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Addyi（flibanserin）tablets
HIGHLIGHTS OF PRESCRIBING INFORMATION
These highlights do not include all the information needed to use ADDYI safely and effectively.
See full prescribing information for ADDYI.
ADDYI (flibanserin) tablets, for oral use
Initial U.S. Approval 2015
WARNING: HYPOTENSION AND SYNCOPE IN CERTAIN SETTINGS
See full prescribing information for complete boxed warning
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Use of ADDYI and alcohol increases the risk of severe hypotension and syncope; therefore alcohol use is contraindicated. Before prescribing ADDYI, assess the likelihood of the patient abstaining from alcohol. Counsel patients prescribed ADDYI about the importance of abstaining from alcohol. (4, 5.1)
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ADDYI is available only through a restricted program called the ADDYI REMS Program. (5.2)
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Severe hypotension and syncope can occur when ADDYI is used with moderate or strong CYP3A4 inhibitors or in patients with hepatic impairment; therefore, ADDYI use in these settings is contraindicated. (4, 5.3, 5.6)
INDICATIONS AND USAGE
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:
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A co-existing medical or psychiatric condition,
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Problems within the relationship, or
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The effects of a medication or other drug substance. (1)
Limitations of Use:
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ADDYI is not indicated for the treatment of HSDD in postmenopausal women or in men. (1)
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ADDYI is not indicated to enhance sexual performance. (1)
DOSAGE AND ADMINISTRATION
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Recommended dosage is 100 mg taken once daily at bedtime (2.1)
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ADDYI is dosed at bedtime because administration during waking hours increases risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression (2.1)
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Discontinue treatment after 8 weeks if no improvement (2.3)
DOSAGE FORMS AND STRENGTHS
CONTRAINDICATIONS
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Alcohol (4, 5.1)
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Moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors (4, 5.3)
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Hepatic impairment (4, 5.6)
WARNINGS AND PRECAUTIONS
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Hypotension and Syncope with ADDYI Alone: Patients with pre-syncope should immediately lie supine and promptly seek medical help if symptoms do not resolve. (5.5)
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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., operating machinery or driving) until at least 6 hours after each dose and until they know how ADDYI affects them. 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., operating machinery or driving) until at least 6 hours after each dose and until they know how ADDYI affects them. (5.4)
ADVERSE REACTIONS
Most common adverse reactions (incidence ≥2%) are dizziness, somnolence, nausea, fatigue, insomnia, 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.
DRUG INTERACTIONS
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Oral Contraceptives and Other Weak CYP3A4 Inhibitors: Increases flibanserin exposures and incidence of adverse reactions (6.1, 7)
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Strong CYP2C19 Inhibitors: Increases flibanserin exposure which may increase risk of hypotension, syncope, and CNS depression (7)
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CYP3A4 Inducers: Use of ADDYI is not recommended; flibanserin concentrations substantially reduced. (7)
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Digoxin: Increases digoxin concentrations, which may lead to digoxin toxicity. Increase monitoring of digoxin concentrations (7)
USE IN SPECIFIC POPULATIONS
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Nursing mothers: ADDYI is not recommended. (8.2)
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CYP2C19 Poor Metabolizers: Increases flibanserin exposure which may increase risk of hypotension, syncope, and CNS depression (8.7)
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling.
Revised: 8/2015
FULL PRESCRIBING INFORMATION: CONTENTS*
1 INDICATIONS AND USAGE
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:
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A co-existing medical or psychiatric condition,
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Problems within the relationship, or
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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
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ADDYI is not indicated for the treatment of HSDD in postmenopausal women or in men.
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ADDYI is not indicated to enhance sexual performance.
2 DOSAGE AND ADMINISTRATION
2.1 Recommended Dosage
The recommended dos age 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).
2.2 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.
2.3 Discontinuation of ADDYI
Discontinue ADDYI after 8 weeks if the patient does not report an improvement in her symptoms.
2.4 Initiation of ADDYI Following Moderate or Strong CYP3A4 Inhibitor Use
If initiating 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 (5.3)].
3 DOSAGE FORMS AND STRENGTHS
Tablets: 100 mg, oval, pink, debossed on one side with "f100" and blank on the other side.
4 CONTRAINDICATIONS
ADDYI is contraindicated:
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With use of alcohol [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.4)].
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With concomitant use with moderate or strong CYP3A4 inhibitors [see Boxed Warning and Warnings and Precautions (5.2, 5.4)].
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In patients with hepatic impairment [see Boxed Warning and Warnings and Precautions (5.6)].
5 WARNINGS AND PRECAUTIONS
5.1 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 [see Drug Interactions (7)].
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 (12.2)]. 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 Warnings and Precautions (5.2)].
5.2 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 Boxed Warning and Warnings and Precautions (5.1)].
Notable requirements of the ADDYI REMS Program include the following:
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Prescribers must be certified with the program by enrolling and completing training.
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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 844-746-5745.
5.3 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 [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)].
5.4 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 [See Adverse Reactions (6.1) and Clinical Studies (14.1)]. 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, 5.3), Adverse Reactions (6.1), and Drug Interactions (7)].
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 (14.2)].
5.5 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 [see Warnings and Precautions (5.1,5.3), Adverse Reactions (6.1), Drug Interactions (7), and Use in Specific Populations (8.7)]. Consider the benefits of ADDYI and the risks of hypotension and syncope in patients with pre- existing 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.
5.7 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 [see Nonclinical Toxicology (13.1)]. The clinical significance of these findings is unknown.
6 ADVERSE REACTIONS
The following adverse reactions are discussed in greater detail in other sections of the labeling:
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Hypotension and Syncope [see Warnings and Precautions (5.1, 5.3, 5.5, 5.6)]
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CNS Depression [see Warnings and Precautions (5.4)]
6.1 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 [see Clinical Studies (14)].
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 (14)]. One of these trials (Study 5) did not eva luate 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.
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 [see Warnings and Precautions (5.4)]. The majority of these adverse reactions began within the first 14 days of treatment.
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:
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Anxiety (ADDYI 1.8%; placebo 1.0%),
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Constipation (ADDYI 1.6%; placebo 0.4%),
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Abdominal pain (ADDYI 1.5%; placebo 0.9%),
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Metrorrhagia (ADDYI 1.4%; placebo 1.4%),
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Rash (ADDYI 1.3%; placebo 0.8%),
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