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ADDYI
(flibanserin) Tablets
WARNING
HYPOTENSION AND SYNCOPE IN CERTAIN SETTINGS
The use of ADDYI and alcohol increases the risk of severe hypotension and syncope [see WARNINGS AND PRECAUTIONS]. Therefore, alcohol use is contraindicated in patients taking ADDYI [see CONTRAINDICATIONS]. Before prescribing ADDYI, assess the likelihood of the patient abstaining from alcohol, taking into account the patient's current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed ADDYI about the importance of abstaining from alcohol use. Because of the increased risk of hypotension and syncope due to an interaction with alcohol, ADDYI is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADDYI REMS Program [see WARNINGS AND PRECAUTIONS].
The concomitant use of ADDYI and moderate or strong CYP3A4 inhibitors increases flibanserin concentrations, which can cause severe hypotension and syncope [see WARNINGS AND PRECAUTIONS]. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking ADDYI [see CONTRAINDICATIONS].
The use of ADDYI in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope [see WARNINGS AND PRECAUTIONS]. Therefore, ADDYI is contraindicated in patients with hepatic impairment [see CONTRAINDICATIONS].
ADDYI (flibanserin) is a tablet for oral administration. The chemical name of flibanserin is 2HBenzimidazol- 2-one, 1,3-dihydro-1-[2-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]ethyl]. Its empirical formula is C20H21F3N4O and its molecular weight is 390.41.
The structural formula is:
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Flibanserin is a white to off-white powder, insoluble in water, sparingly soluble in methanol, ethanol, acetonitrile and toluene, soluble in acetone, freely soluble in chloroform, and very soluble in methylene chloride.
Each ADDYI tablet contains 100 mg of flibanserin. Inactive ingredients consist of lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate, talc, macrogol, and the coloring agents, titanium dioxide and iron oxide.
ADDYI is indicated for the treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to:
Acquired HSDD refers to HSDD that develops in a patient who previously had no problems with sexual desire. Generalized HSDD refers to HSDD that occurs regardless of the type of stimulation, situation or partner.
The recommended dosage of ADDYI is 100 mg administered orally once per day at bedtime. ADDYI is dosed at bedtime because administration during waking hours increases the risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (such as somnolence and sedation).
If a dose of ADDYI is missed at bedtime, instruct the patient to take the next dose at bedtime on the next day. Instruct the patient to not double the next dose.
Discontinue ADDYI after 8 weeks if the patient does not report an improvement in her symptoms.
If intiating ADDYI following moderate or strong CYP3A4 inhibitor use, start ADDYI 2 weeks after the last dose of the CYP3A4 inhibitor.
If initiating a moderate or strong CYP3A4 inhibitor following ADDYI use, start the moderate or strong CYP3A4 inhibitor 2 days after the last dose of ADDYI [see WARNINGS AND PRECAUTIONS].
100 mg, oval, pink, debossed on one side with “f100” and blank on the other side.
ADDYI is available as a 100 mg oval, pink, film-coated tablet debossed on one side with “f100” and blank on the other side. Available in bottles of 30 tablets. (NDC 58604-214-30)
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP controlled room temperature].
Manufactured for: Sprout Pharmaceuticals, Inc. Raleigh, NC 27609. Revised: Aug 2015
The following adverse reactions are discussed in greater detail in other sections of the labeling:
Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to the rates in the clinical trials of another drug and may not reflect the rates observed in practice.
The approved 100 mg ADDYI dosage at bedtime was administered to 2,997 premenopausal women with acquired, generalized HSDD in clinical trials, of whom 1672 received treatment for at least 6 months, 850 received treatment for at least 12 months, and 88 received treatment for at least 18 months [see Clinical Studies].
Data from Five 24-Week, Randomized, Double-Blind Placebo-Controlled Trials in Premenopausal Women with HSDD
The data presented below are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these five trials, the frequency and quantity of alcohol use was not recorded. Three of these trials (Studies 1 through 3) also provided efficacy data [see Clinical Studies]. One of these trials (Study 5) did not evaluate the 100 mg bedtime dose.
In four trials, 100 mg ADDYI at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment. The clinical trial population was generally healthy without significant comorbid medical conditions or concomitant medications. The age range was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black.
Serious adverse reactions were reported in 0.9% and 0.5% of ADDYI-treated patients and placebo-treated patients, respectively.
The discontinuation rate due to adverse reactions was 13% among patients treated with 100 mg ADDYI at bedtime and 6% among patients treated with placebo. Table 1 displays the most common adverse reactions leading to discontinuation in four trials of premenopausal women with HSDD.
Table 1. Adverse Reactions* Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD
| Placebo (N=1556) | ADDYI (N=1543) | |
| Dizziness | 0.1% | 1.7% |
| Nausea | 0.1% | 1.2% |
| Insomnia | 0.2% | 1.1% |
| Somnolence | 0.3% | 1.1% |
| Anxiety | 0.3% | 1% |
| *Adverse reactions leading to discontinuation of ≥1% of patients receiving 100 mg ADDYI at bedtime and at a higher incidence than placebo-treated patients. | ||
Table 2 summarizes the most common adverse reactions reported in four trials of premenopausal women with HSDD. This table shows adverse reactions reported in at least 2% of patients treated with ADDYI and at a higher incidence than with placebo [see WARNINGS AND PRECAUTIONS]. The majority of these adverse reactions began within the first 14 days of treatment.
Table 2. Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD
| Placebo (N=1556) | ADDYI (N=1543) | |
| Dizziness | 2.2% | 11.4% |
| Somnolence | 2.9% | 11.2% |
| Nausea | 3.9% | 10.4% |
| Fatigue | 5.5% | 9.2% |
| Insomnia | 2.8% | 4.9% |
| Dry mouth | 1.0% | 2.4% |
| * Adverse reactions reported in ≥2% of patients receiving 100 mg ADDYI at bedtime and at a higher incidence than placebo-treated patients. | ||
In four trials in premenopausal women with HSDD treated with 100 mg ADDYI at bedtime, less common adverse reactions (reported in ≥1% but <2% of ADDYI-treated patients and at a higher incidence than with placebo) included:
In the five trials of premenopausal women with HSDD, appendicitis was reported in 6/3973 (0.2%) flibanserin-treated patients, while there were no reports of appendicitis in the 1905 placebo-treated patients.
In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) ADDYI-treated patients and 47/1905 (2.5%) placebo-treated patients. Among these 89 patients who experienced injuries,9/42 (21%) ADDYI-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours.
