexual performance.[20]

CONTRAINDICATIONS

Alcohol use – associated with severe hypotension and syncope

Use of moderate or strong CYP3A4 inhibitors

Hepatic impairment.[1920]

ADVERSE REACTIONS

Flibanserin may cause CNS depression with somnolence and sedation. Fatigue, insomnia, and dry mouth can also occur. Patients should not drive or engage in other activities requiring full alertness until at least 6 h after taking flibanserin. Concomitant use of CNS depressants such as diphenhydramine, opioids, hypnotics, and benzodiazepines may increase this risk.

Flibanserin by itself can cause hypotension and syncope.

Mice studies have shown dose-related increase in the incidence of malignant mammary tumors in female mice at exposures 3 and 10 times the recommended clinical dose. This was not seen in male mice or in male or female rats. However, clinical implications of these findings are unknown at present.[19]

PREGNANCY AND LACTATION

Adverse events were observed in some animal reproduction studies. It should be avoided in pregnancy. Flibanserin is excreted in rat milk. However, human data are not available and it is not recommended during breastfeeding at present.[1920]

CONTROVERSIES PLAGUING FLIBANSERIN

Does HSDD at all exist? Considering that it was no more included as a separate entity in DSM-V, is drug treatment the right way forward?[21]

Is flibanserin safe enough to recommend its use? Safety and adverse effect date of flibanserin are still accumulating. According to meta-analysis by Jaspers et al., premenopausal and postmenopausal women taking flibanserin experienced 0.5 more satisfying sexual encounters a month and scored 0.3 points higher on a 5-point sexual desire scale. They concluded that these modest benefits did not outweigh harms.[202122] According to FDA, flibanserin increased somnolence, sedation, or fatigue compared with placebo: 21% versus 8%![23]

Approval controversy: In 2009, Boehringer Ingelheim applied for approval of flibanserin to treat HSDD in premenopausal women. However, the FDA's clinical reviewers and an external advisory committee voted unanimously against the drug 11-0. This was because the drug was noted to cause substantial somnolence and dangerous interactions with alcohol and other drugs and having failed to improve sexual desire measured with a daily electronic diary. Boehringer sold the rights of flibanserin to Sprout which resubmitted it for FDA approval in 2013 and was rejected yet again. The FDA concluded that only “numerically small treatment differences compared to placebo” were obtained with the drug which “do not clearly outweigh safety concerns.” In 2015, Sprout resubmitted flibanserin to the FDA and the drug was approved. However, the resubmission included no new benefit data! Within 48 h of the FDA approval, flibanserin was sold to Valeant Pharmaceuticals for about billion 1$ in cash[21]

A coalition of women's groups, even the score, had actively campaigned for the drug's approval, emphasizing that several approved drugs for male sexual dysfunction exist but not so for women. Quite ironically, the campaign was managed by blue engine message and media, a public relations firm, and received funding from Sprout.

CONCLUSION

Flibanserin is a controversial drug approved for a controversial disorder amid huge controversy. While it may serve as the lamp in the light in the long search for female sexual problems, it has still a long way to go. Women taking this drug must well be educated about the adverse events associated with this drug and the possible interactions. Until further data are available, a cautious use of the drug is warranted.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.