Dosage & Administration
Addyi Prescribing Information
Interaction with Alcohol
The use of ADDYI and alcohol together close in time increases the risk of severe hypotension and syncope [see Warnings and Precautions (5.1)]. 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 standard alcoholic drinks that evening.
Contraindicated with Strong or Moderate CYP3A4 Inhibitors
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 (5.2)]. Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated in patients taking ADDYI [see Contraindications (4)].
Contraindicated in Patients with Hepatic Impairment
The use of ADDYI in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope [see Warnings and Precautions (5.5)]. Therefore, ADDYI is contraindicated in patients with hepatic impairment [see Contraindications (4)].
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.
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 (5.2)].
Tablets: 100 mg, oval, pink, debossed on one side with "f100" and blank on the other side.
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 [see Adverse Reactions (6.1) and Clinical Pharmacology (12.5)]. 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.
ADDYI is contraindicated in patients:
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- Using concomitant moderate or strong CYP3A4 inhibitors [see Boxed Warning and Warnings and Precautions (5.2)].
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- With hepatic impairment [see Boxed Warning and Warnings and Precautions (5.5)].
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- With known hypersensitivity to ADDYI or any of its components. Reactions, including anaphylaxis, reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth), pruritus, and urticaria have been reported [see Adverse Reactions (6.2)].
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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval of ADDYI. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.
Immune system disorders: hypersensitivity reactions, including anaphylaxis, reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth), pruritus, and urticaria.
Table 3 contains clinically significant drug interactions (DI) 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). |
ADDYI (flibanserin) is a tablet for oral administration. The chemical name of flibanserin is 2H-Benzimidazol-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:
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.
Pharmacogenomics
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.
CYP2C19 Poor Metabolizers
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 (6.1) and Use in Specific Populations (8.7)].
The frequencies of poor metabolizers of CYP2C19 are approximately 2–5% among Caucasians and Africans and approximately 2–15% among Asians.
CYP2D6 Poor Metabolizers
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.
CYP2C9 Poor Metabolizers
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.
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 (adenoacanthomas 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 clinical 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).
Effects on Driving
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 (5.3)].
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) [see USP controlled room temperature].
Mechanism of Action
The mechanism of action of ADDYI in the treatment of premenopausal women with hypoactive sexual desire disorder is not known.