In four trials of premenopausal women with HSDD, 1466 patients (43%) reported concomitant use of hormonal contraceptives (HC) at study enrollment. These trials were not prospectively designed to assess an interaction between ADDYI and HC. ADDYI-treated patients who reported HC use had a greater incidence of dizziness, somnolence, and fatigue compared to ADDYI-treated patients who did not report HC use (dizziness 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% in HC users). There were no meaningful differences in the incidence of these adverse reactions in placebo-treated patients who reported or did not report HC use [see DRUG INTERACTIONS].
Data from Other Trials
One death occurred in a 54 year-old postmenopausal woman treated with 100 mg ADDYI taken at bedtime (ADDYI is not approved for the treatment of postmenopausal women with HSDD) [see Indications and Usage (1)]. This patient had a history of hypertension and hypercholesterolemia and baseline alcohol consumption of 1-3 drinks daily. She died of acute alcohol intoxication 14 days after starting ADDYI. Blood alcohol concentration on autopsy was 0.289 g/dL. The autopsy report also noted coronary artery disease. A relationship between this patient’s death and use of ADDYI is unknown [see BOX WARNING and WARNINGS AND PRECAUTIONS].
Hypotension, Syncope, and CNS Depression with Alcohol
In a cross-over alcohol interaction study of 100 mg ADDYI and alcohol in 25 healthy subjects dosed in the morning [see CLINICAL PHARMACOLOGY], somnolence was reported in 67%, 74%, and 92% of subjects who received ADDYI alone, ADDYI in combination with 0.4 g/kg ethanol, and ADDYI in combination with 0.8 g/kg ethanol, respectively. In the group receiving ADDYI in combination with 0.4 g/kg ethanol, 4/23 (17%) subjects had substantial reductions in blood pressure, resulting in hypotension and/or syncope requiring medical intervention. In the group receiving ADDYI in combination with 0.8 g/kg ethanol, 6/24 (25%) subjects experienced orthostatic hypotension [see BOX WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
Hypotension and Syncope with Fluconazole
In a pharmacokinetic drug interaction study of 100 mg ADDYI and 200 mg fluconazole (a moderate CYP3A4 inhibitor, moderate CYP2C9 inhibitor, and a strong CYP2C19 inhibitor) in healthy subjects, hypotension or syncope requiring placement supine with legs elevated occurred in 3/15 (20%) subjects treated with concomitant ADDYI and fluconazole compared to no such adverse reactions in subjects treated with ADDYI alone or fluconazole alone. One of these 3 subjects became unresponsive with a blood pressure of 64/41 mm Hg and required transportation to the hospital emergency department where she required intravenous saline. Due to these adverse reactions, the study was stopped. In this study, the concomitant use of ADDYI and fluconazole increased flibanserin exposure 7-fold [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Syncope with Ketoconazole
In a pharmacokinetic drug interaction study of 50 mg flibanserin and 400 mg ketoconazole, a strong CYP3A4 inhibitor, syncope occurred in 1/24 (4%) healthy subjects treated with concomitant flibanserin and ketoconazole, 1/24 (4%) receiving flibanserin alone, and no subjects receiving ketoconazole alone. In this study, the concomitant use of flibanserin and ketoconazole increased flibanserin exposure 4.5-fold [see WARNINGS AND PRECAUTIONS, DRUG INTERACTIONS and CLINICAL PHARMACOLOGY].
Syncope in Poor CYP2C19 Metabolizers
In a pharmacogenomic study of 100 mg ADDYI in subjects who were poor or extensive CYP2C19 metabolizers, syncope occurred in 1/9 (11%) subjects who were CYP2C19 poor metabolizers (this subject had a 3.2 fold higher flibanserin exposure compared to CYP2C19 extensive metabolizers) compared to no such adverse reactions in subjects who were CYP2C19 extensive metabolizers [see DRUG INTERACTIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY].
Table 3 contains clinically significant drug interactions (DI) with ADDYI.
Table 3: Clinically Significant Drug Interactions with ADDYI
| Alcohol | |
| Clinical Implications | The concomitant use of ADDYI with alcohol increased the risk of hypotension syncope, and CNS depression compared to the use of ADDYI alone or alcohol alone [see WARNINGS AND PRECAUTIONS and CLINICAL PHARMACOLOGY]. |
| Preventing or Managing DI | The concomitant use of ADDYI with alcohol is contraindicated. |
| Other CNS Depressants | |
| Examples | Diphenhydramine, opioids, hypnotics, benzodiazepines |
| Clinical Implications | The concomitant use of ADDYI with CNS depressants may increase the risk of CNS depression (e.g., somnolence) compared to the use of ADDYI alone. |
| Preventing or Managing DI | Discuss the concomitant use of other CNS depressants with the patient when prescribing ADDYI. |
| Moderate or Strong CYP3A4 Inhibitors | |
| Examples of strong CYP3A4 inhibitors | Ketoconazole, itraconazole, posaconazole, clarithromycin, nefazodone, ritonavir, saquinavir, nelfinavir, indinavir, boceprevir, telaprevir, telithromycin and conivaptan |
| Examples of moderate CYP3A4 inhibitors | Amprenavir, atazanavir, ciprofloxacin, diltiazem, erythromycin, fluconazole, fosamprenavir, verapamil, and grapefruit juice |
| Clinical Implications | The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors increases flibanserin exposure compared to the use of ADDYI alone. The risk of hypotension and syncope is increased with concomitant use of ADDYI and moderate or strong CYP3A4 inhibitors [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS, and CLINICAL PHARMACOLOGY]. |
| Preventing or Managing DI | The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors is contraindicated. |
| Weak CYP3A4 Inhibitors | |
| Examples | Oral contraceptives, cimetidine, fluoxetine, ginkgo, ranitidine |
| Clinical Implications | The concomitant use of ADDYI with multiple weak CYP3A4 inhibitors may increase the risk of adverse reactions. |
| Preventing or Managing DI | Discuss the use of multiple weak CYP3A4 inhibitors with the patient when prescribing ADDYI. |
| Strong CYP2C19 Inhibitors | |
| Examples | Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals |
| Clinical Implications | The concomitant use of ADDYI with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression. |
| Preventing or Managing DI | Discuss the use of a strong CYP2C19 inhibitor with the patient when prescribing ADDYI. |
| CYP3A4 Inducers | |
| Examples | Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. Johns Wort |
| Clinical Implications | The concomitant use of ADDYI with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of ADDYI alone. |
| Preventing or Managing DI | The concomitant use of ADDYI with CYP3A4 inducers is not recommended. |
| Digoxin or Other P-glycoprotein Substrates | |
| Examples | Digoxin, sirolimus |
| Clinical Implications | The concomitant use of ADDYI with digoxin, a drug that is transported by Pglycoprotein (P-gp), increases the digoxin concentration [see CLINICAL PHARMACOLOGY]. This may lead to digoxin toxicity. |
| Preventing or Managing DI | Increase monitoring of concentrations of drugs transported by P-gp that have a narrow therapeutic index (e.g., digoxin). |
Included as part of the "PRECAUTIONS" Section
Alcohol use is contraindicated in patients taking ADDYI. Before prescribing ADDYI, the healthcare provider must assess the likelihood of the patient abstaining from alcohol use, taking into account the patient's current and past drinking behavior, and other pertinent social and medical history. Counsel patients who are prescribed ADDYI about the importance of abstaining from alcohol use [see DRUG INTERACTIONS].
