What you need to know (and do) to prescribe the new drug flibanserin

11 questions and answers highlight indications, risks, adverse reactions, and requirements for prescribers

Janelle Yates, Senior Editor

t was a long road to approval by the US this meeting did not focus on flibanserin, Food and Drug Administration (FDA), it provided an opportunity for the FDA to I but flibanserin (Addyi) got the nod on hear directly from patients about the impact August 18, 2015. Its New Drug Application of their condition,” Ms. Fischer says. During (NDA) originally was filed October 27, 2009. the second day of the meeting, the FDA “dis- The drug launched October 17, 2015. cussed scientific issues and challenges with Although there has been a lot of fanfare experts in sexual medicine.” about approval of this drug, most of the cov- As a result, by the time of the FDA’s IN THIS ARTICLE erage has focused on its status as the “first June 4, 2015 Advisory Committee meeting on female Viagra”—a less than accurate depic- the flibanserin NDA, FDA physician-scientists How is HSDD tion. For a more realistic and practical assess- were well versed in many nuances of female diagnosed? ment of the drug, OBG Management turned sexual function. That meeting included an page 32 to Michael Krychman, MD, executive director open public hearing “that provided an oppor- of the Southern California Center for Sexual tunity for members of the public, including Health and Survivorship Medicine in Newport patients, to provide input specifically on the What are clinicians Beach, to determine the types of information flibanserin application,” Ms. Fischer notes. required to do? clinicians need to know to begin prescribing page 33 flibanserin. This article highlights 11 questions Nuances of the deliberations (and answers) to help you get started. “The FDA’s regulatory decision making on Is the drug any drug product is a science-based process safe in pregnancy? that carefully weighs each drug in terms of its page 52 1. How did the FDA arrive risks and benefits to the patient population at its approval? for which the drug would be indicated,” says In 2012, the agency determined that female Ms. Fischer. sexual dysfunction was one of 20 disease The challenge in the case of flibanserin areas that warranted focused attention. In was determining whether the drug provides October 2014, as part of its intensified look “clinically meaningful” improvements in sex- at female sexual dysfunction, the FDA con- ual activity and desire. vened a 2-day meeting “to advance our un- “For many conditions and diseases, derstanding,” reports Andrea Fischer, FDA what constitutes ‘clinically meaningful’ is press officer. well known and accepted,” Ms. Fischer notes, “During the first day of the meeting, the “such as when something is cured or a severe FDA solicited patients’ perspectives on their symptom that is life-altering resolves com- condition and its impact on daily life. While pletely. For others, this is not the case. For

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example, a condition that has a wide range were sufficient to demonstrate clinically mean- of degree of severity can offer challenges in ingful improvements with use of the drug. assessing what constitutes a clinically mean- Although the drug was approved by the ingful treatment effect. Ascertaining this re- FDA, the agency was sufficiently concerned quires a comprehensive knowledge of the about some of its potential risks (see ques- disease, affected patient population, man- tions 4 and 5) that it implemented rigorous agement strategies and the drug in question, mitigation strategies (see question 7). Addi- as well as an ability to look at the clinical trial tional investigations were requested by the data taking this all into account.” agency, including drug-drug interaction, al- “In clinical trials, an important method cohol challenge, and driving studies. for assessing the impact of a treatment on a patient’s symptoms, mental state, or func- tional status is through direct self-report 2. What are the indications? using well developed and thoughtfully in- Flibanserin is intended for use in premeno- tegrated patient-reported outcome (PRO) pausal women who have acquired, gener- assessments,” Ms. Fischer says. “PROs can alized hypoactive sexual desire disorder provide valuable information on the patient (HSDD). That diagnosis no longer is includ- perspective when determining whether ben- ed in the 5th edition of the Diagnostic and efits outweigh risks, and they also are used Statistical Manual of Mental Disorders but is to support medical product labeling claims, described in drug package labeling as “low which are a key source of information for sexual desire that causes marked distress or both health care providers and patients. interpersonal difficulty and is not due to: PROs have been and continue to be a high • a coexisting medical or psychiatric condition, priority as part of FDA’s commitment to ad- • problems within the relationship, or vance patient-focused drug development, • the effects of a medication or other drug and we fully expect this to continue. The clin- substance.”1 The FDA was ical trials in the flibanserin NDA all utilized Although the drug has been tested in sufficiently PRO assessments.” both premenopausal and postmenopausal concerned about Those assessments found that patients women, it was approved for use only in pre- some of the drug’s taking flibanserin had a significant increase menopausal women. Also note inclusion of potential risks that in “sexually satisfying events.” Three 24-week the term “acquired” before the diagnosis of it implemented randomized controlled trials explored this HSDD, indicating that the drug is inappropri- endpoint for flibanserin (studies 1–3). ate for women who have never experienced a rigorous mitigation As for improvements in desire, the first period of normal sexual desire. strategies 2 trials utilized an e-diary to assess this aspect of sexual function, while the 3rd trial utilized the Female Sexual Function Index (FSFI). 3. How is HSDD diagnosed? Although the e-diary reflected no statis- One of the best screening tools is the tically significant improvement in desire in Decreased Sexual Desire Screener, says the first 2 trials, the FSFI did find significant Dr. Krychman. It is available at http://www improvement in the 3rd trial. In addition, .obgynalliance.com/filesfsd/DSDS_Pocketcard when the FSFI was considered across all 3 tri- .pdf. This tool is a validated instrument to help als, results in the desire domain were consis- clinicians identify what HSDD is and is not. tent. (The FSFI was used as a secondary tool in the first 2 trials.) In addition, sexual distress, as measured 4. Does the drug carry by the Female Sexual Distress Scale (FSDS), any warnings? was decreased in the trials with use of fliban- Yes, it carries a black box warning about the serin, notes Dr. Krychman. The Advisory risks of hypotension and syncope: Committee determined that these findings • when alcohol is consumed by users of the

