Addyi

Addyi information, interactions and side effects, 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:

addyi

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.

INDICATIONS

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:

  • A co-existing medical or psychiatric condition,
  • Problems within the relationship, or
  • The effects of a medication or other drug substance.

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.

Limitations of Use

  • ADDYI is not indicated for the treatment of HSDD in postmenopausal women or in men.
  • ADDYI is not indicated to enhance sexual performance.

DOSAGE AND ADMINISTRATION

Recommended Dosage

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).

Missed Dose

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.

Discontinuation Of ADDYI

Discontinue ADDYI after 8 weeks if the patient does not report an improvement in her symptoms.

Initiation Of ADDYI Following Moderate Or Strong CYP3A4 Inhibitor Use

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.

HOW SUPPLIED

Dosage Forms And Strengths

Tablets: 100 mg, oval, pink, debossed on one side with “f100” and blank on the other side.

Storage And Handling

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)

Storage

Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F).

SIDE EFFECTS

The following adverse reactions are discussed in greater detail in other sections of the labeling:

  • Hypotension and syncope
  • CNS depression

Clinical Trials Experience

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.

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. 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.

Adverse Reactions Leading to Discontinuation

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.

 

Most Common Adverse Reactions

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. 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.

 

Less Common Adverse Reactions

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:

  • Anxiety (ADDYI 1.8%; placebo 1.0%),
  • Constipation (ADDYI 1.6%; placebo 0.4%),
  • Abdominal pain (ADDYI 1.5%; placebo 0.9%),
  • Metrorrhagia (ADDYI 1.4%; placebo 1.4%),
  • Rash (ADDYI 1.3%; placebo 0.8%),
  • Sedation (ADDYI 1.3%; placebo 0.2%), and
  • Vertigo (ADDYI 1%; placebo 0.3%).
Appendicitis

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.

Accidental Injury

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.

Adverse Reactions in Patients Who Reported Hormonal Contraceptive Use

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.

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). 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.

Hypotension, Syncope, and CNS Depression in Studies of Healthy Subjects

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, 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.

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.

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.

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.

DRUG INTERACTIONS

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.
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.
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 P-glycoprotein (P-gp), increases the digoxin concentration. 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).

 

PRECAUTIONS

Hypotension And Syncope Due To An Interaction With Alcohol

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.

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). 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.

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.

Notable requirements of the ADDYI REMS Program include the following:

  • Prescribers must be certified with the program by enrolling and completing training.
  • Pharmacies must be certified with the program and must only dispense to patients pursuant to a prescription from a certified prescriber.

Further information, including a list of qualified pharmacies, is available at www.AddyiREMS.com or 844­746-5745.

Hypotension And Syncope With CYP3A4 Inhibitors

Moderate or Strong CYP3A4 Inhibitors

The concomitant use of ADDYI with moderate or strong CYP3A4 inhibitors significantly increases flibanserin concentrations, which can lead to hypotension and syncope. 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.

Multiple Concomitant Weak CYP3A4 Inhibitors

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.

Central Nervous System Depression

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. 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.

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.

Hypotension And Syncope With ADDYI Alone

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. 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.

Syncope And Hypotension In Patients With Hepatic Impairment

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.

Mammary Tumors In Female Mice

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. The clinical significance of these findings is unknown.

Patient Counseling Information

Hypotension and Syncope

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.

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.

CNS Depression

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.

Nursing Mothers

Advise patients not to breastfeed if they are taking ADDYI.

Bedtime Dosing

Advise patients to take only one tablet at bedtime and not to take ADDYI at any other time of day.

Nonclinical Toxicology

Carcinogenesis, Mutagenesis, Impairment Of Fertility

Carcinogenesis

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).

Mutagenesis

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.

Impairment of Fertility

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).

Use In Specific Populations

Pregnancy

Risk Summary

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%.

Data

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.

Lactation

Risk Summary 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.

Pediatric Use

ADDYI is not indicated for use in pediatric patients.

Geriatric Use

ADDYI is not indicated for use in geriatric patients. Safety and effectiveness have not been established in geriatric patients.

Hepatic Impairment

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.

CYP2C19 Poor Metabolizers

CYP2C19 poor metabolizers had increased flibanserin exposures compared to CYP2C19 extensive metabolizers. Additionally, syncope occurred in a subject who was a CYP2C19 poor metabolizer. 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.

OVERDOSE

Overdosage of ADDYI may cause an increase in the incidence or severity of any of the reported 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.

CONTRAINDICATIONS

ADDYI is contraindicated:

  • With use of alcohol.
  • With concomitant use with moderate or strong CYP3A4 inhibitors.
  • In patients with hepatic impairment.
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