The use of ADDYI and alcohol increases the risk of severe hypotension and syncope. In a dedicated alcohol interaction study conducted in 25 subjects (23 men and 2 premenopausal women), hypotension or syncope requiring therapeutic intervention (ammonia salts and/or placement in supine or Trendelenberg position) occurred in 4 (17%) of the 23 subjects co-administered ADDYI 100 mg and 0.4 g/kg alcohol (equivalent of two 12 ounce cans of beer containing 5% alcohol content, two 5 ounce glasses of wine containing 12% alcohol content, or two 1.5 ounce shots of 80-proof spirit in a 70 kg person, consumed over 10 minutes in the morning) [see CLINICAL PHARMACOLOGY]. In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from about 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from about 24 to 46 mmHg. In addition, 6 (25%) of the 24 subjects co-administered ADDYI 100 mg and 0.8 g/kg alcohol experienced orthostatic hypotension when standing from a sitting position. The magnitude of the systolic blood pressure reductions in these 6 subjects ranged from 22 to 48 mmHg, and the diastolic blood pressure reductions ranged from 0 to 27 mmHg. One of these subjects required therapeutic intervention (ammonia salts and placement supine with the foot of the bed elevated). There were no events requiring therapeutic interventions when ADDYI or alcohol were administered alone.
ADDYI is available only through a restricted program under a REMS [see ADDYI REMS Program].
ADDYI is available only through a restricted program under a REMS called the ADDYI REMS Program, because of the increased risk of severe hypotension and syncope due to an interaction between ADDYI and alcohol [see BOX WARNING and Hypotension And Syncope Due To An Interaction With Alcohol].
Notable requirements of the ADDYI REMS Program include the following:
Further information, including a list of qualified pharmacies, is available at www.AddyiREMS.com or 844746-5745.
The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations, which can lead to hypotension and syncope [see ADVERSE REACTIONS]. The concomitant use of ADDYI with a moderate or strong CYP3A4 inhibitor is contraindicated. If the patient requires a moderate or strong CYP3A4 inhibitor, discontinue ADDYI at least 2 days prior to starting the moderate or strong CYP3A4 inhibitor. In cases where the benefit of initiating a moderate or strong CYP3A4 inhibitor within 2 days of stopping ADDYI clearly outweighs the risk of flibanserin exposure related hypotension and syncope, monitor the patient for signs of hypotension and syncope. Discontinue the moderate or strong CYP3A4 inhibitor for 2 weeks before restarting ADDYI [see DRUG INTERACTIONS].
Concomitant use of multiple weak CYP3A4 inhibitors that may include herbal supplements (e.g., ginkgo, resveratrol) or non-prescription drugs (e.g., cimetidine) could also lead to clinically relevant increases in flibanserin concentrations that may increase the risk of hypotension and syncope [see DRUG INTERACTIONS].
ADDYI can cause CNS depression (e.g., somnolence, sedation). In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, the incidence of somnolence, sedation or fatigue was 21% and 8% in patients treated with 100 mg ADDYI once daily at bedtime and placebo, respectively [see ADVERSE REACTIONS and Clinical Studies]. The risk of CNS depression is increased if ADDYI is taken during waking hours, or if ADDYI is taken with alcohol or other CNS depressants, or with medications that increase flibanserin concentrations, such as CYP3A4 inhibitors [see CONTRAINDICATIONS, Hypotension And Syncope Due To An Interaction With Alcohol, Hypotension And Syncope With CYP3A4 Inhibitors, ADVERSE REACTIONS, and DRUG INTERACTIONS].
Patients should not drive or engage in other activities requiring full alertness until at least 6 hours after taking ADDYI and until they know how ADDYI affects them [see Clinical Studies].
The use of ADDYI -' without other concomitant medications known to cause hypotension or syncope - can cause hypotension and syncope. In five 24-week, randomized, placebo-controlled, double-blind trials of premenopausal women with HSDD, hypotension was reported in 0.2% and <0.1% of ADDYI-treated patients and placebo-treated patients, respectively; syncope was reported in 0.4% and 0.2% of ADDYI-treated patients and placebo-treated patients, respectively. The risk of hypotension and syncope is increased if ADDYI is taken during waking hours or if higher than the recommended dose is taken [see Hypotension And Syncope Due To An Interaction With Alcohol, Hypotension And Syncope With CYP3A4 Inhibitors, ADVERSE REACTIONS, DRUG INTERACTIONS, and Use In Specific Populations]. Consider the benefits of ADDYI and the risks of hypotension and syncope in patients with preexisting conditions that predispose to hypotension. Patients who experience pre-syncope should immediately lie supine and promptly seek medical help if the symptoms do not resolve. Prompt medical attention should also be obtained for patients who experience syncope.
The use of ADDYI in patients with any degree of hepatic impairment significantly increases flibanserin concentrations, which can lead to hypotension and syncope. Therefore, the use of ADDYI is contraindicated in patients with hepatic impairment [see CONTRAINDICATIONS, Use In Specific Populations and CLINICAL PHARMACOLOGY].
In a 2-year carcinogenicity study in mice, there was a statistically significant and dose-related increase in the incidence of malignant mammary tumors in female mice at exposures 3 and 10 times the recommended clinical dose. No such increases were seen in male mice or in male or female rats [see Nonclinical Toxicology]. The clinical significance of these findings is unknown.
