ADDYI flibanserin 100 mg Tablet, Film Coated, 30-count

5 WARNINGS AND PRECAUTIONS • Hypotension and Syncope due to an Interaction with Alcohol : After taking ADDYI at bedtime, advise patients to avoid alcohol until the following day. (5.1) • Central Nervous System (CNS) Depression (e.g., Somnolence, Sedation) : Can occur with ADDYI alone. Exacerbated by other CNS depressants, and in settings where flibanserin concentrations are increased.

Patients should avoid activities requiring full alertness (e.g., driving or operating machinery) until at least six hours after each dose and until they know how ADDYI affects them. (5.3) • Hypotension and Syncope with ADDYI Alone : Patients with pre-syncope should immediately lie supine and promptly seek medical help if symptoms do not resolve. (5.4) • Hypersensitivity Reactions, including anaphylaxis, angioedema, pruritus, urticaria : Avoid in women with known hypersensitivity to ADDYI or any of its components ( 5.6 )

5.1Hypotension and Syncope due to an Interaction with Alcohol Taking ADDYI within two hours after consuming alcohol increases the risk of severe hypotension and syncope. To reduce this risk, counsel patients to wait at least two hours after drinking one or two standard alcoholic drinks before taking ADDYI at bedtime [see Boxed Warning and Adverse Reactions (6.1) ] . Patients who drink three or more standard alcoholic drinks should skip their ADDYI dose that evening.

One standard alcoholic drink contains 14 grams of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol). After taking ADDYI at bedtime, advise patients to not use alcohol until the following day.

5.2Hypotension 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 [see Adverse Reactions (6.1) ]. 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 (7) ]. 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 [see Drug Interactions (7) ] .

5.3Central 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 [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . In two similarly designed trials in naturally postmenopausal women with acquired, generalized HSDD, the incidence of somnolence, sedation or fatigue was 10% and 6% in patients less than 65 years of age 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 [see Contraindications (4), Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1) , and Drug Interactions (7) ]. Patien…

6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Hypotension and syncope [see Warnings and Precautions (5.1, 5.2, 5.4, 5.5) ] • CNS depression [see Warnings and Precautions (5.3) ] Most common adverse reactions (incidence ≥2%) are dizziness, somnolence, nausea, fatigue, insomnia, urinary tract infection, anxiety, sinusitis, constipation and dry mouth. (6.1) To report SUSPECTED ADVERSE REACTIONS, contact Sprout Pharmaceuticals, Inc. at 1-844-746-5745, or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical 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 1,672 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 (14) ].

In clinical trials, ADDYI 100 mg once daily at bedtime was administered to 801 postmenopausal women less than 65 years of age with acquired, generalized HSDD, of whom 460 received ADDYI treatment for at least 6 months, and 23 received ADDYI treatment for longer than 6 months. Premenopausal Women The data presented below in Table 1 and Table 2 (left columns) are derived from five 24-week randomized, double-blind, placebo-controlled trials in premenopausal women with acquired, generalized HSDD. In these trials, the frequency and quantity of alcohol use was not recorded.

Three of these trials (Studies 1, 2, and 3) also provided efficacy data [see Clinical Studies (14.1) ]. One trial (Study 5) did not evaluate the 100 mg bedtime dose. In four trials in premenopausal women (Studies 1 through 4), 100 mg ADDYI at bedtime was administered to 1543 premenopausal women with HSDD, of whom 1060 completed 24 weeks of treatment.

The age range of women enrolled was 18-56 years old with a mean age of 36 years old, and 88% were Caucasian and 9% were Black. In Studies 1 through 4 in premenopausal women, serious adverse reactions were reported in 0.9% and 0.5% of ADDYI-treated patients and placebo-treated patients, respectively. Postmenopausal Women The data presented below in Table 1 and Table 2 (right columns) are derived from two randomized, double-blind, placebo-controlled trials intended to be of 24-week duration in naturally postmenopausal women with acquired, generalized HSDD (Studies 6 and 7).

One trial (Study 7) was discontinued prematurely. In these trials, 100 mg ADDYI at bedtime was administered to 801 postmenopausal women less than 65 years of age with HSDD, of whom 460 completed 24 weeks of treatment. The age range of women enrolled was 34-80 years old with a mean age of 56 years old, and 91% were Caucasian, 7% were Black and 94% were less than 65 years of age.

The clinical trial population had no significant comorbid medical conditions and were not taking concomitant medications. Serious adverse reactions were reported in 1.5% and 0.7% of ADDYI-treated patients and placebo-treated patients less than 65 years of age, respectively. Adverse Reactions Leading to Discontinuation Table 1 displays the most common adverse reactions leading to discontinuation in six trials of women less than 65 years of age with HSDD that evaluated the ADDYI 100 mg once daily at bedtime dosage by population studied.

Table 1 Adverse Reactions Adverse reactions leading to discontinuation of > 1% of patients who received ADDYI 100 mg once daily at bedtime and at a higher incidence than placebo-treated patients in the pooled premenopausal women and postmenopausal women trials. Leading to Discontinuation in Randomized, Double-blind, Placebo-controlled Trials in Women with HSDD (< 65 Ye…

7 DRUG INTERACTIONS Table 3 contains clinically significant drug interactions (DI) with ADDYI. Table 3 Clinically Significant Drug Interactions with ADDYI Alcohol Clinical Implications The coadministration 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 (5.1) and Clinical Pharmacology (12.2) ]. Preventing or Managing DI Counsel patients to wait at least two hours after consuming one or two standard alcoholic drinks before taking ADDYI at bedtime or to skip their ADDYI dose if they have consumed three or more alcoholic drinks that evening. [see Boxed Warning , Warnings and Precautions (5.1) , and Adverse Reactions (6.1) ] .

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 (5.2) , Adverse Reactions (6.1) , and Clinical Pharmacology (12.3) ]. 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. John's 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 [see Clinical Pharmacology (12.3) ] . 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). • Oral Contraceptives and Other Weak CYP3A4 Inhibitors : Increases flibanserin exposures and incidence of adverse reactions (6.1, 7) • Strong CYP2C19 Inhibitors : Increases flibanserin exposure which may increase risk of hypotension, syncope, and CNS depression (7) • CYP3A4 Inducers : Use of ADDYI not recommended; flibanserin concentrations substantially reduced (7) • Digoxin : Increase…