32 OBG Management | November 2015 | Vol. 27 No. 11 obgmanagement.com drug. (Alcohol use is contraindicated.) bedtime to reduce the risks of hypotension, • when the drug is taken in conjunction with syncope, accidental injury, and central ner- moderate or strong CYP3A4 inhibitors or vous system (CNS) depression, which can oc- by patients with hepatic impairment. (The cur even in the absence of alcohol. drug is contraindicated in both circum- stances.) See question 9 for a list of drugs that are CYP3A4 inhibitors. 7. Are there any requirements for clinicians who want to prescribe the drug? 5. Are there any other risks Yes. Because of the risks of hypotension, syn- worth noting? cope, and CNS depression, the drug is subject The medication can increase the risks of hy- to Risk Evaluation and Mitigation Strategies potension and syncope even without con- (REMS), as determined by the FDA. To pre- comitant use of alcohol. For example, in scribe the drug, providers must: clinical trials, hypotension was reported in • review its prescribing information 0.2% of flibanserin-treated women versus less • review the Provider and Pharmacy than 0.1% of placebo users. And syncope was Training Program reported in 0.4% of flibanserin users versus • complete and submit the Knowledge 0.2% of placebo-treated patients. Flibanserin Assessment Form is prescribed as a once-daily medication that • enroll in REMS by completing and submit- is to be taken at bedtime; the risks of hypo- ting the Prescriber Enrollment Form. tension and syncope are increased if fliban- Before giving a patient her initial pre- serin is taken during waking hours. scription, the provider must counsel her The risk of adverse effects when flibanse- about the risks of hypotension and syncope rin is taken with alcohol is highlighted by one and the interaction with alcohol using the case reported in package labeling: A 54-year- Patient-Provider Agreement Form. The pro- old postmenopausal woman died after tak- vider must then complete that form, provide Alcohol use is ing flibanserin (100 mg daily at bedtime) for a designated portion of it to the patient, and contraindicated 14 days. This patient had a history of hyper- retain the remainder for the patient’s file. with flibanserin tension and hypercholesterolemia and con- For more information and to download sumed a baseline amount of 1 to 3 alcoholic the relevant forms, visit https://www.addyi beverages daily. She died of acute alcohol in- rems.com. toxication, with a blood alcohol concentration of 0.289 g/dL.1 Whether this patient’s death was related to flibanserin use is unknown.1 8. What are the most common It is interesting to note that, in the stud- adverse reactions to the drug? ies of flibanserin leading up to the drug’s According to package labeling, the most com- approval, alcohol use was not an exclusion, says mon adverse reactions, with an incidence Dr. Krychman. “Approximately 58% of women greater than 2%, are dizziness, somnolence, were self-described as mild to moderate drink- nausea, fatigue, insomnia, and dry mouth. ers. The clinical program was extremely large— Less common reactions include anxiety, more than 11,000 women were studied.” constipation, abdominal pain, rash, seda- Flibanserin is currently not approved for tion, and vertigo. use in postmenopausal women, and concom- In studies of the drug, appendicitis was itant alcohol consumption is contraindicated. reported among 0.2% of flibanserin-treated patients, compared with no reports of appen- dicitis among placebo-treated patients. The 6. What is the dose? FDA has requested additional investigation The recommended dose is one tablet of of the association, if any, between flibanserin 100 mg daily. The drug is to be taken at and appendicitis. CONTINUED ON PAGE 52

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9. What drug interactions are notable? As stated earlier, the concomitant use of flibanserin with alcohol or a moderate or strong CYP3A4 inhibitor can re- sult in severe hypotension and syncope. Flibanserin also should not be prescribed for patients who use other CNS depressants such as diphenhydramine, opioids, benzo- diazepines, and hypnotic agents. Some examples of strong CYP3A4 inhibitors are ke- toconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin, and conivaptan. Moderate CYP3A4 inhibitors include amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluco- nazole, fosamprenavir, verapamil, and grapefruit juice. In addition, the concomitant use of flibanserin with multiple weak CYP3A4 inhibitors—which include herbal supplements such as ginkgo and resveratrol and nonpre- scription drugs such as cimetidine—also may increase the risks of hypotension and syncope. The concomitant use of flibanserin with digoxin in- creases the digoxin concentration and may lead to toxicity. This space has purposely been left blank. 10. Is the drug safe in pregnancy and lactation? There are currently no data on the use of flibanserin in human pregnancy. In animals, fetal toxicity occurred only in the presence of significant maternal toxicity. Ad- verse effects included decreased fetal weight, structural anomalies, and increases in fetal loss when exposure ex- ceeded 15 times the recommended human dosage. As for the advisability of using flibanserin during lactation, it is unknown whether the drug is excreted in human milk, whether it might have adverse effects in the breastfed infant, or whether it affects milk production. Package labeling states: “Because of the potential for se- rious adverse reactions, including sedation in a breastfed infant, breastfeeding is not recommended during treat- ment with [flibanserin].”1

11. When should the drug be discontinued? If there is no improvement in sexual desire after an 8-week trial of flibanserin, the drug should be discontinued.

Reference 1. Addyi [package insert]. Raleigh, NC: Sprout Pharmaceuticals; 2015.

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