See FDA-Approved Patient Labeling (PATIENT INFORMATION).
Inform patients that ADDYI can cause severe hypotension and syncope, particularly with alcohol or with moderate or strong CYP3A4 inhibitors. Inform patients that alcohol use and moderate or strong CYP3A4 inhibitors are contraindicated. Counsel patients about the importance of abstaining from alcohol and to ask about drug interactions before starting a new prescription or non-prescription medication or using other products that contain CYP3A4 inhibitors (e.g., grapefruit juice or St. John's Wort). Advise patients who experience pre-syncope or lightheadedness to lie down and to call for help if symptoms persist [see CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS].
ADDYI is available only through a restricted program called the ADDYI REMS Program. Patients can only obtain ADDYI from certified pharmacies participating in the program. Therefore, provide patients with the telephone number and website for information on how to obtain ADDYI.
Advise patients that ADDYI can cause CNS depression, such as somnolence and sedation, and that the risk is increased with other CNS depressants and with certain drug interactions (e.g., hypnotics, benzodiazepenes, opioids). The risk is also increased if ADDYI is taken during waking hours. Advise patients to avoid engaging in activities requiring full alertness (e.g., operating machinery or driving) until at least 6 hours after the ADDYI dose and until they know how ADDYI affects them [see WARNINGS AND PRECAUTIONS].
Advise patients not to breastfeed if they are taking ADDYI [see Use In Specific Populations].
Advise patients to take only one tablet at bedtime and not to take ADDYI at any other time of day [see DOSAGE AND ADMINISTRATION].
A two-year carcinogenicity study was conducted in CD-1 mice with dietary administration of 0, 10, 80, 200 and 1000/1200 mg/kg/day of flibanserin. Statistically significant increases in combined mammary tumors (adenocanthomas and adenocarcinomas) were observed in female mice administered flibanserin at doses of 200 and 1200 mg/kg/day (exposures, based on AUC, were 3 and 10 times the clinical exposures at the recommended climical dose). No increases in mammary tumors were observed in male mice. Statistically significant increases were also seen for combined hepatocellular adenomas/carcinomas in female mice treated with flibanserin 1200 mg/kg/day and for hepatocellular carcinomas in male mice treated with flibanserin 1000 mg/kg/day (exposures, based on AUC, were 8 times the clinical exposure at the recommended clinical dose).
There were no significant increases in tumor incidence in a two year carcinogenicity study conducted in Wistar rats with dietary administration of 0, 10, 30 and 100 mg/kg/day flibanserin (up to 5-8 times human exposure at the recommended clinical dose).
Flibanserin was negative for mutagenesis in vitro in Salmonella typhimurium (Ames test) and in Chinese hamster ovary cells. Flibanserin was positive for chromosomal aberrations in cultured human lymphocytes but negative for chromosomal aberrations in vivo in the rat bone marrow micronucleus assay and negative for DNA damage in rat liver in the Comet assay.
Female and male rats were administered flibanserin 14 and 28 days before mating, respectively, to assess for potential effects on fertility and early reproductive performance. Flibanserin slightly increased the duration of the estrus cycle but had no adverse effects on fertility or early embryonic development at doses up to 200 mg/kg/day (~20 times human exposure at the recommended clinical dose).
There are no studies of ADDYI in pregnant women to inform whether there is a drug-associated risk in humans. In animals, fetal toxicity only occurred in the presence of significant maternal toxicity including reductions in weight gain and sedation. Adverse reproductive and developmental effects consisted of decreased fetal weight, structural anomalies and increases in fetal loss at exposures greater than 15 times exposures achieved with the recommended human dosage [see Data]. Animal studies cannot rule out the potential for fetal harm.
In the general population (not taking ADDYI), the estimated background risk of major birth defects is 2% to 4% of live births, and the estimated background risk of miscarriage of clinically recognized pregnancies is 15% to 20%.
Animal Data
Pregnant rats were administered flibanserin at doses of 0, 20, 80 and 400 mg/kg/day (3, 15 and 41 times clinical exposures at the recommended human dose based on AUC) during organogenesis. The highest dose was associated with significant maternal toxicity as evidenced by severe clinical signs and marked reductions in weight gain during dosing. In the litters of high-dose dams, there were decreased fetal weights, decreased ossification of the forelimbs and increased number of lumbar ribs, and two fetuses with anophthalmia secondary to severe maternal toxicity. The no adverse effect level for embryofetal toxicity was 80 mg/kg/day (15 times clinical exposure based on AUC).
Pregnant rabbits were administered flibanserin at doses of 0, 20, 40 and 80 mg/kg/day (4, 8 and 16 times the clinical exposure at the recommended human dose) during organogenesis. Marked decreases in maternal body weight gain (>75%), abortion and complete litter resorption were observed at 40 and 80 mg/kg/day indicating significant maternal toxicity at these doses. Increases in resorptions and decreased fetal weights were observed at ≥ 40 mg/kg/day. No treatment-related teratogenic effects were observed in fetuses at any dose level. The no adverse effect level for maternal and embryofetal effects was 20 mg/kg/day (3-4 times clinical exposure based on AUC).
Pregnant rats were administered flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and ~ 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri-and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day [see Nonclinical Toxicology].
Flibanserin is excreted in rat milk. It is unknown whether flibanserin is present in human milk, whether ADDYI has effects on the breastfed infant, or whether ADDYI affects milk production. Because of the potential for serious adverse reactions including sedation in a breastfed infant, breastfeeding is not recommended during treatment with ADDYI.
ADDYI is not indicated for use in pediatric patients.
ADDYI is not indicated for use in geriatric patients. Safety and effectiveness have not been established in geriatric patients.
ADDYI is contraindicated for use in patients with any degree of hepatic impairment. Flibanserin exposure increased 4.5-fold in patients with hepatic impairment, compared to those with normal hepatic function, increasing the risk of hypotension, syncope, and CNS depression [see BOX WARNING, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and CLINICAL PHARMACOLOGY].
CYP2C19 poor metabolizers had increased flibanserin exposures compared to CYP2C19 extensive metabolizers. Additionally, syncope occurred in a subject who was a CYP2C19 poor metabolizer [see ADVERSE REACTIONS and CLINICAL PHARMACOLOGY]. Therefore, increase monitoring for adverse reactions (e.g., hypotension) in patients who are CYP2C19 poor metabolizers. The frequencies of poor CYP2C19 metabolizers are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians.
