ADDYI (flibanserin) tablets
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.
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 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:
- A co-existing medical or psychiatric condition,
- Problems within the relationship, or
- The effects of a medication or other drug substance
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.
Mechanism of Action
The mechanism of action of ADDYI in the treatment of premenopausal women with hypoactive sexual desire disorder is not known.
Dosage and administration
- Recommended dosage is 100 mg taken once daily at bedtime
- ADDYI is dosed at bedtime because administration during waking hours increases risks of hypotension, syncope, accidental injury, and central nervous system (CNS) depression
- Discontinue treatment after 8 weeks if no improvement
- Moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors
- Hepatic impairment
Most common adverse reactions (incidence ≥2%) are dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth
Warnings and precautions
Hypotension 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. 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).
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.
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).
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
Alcohol: 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
Other CNS Depressants: Examples; Diphenhydramine, opioids, hypnotics, benzodiazepines. 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.
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
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
Weak CYP3A4 Inhibitors
- Examples; Oral contraceptives, cimetidine, fluoxetine, ginkgo, ranitidine.
The concomitant use of ADDYI with multiple weak CYP3A4 inhibitors may increase the risk of adverse reactions
Strong CYP2C19 Inhibitors
- Examples; Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals.
The concomitant use of ADDYI with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression.
- Examples; Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John’s Wort.
The concomitant use of ADDYI with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of ADDYI alone.
Digoxin or Other P-glycoprotein Substrates
- Examples; Digoxin, sirolimus.
The concomitant use of ADDYI with digoxin, a drug that is transported by Pglycoprotein (P-gp), increases the digoxin concentration. This may lead to digoxin toxicity.
Use in specific populations
Pregnancy: 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. Animal studies cannot rule out the potential for fetal harm.
Lactation: 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
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.
Store at 25°C (77°F); excursions permitted to 15°-30°C (59°-86°F) [see USP controlled room temperature].