Overdosage of ADDYI may cause an increase in the incidence or severity of any of the reported adverse reactions [see WARNINGS AND PRECAUTIONS and ADVERSE REACTIONS]. In the event of overdosage, treatment should address the symptoms and supportive measures, as needed. There is no known specific antidote for flibanserin.
ADDYI is contraindicated:
The mechanism of action of ADDYI in the treatment of premenopausal women with hypoactive sexual desire disorder is not known.
In vitro, flibanserin demonstrated high affinity for the following serotonin (5-hydroxytryptamine or 5-HT) receptors: agonist activity at 5-HT1A and antagonist activity at 5-HT2A. Flibanserin also has moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors.
A randomized, double-blind, single-dose, cross-over, dedicated alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). In this study, 68%, 16%, 8% and 8% subjects reported a history of drinking 5-6, 7-10, 11-15 and 16-21 drinks per week, respectively. Subjects received one of the following five treatments [ADDYI and alcohol were administered in the morning and the alcohol was consumed in 10 minutes. ADDYI is to be only administered at bedtime, see DOSAGE AND ADMINISTRATION]:
Patients who received ADDYI with alcohol had a higher incidence of somnolence than patients who received ADDYI alone or alcohol alone [see WARNINGS AND PRECAUTIONS]. There were no significant changes in the pharmacokinetics of flibanserin when administered with or without alcohol.
The effect of ADDYI on the QT interval was evaluated in a randomized, double-blind, placebo-and active(single dose moxifloxacin) controlled crossover study in 56 healthy men and women. Subjects in the ADDYI groups received either 50 mg twice a day (equivalent to the daily recommended dosage) or 100 mg three times a day (3 times the daily recommended dosage) administered for 5 days. The time frame for electrocardiogram (ECG) measurements covered maximum plasma concentrations of flibanserin and relevant metabolites. In this study, ADDYI did not prolong the QT interval to any clinically relevant extent. The mean increase in heart rate associated with the 100 mg three times a day dose of ADDYI compared to placebo ranged from 1.7 to 3.2 beats per minute.
Flibanserin showed dose-proportional pharmacokinetics for Cmax after single oral doses of 100 mg to 250 mg (the recommended and 2.5 times the recommended dosage, respectively) in healthy female subjects. Steady state was achieved after 3 days of dosing. The extent of exposure (AUC0-∞) with once-daily dosing of 100 mg of flibanserin was increased 1.4-fold as compared to a single dose.
Figure 1 Mean + SD Plasma Flibanserin Concentration-Time Profiles in Healthy Female Subjects Following a Single Oral Dose of 100 mg of Flibanserin (Linear Scale)
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Following oral administration of a single 100 mg dose of flibanserin in healthy premenopausal women (N=8), mean (SD) Cmax was 419 (206) ng/mL and mean (SD) AUC0-inf was 1543 (511) ng*hr/mL. Median (range) time to reach Cmax was 0.75 (0.75 to 4.0) hours. Absolute bioavailability of flibanserin following oral dosing is 33%.
Food increased the extent of absorption and slowed the rate of absorption of a 50 mg dose of flibanserin (one half the recommended dosage). Low-, moderate-, and high-fat meals increased flibanserin AUC0-inf by 1.18-, 1.43-, and 1.56-fold; increased Cmax by 1.02-, 1.13-, and 1.15-fold; and prolonged median Tmax to 1.5, 0.9, 1.8 hours from 0.8 hours under fasted conditions, respectively.
Approximately 98% of flibanserin is bound to human serum proteins, mainly to albumin.
Metabolism
Flibanserin is primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19. Based on in vitro and/or in vivo data, CYP1A2, CYP2B6, CYP2C8, CYP2C9, and CYP2D6 contribute minimally to the metabolism of flibanserin. After a single oral solution dose of 50 mg 14C-radiolabeled flibanserin , 44% of the total 14C-flibanserin related radioactivity was recovered in urine, and 51% was recovered in feces. Flibanserin is extensively metabolized to at least 35 metabolites, most of them occurring in low concentrations in plasma. Two metabolites could be characterized that showed plasma concentrations similar to that achieved with flibanserin: 6,21-dihydroxy-flibanserin-6,21-disulfate and 6-hydroxyflibanserin-6-sulfate. These two metabolites are inactive.
Excretion
Flibanserin has a mean terminal half-life of approximately 11 hours.
Single 50 mg oral doses of flibanserin were administered to 10 patients with mild hepatic impairment (Child-Pugh score of 6 points), 4 patients with moderate hepatic impairment (Child-Pugh score of 8-9 points), and 14 healthy subjects matched by age, weight, and gender. Systemic flibanserin exposure (AUC0-inf) increased 4.5-fold in patients with mild hepatic impairment, compared to subjects with normal hepatic function, and t1/2 was longer (26 hours compared to 10 hours in matching healthy controls). Due to the small number of patients (n=4) with moderate hepatic impairment enrolled in the study, it is not possible to make conclusions about the quantative effect of moderate hepatic impairment on flibanserin exposure. ADDYI is contraindicated in patients with hepatic impairment [see WARNINGS AND PRECAUTIONS].
Single 50 mg oral doses of flibanserin were administered to 7 patients with mild to moderate renal impairment (GFR 30 to 80 mL/min), 9 patients with severe renal impairment (GFR <30 mL/min, not on dialysis), and 16 healthy subjects matched by age, weight, and gender. Flibanserin exposure (AUC0-inf) increased 1.1-fold in patients with mild to moderate renal impairment and 1.2-fold in patients with severe renal impairment, compared to the healthy control subjects.
A cross-study comparison between healthy Japanese women and Caucasian women with HSDD showed that flibanserin exposure was approximately 1.4-fold higher in Japanese women. When the mean flibanserin exposure in Japanese women was adjusted for weight, the AUCtau,ss in Japanese women was 2246 ng*hr/mL, which is comparable to 2080 ng*hr/mL in Caucasian women. The similarity in weight- adjusted AUCtau,ss suggests that weight, not race, is the factor contributing to the observed difference in flibanserin exposure between Japanese and Caucasian women.
No formal study has been conducted to study the effect of age on flibanserin exposures.
The effects of other drugs on the pharmacokinetics of flibanserin are presented in Table 4 as change relative to flibanserin administered alone (test/reference).
Moderate CYP3A4/Moderate CYP2C9/Strong CYP2C19 Inhibitor (Fluconazole)
In a study of 15 healthy female subjects, a fluconazole 400 mg loading dose followed by 200 mg administered once daily for 5 days increased flibanserin 100 mg single dose exposure (AUC0-inf) 7-fold and Cmax 2.2-fold compared to flibanserin 100 mg alone. Three of 15 subjects (20%) experienced hypotension or syncope from concomitant use of fluconazole and flibanserin; therefore, the study was stopped early. [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and DRUG INTERACTIONS].
Strong CYP3A4 Inhibitor (Ketoconazole)
In a study of 24 healthy female subjects, ketoconazole 400 mg administered once daily for 5 days following a light breakfast increased flibanserin 50 mg single-dose exposure (AUC0-inf) 4.5-fold and Cmax 1.8-fold compared to flibanserin 50 mg alone [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and DRUG INTERACTIONS].
Strong CYP3A4 Inhibitor (Itraconazole)
In a study of 12 healthy male and female subjects, itraconazole 200 mg administered once daily for 4 days following a loading dose of 400 mg increased flibanserin 50 mg single dose exposure (AUC0-inf) 2.6-fold and Cmax 1.7-fold when flibanserin was given 2 hours after itraconazole on Day 5, compared to exposures with flibanserin 50 mg alone. The 200 mg itraconazole dose does not maximally inhibit the CYP3A4 enzyme [see DRUG INTERACTIONS].
Moderate CYP3A4 Inhibitor (Grapefruit Juice)
In a study of 26 healthy female subjects, grapefruit juice (240 mL) increased flibanserin 100 mg single dose exposure (AUC0-inf) by 1.4-fold and Cmax 1.1-fold compared to flibanserin 100 mg alone. [see WARNINGS AND PRECAUTIONS, ADVERSE REACTIONS and DRUG INTERACTIONS].
Weak CYP3A4 Inhibitor (Oral Contraceptives)
In a meta-analysis of 17 oral contraceptive users and 91 non-users in Phase 1 studies, the oral contraceptive users had a 1.4-fold higher flibanserin AUC and 1.3-fold higher Cmax compared to the non-users [see ADVERSE REACTIONS and DRUG INTERACTIONS].
Strong CYP2D6 Inhibitor (Paroxetine)
Paroxetine is a strong CYP2D6 inhibitor. In a study of 19 healthy male and female subjects, flibanserin exposure decreased by approximately 4% when flibanserin 50 mg twice daily was given with paroxetine compared to flibanserin alone. Paroxetine was dosed at 20 mg once daily for 3 days followed by 40 mg once daily for 7 days.
Strong CYP3A4 Inducer (Rifampin)
In a study of 24 healthy female subjects, rifampin 600 mg given once daily for 7 days prior to administration of 100 mg flibanserin significantly decreased flibanserin exposure by 95% [see DRUG INTERACTIONS].
Moderate CYP3A4 Inducer (Etravirine)
Steady state etravirine, a moderate CYP3A4 inducer, decreased flibanserin exposures by approximately 21% [see DRUG INTERACTIONS].
Table 4 Drugs That Increase Flibanserin Exposure
| Coadministered Drug(s) and Dose(s) | Dose of ADDYI | n | Geometric Mean Ratio (90% Confidence Interval) of Pharmacokinetic Parameters of Flibanserin with/without Coadministered Drug No Effect =1.00 |
|
| Cmax | AUC0-inf | |||
| Fluconazole 200 mg | 100 mg | 15 | 2.2 (1.8 – 2.8) | 7.0 (6.0 – 8.2) |
| Ketoconazole 400 mg | 50 mg | 24 | 1.8 (1.7 – 2.1) | 4.5 (4.0 – 5.1) |
| Itraconazole 200 mg* | 50 mg | 12 | 1.7 (1.4 – 2.0) | 2.6 (2.1 – 3.0 ) |
| Oral Contraceptives | 50 mg | 39 | 1.3 (1.1 – 1.6) | 1.4 (1.2 – 1.7) |
| Paroxetine 40 mg | 50 mg twice daily | 19 | 1.0 (0.9 – 1.2) | 1.0 (0.9 – 1.0) |
| *itraconazole dose was not optimal for maximal inhibition of CYP3A4 enzyme. | ||||
The effects of flibanserin on the pharmacokinetics of other drugs are presented in Table 5 as change relative to the other drug administered alone (test/reference).
Digoxin and P-glycoprotein Substrates
A single center, open-label, randomized, two-way crossover study in 24 healthy men and women evaluated the effect of flibanserin on the pharmacokinetics of digoxin. Flibanserin 100 mg was administered once daily over 5 days followed by a single dose of 0.5 mg digoxin, a P-gp substrate. Flibanserin increased digoxin AUC0-inf by 2.0-fold and Cmax by 1.5-fold, compared to digoxin alone [see DRUG INTERACTIONS].
Drugs Metabolized by CYP3A4 (Simvastatin)
An open-label, randomized, crossover study in 12 healthy men and women evaluated the effect of flibanserin 50 mg twice daily for 4 days on the pharmacokinetics of simvastatin 40 mg once daily. Flibanserin increased the AUC0-inf of simvastatin, a substrate of CYP3A4, 1.3-fold and Cmax by 1.2fold. Flibanserin co-administered with simvastatin increased simvastatin acid AUC0-inf by 1.5-fold and Cmax by 1.4-fold.
Oral Contraceptives
A study in 24 healthy women evaluated the effect of 100 mg flibanserin once daily for 2 weeks on the pharmacokinetics of a single-dose of ethinyl estradiol (EE) 30 mcg/levonorgestrel (LNG) 150 mcg. Flibanserin increased the EE AUC0-inf by 1.09-fold and the EE Cmax by 1.1-fold. Flibanserin decreased the LNG AUC0-inf by 1.06-fold and did not change the LNG Cmax. [see ADVERSE REACTIONS, DRUG INTERACTIONS].
Drugs Metabolized by CYP2B6 (Bupropion)
An open-label, randomized, two-period crossover study in 28 healthy women evaluated the effect of flibanserin on the pharmacokinetics of bupropion. Flibanserin 50 mg twice daily was administered for 2 days followed by 100 mg once daily for 13 days. Bupropion 150 mg twice daily was given for 8 days beginning on Day 6 of flibanserin treatment. Flibanserin did not change bupropion AUCt,ss (1.0-fold change) and Cmax (1.0-fold change) but hydroxybupropion AUCt,ss decreased by 9% and Cmax by 11%.
Table 5 Effects of Flibanserin on Exposure of Other Drugs
| Coadministered Drug(s) and Dose(s) | Dose of ADDYI | n | Geometric Mean Ratio (90% Confidence Interval) of Pharmacokinetic Parameters of Coadministered Drug with/without Flibanserin No Effect =1.00 |
|
| Cmax | AUC0-inf | |||
| Simvastatin 40 mg | 50 mg twice daily | 12 | 1.7 (1.4 – 2.0) | 2.6 (2.1 – 3.1) |
| Digoxin 0.5 mg | 100 mg | 24 | 1.5 (1.3 – 1.6) | 2.0 (1.5 – 2.5) |
| Ethinyl estradiol 30 mcg/ Levonorgestrel 150 mcg | 100 mg | 24 | 1.1 (1.0 – 1.1) 1.0 (0.9 – 1.0) | 1.1 (1.0 – 1.2) 1.0 (0.9 – 1.1) |
| Bupropion 150 mg | 100 mg | 28 | 1.0 (0.9 – 1.1) | 1.0 (1.0 – 1.1) |
Patients who are poor metabolizers of CYP2D6, CYP2C9 or CYP2C19 are deficient in CYP2D6, CYP2C9 or CYP2C19 enzyme activity, respectively. Extensive metabolizers have normal functioning CYP enzymes.
A study comparing flibanserin exposure in CYP2C19 poor metabolizers to CYP2C19 extensive metabolizers was conducted in lieu of a drug interaction study with ADDYI and a strong CYP2C19 inhibitor. In 9 women who were poor metabolizers of CYP2C19, Cmax and AUC0-inf of flibanserin 100 mg once daily increased 1.5-fold (1.1-2.1) and 1.3-fold (0.9-2.1), compared to exposures among 8 extensive metabolizers of CYP2C19. Flibanserin half-life was increased from 11.1 hours in the extensive metabolizers of CYP2C19 to 13.5 hours in the poor metabolizers of CYP2C19 [see ADVERSE REACTIONS and Use In Specific Populations].
The frequencies of poor metabolizers of CYP2C19 are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians.
A study comparing flibanserin exposure in CYP2D6 poor metabolizers to CYP2D6 extensive metabolizers was conducted in addition to a drug interaction study with paroxetine, a strong CYP2D6 inhibitor. In 12 poor metabolizers of CYP2D6, steady state Cmax and AUC of flibanserin 50 mg twice daily was decreased by 4% and increased by 18%, respectively, compared to exposures among 19 extensive metabolizers, intermediate metabolizers and ultra rapid metabolizers of CYP2D6.
A study comparing flibanserin exposure in CYP2C9 poor metabolizers to CYP2C9 extensive metabolizers was conducted in lieu of a drug interaction study with ADDYI and a strong CYP2C9 inhibitor. In 8 women who were poor metabolizers of CYP2C9, Cmax and AUC0-inf of flibanserin 100 mg once daily decreased 23% and 18%, compared to exposures among 8 extensive metabolizers of CYP2C9.
The efficacy of ADDYI for the treatment of HSDD in premenopausal women was established in three 24week, randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3). The three trials included premenopausal women with acquired, generalized HSDD of at least 6 months duration. In the clinical trials, acquired HSDD was defined as HSDD that developed in patients who previously had no problems with sexual desire. Generalized HSDD was defined as HSDD that was not limited to certain types of stimulation, situations or partners. The patients were treated with ADDYI 100 mg once daily at bedtime (n = 1187) or placebo (n = 1188). Most of the trial participants were Caucasian (88.6%); the remainder were Black (9.6%) and Asian (1.5%). The mean age of study participants was 36 years old (range 19 to 55 years old); the mean duration in the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years. The completion rate across these three trials was 69% and 78% for the ADDYI and placebo groups, respectively.
These trials each had two co-primary efficacy endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire:
The desire domain of the Female Sexual Function Index (FSFI Desire) was also used as a secondary endpoint in Studies 1 and 2.
The three trials had a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R). This question asks “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 7-day recall period and responded on a scale of 0 (never) to 4 (always).
The efficacy results from Studies 1, 2, and 3 are summarized in Table 6. In all three trials, ADDYI resulted in statistically significant improvement compared to placebo in the change from baseline in monthly SSEs at Week 24. In Study 1 and 2, there were no statistically significant differences between ADDYI and placebo for the eDiary sexual desire endpoint (change in baseline to Week 24). In contrast, in Study 3 there was statistically significant improvement in the change from baseline to Week 24 in sexual desire (using the FSFI Desire Domain) with ADDYI compared to placebo. The FSFI Desire Domain findings were consistent across all three trials as were the findings for the secondary endpoint that assessed distress using Question 13 of the FSDS-R.
Table 6 Efficacy Results in Premenopausal HSDD Patients in Studies 1, 2, and 3
| Full Analysis Set | Study 1 | Study 21 | Study 3 | |||
| ADDYI | Placebo | ADDYI | Placebo | ADDYI | Placebo | |
| n=280 | n=290 | n=365 | n=372 | n=532 | n=536 | |
| Number of satisfying sexual events (per 28 days) | ||||||
| Baseline (Mean) | 3.0 | 2.7 | 2.6 | 2.7 | 2.5 | 2.7 |
| Change from baseline (Mean) | 1.6 | 0.8 | 1.8 | 1.1 | 2.5 | 1.5 |
| Treatment diff. (95% CI) | 0.9 (0.3, 1.4) | 0.6 (-0.03, 1.2) | 1.0 (0.4, 1.5) | |||
| Change from baseline (Median) | 1.0 | 0.0 | 1.0 | 0.5 | 1.0 | 0.5 |
| Median treatment difference | 1.0 | 0.5 | 0.5 | |||
| p-value vs placebo | p<0.01 | p<0.01 | p<0.0001 | |||
| e-Diary Desire | ||||||
| Baseline (Mean) | 12.9 | 11.8 | 12.1 | 10.2 | Not Used | Not Used |
| Change from baseline at Week 24 (Mean) | 9.1 | 6.9 | 8.3 | 6.7 | ||
| Treatment diff. (95% CI) | 2.3 (-0.1, 4.7) | 1.7 (-0.5, 4.0) | ||||
| p-value vs placebo | NS | NS | ||||
| FSFI Desire | ||||||
| Baseline (Mean) | 1.9 | 1.9 | 1.8 | 1.8 | 1.9 | 1.9 |
| Change from baseline at Week 24 (Mean) | 0.9 | 0.5 | 0.9 | 0.5 | 1.0 | 0.7 |
| Treatment diff. (95% CI) | 0.4 (0.2, 0.5) | 0.3 (0.2, 0.5) | 0.3 (0.2, 0.4) | |||
| p-value vs placebo | N/A2 | N/A2 | p<0.0001 | |||
| FSDS-R Question 133 | ||||||
| Baseline (Mean) | 3.2 | 3.2 | 3.2 | 3.2 | 3.4 | 3.4 |
| Change from baseline at Week 24 (Mean) | -0.8 | -0.5 | -0.8 | -0.5 | -1.0 | -0.7 |
| Treatment diff. (95% CI) | -0.4 (-0.5,-0.2) | -0.3 (-0.4,-0.1) | -0.3 (-0.4 -0.1) | |||
| p-value vs placebo | N/A2 | N/A2 | p=0.0001 | |||
| CI = Confidence Interval; NS= not statistically significant; N/A=not applicable Shaded cells show the results for the co-primary efficacy endpoints for each trial. e-Diary desire was evaluated as a co-primary endpoint in Studies 1 and 2; FSFI desire was evaluated as a co-primary endpoint in Study 3. The efficacy results are based on the full analysis set comprised of all randomized patients who took at least one dose of study medication and had at least one on-treatment efficacy assessment. Missing values were imputed using last-observation-carriedforward. The unadjusted means are presented for the baseline values. For satisfying sexual events, p-values are based on the Wilcoxon rank sum test stratified by pooled center. Median change from baseline is shown because the data are not normally distributed. For FSFI-desire, e-Diary desire, and FSDS-R Question 13, reported p-values are based on an ANCOVA model using baseline as a covariate with treatment and pooled center as main effect terms. For the change from baseline, the adjusted least squares mean (standard error) are presented. 1Excludes subjects from two study sites that had data integrity issues 2p-value not reported for secondary endoints because the trial failed on the eDiary Desire co-primary efficacy endpoint 3A decrease in score represents improvement |
||||||
Exploratory analyses were conducted to assess whether the treatment effects varied depending on baseline number of SSEs, FSFI desire score, and FSDS-R Question 13 distress score. No notable differences were identified among these subgroups.
Supportive analyses were conducted to help interpret the clinical meaningfulness of the observed treatment effects. These analyses defined responders for each efficacy endpoint by anchoring change from baseline to end of treatment with the Patient's Global Impression of Improvement (PGI-I). The first analysis considered responders to be those who reported being “much improved” or “very much improved.” In this analysis, the absolute difference in the percentage of responders with ADDYI and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for ADDYI; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for ADDYI; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (2134% for ADDYI; 14-25% for placebo). The second analysis considered responders to be those who reported being at least minimally improved. The absolute difference in the percentage of responders with ADDYI and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for ADDYI; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for ADDYI; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for ADDYI; 41-48% for placebo).
In a randomized, placebo-controlled, 4-way crossover study in 83 healthy premenopausal female subjects, no adverse effect was detected on measures of driving performance itself or psychomotor performance thought to be important for driving performance when assessed 9 hours following single and multiple doses of ADDYI 100 mg once daily at bedtime or single doses of ADDYI 200 mg at bedtime (two times the maximum recommended dosage) [see WARNINGS AND PRECAUTIONS].
ADDYI™
(add-ee)
(flibanserin) Tablets
Read this Medication Guide before you start taking ADDYI™ and each time you get a refill. There may be new information. This information does not take the place of talking to your doctor.
What is the most important information I should know about ADDYI?
Your risk of severe low blood pressure and fainting (loss of consciousness) is increased if you take ADDYI and:
If you take ADDYI and you feel lightheaded or dizzy, lie down right away. Get emergency medical help or ask someone to get emergency medical help for you if the symptoms do not go away or if you faint (lose consciousness). If you faint (lose consciousness), tell your doctor as soon as you can.
ADDYI is only available through the ADDYI risk evaluation and mitigation strategy (REMS) Program because of the increased risk of severe low blood pressure and fainting (loss of consciousness) with alcohol use. You can only get ADDYI from pharmacies that are enrolled in the ADDYI REMS Program. For more information about the Program and a list of pharmacies that are enrolled in the ADDYI REMS Program, go to www.AddyiREMS.com or call 1-844-PINK-PILLL (1-844-746-5745).
What is ADDYI?
ADDYI is a prescription medicine used to treat hypoactive (low) sexual desire disorder (HSDD) in women who have not gone through menopause, who have not had problems with low sexual desire in the past, and who have low sexual desire no matter the type of sexual activity, the situation, or the sexual partner. Women with HSDD have low sexual desire that is troubling to them. Their low sexual desire is not due to:
ADDYI is not for use for the treatment of HSDD in women who have gone through menopause or in men.
ADDYI is not for use to improve sexual performance.
ADDYI is not for use in children.
Who should not take ADDYI?
Do not take ADDYI if you:
These are examples of the medicines that you should not take if you are taking ADDYI. Tell your doctor about all of the medicines you take before you start taking ADDYI.
What should I tell my doctor before taking ADDYI?
Before you take ADDYI, tell your doctor about all of your medical conditions, including if you:
Tell your doctor about all of the medicines you take, including prescription and over-the-counter medicines, vitamins, and herbal supplements. ADDYI can affect the way other medicines work, and other medicines can affect the way ADDYI works, and can cause serious side effects.
Know the medicines and herbal supplements you take. Keep a list of them to show your doctor or pharmacist each time you get a new medicine.
How should I take ADDYI?
What should I avoid while taking ADDYI?
What are the possible side effects of ADDYI?
ADDYI can cause serious side effects, including:
The most common side effects of ADDYI include:
These are not all of the possible side effects of ADDYI.
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.
How should I store ADDYI?
Keep ADDYI and all medicines out of the reach of children.
General information about the safe and effective use of ADDYI
Medicines are sometimes prescribed for purposes other than those listed in a Medication Guide. Do not use ADDYI for a condition for which it was not prescribed. Do not give ADDYI to other people, even if they have the same symptoms that you have. It may harm them. You can ask your doctor or pharmacist for information about ADDYI that is written for health professionals.
What are the ingredients in ADDYI?
Active ingredient: flibanserin
Inactive ingredients: lactose monohydrate, microcrystalline cellulose, hypromellose, croscarmellose sodium, magnesium stearate, talc, macrogol, and the coloring agents, titanium dioxide and iron oxide.
