Addyi Drug Information
Generic name: FLIBANSERIN
Uses of Addyi
- ADDYI is indicated for the treatment of women less than 65 years of age 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 in men.
- The effects of a medication or other drug substance. Limitations of Use:
- ADDYI is not indicated to enhance sexual performance.
Dosage & Administration of Addyi
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 HSDD symptoms.
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.
Side Effects of Addyi
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. 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. One trial (Study 5) did not evaluate the 100 mg bedtime dose. 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. 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 Years of Age) s Table 2 summarizes the most common adverse reactions reported in six trials of women less than 65 years of age 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 Adverse reactions reported in ≥2% of patients who received ADDYI 100 mg once daily at bedtime and at a higher incidence than placebo-treated patients in premenopausal women or postmenopausal women trials. in Randomized, Double-blind, Placebo-controlled Trials in Women with HSDD (<65 Years of Age) s In six trials in women less than 65 years of age with HSDD treated with ADDYI 100 mg once daily at bedtime, less common adverse reactions (reported in ≥1% but <2% of ADDYI-treated patients and at a higher incidence than with placebo) in the premenopausal population included: abdominal pain, metrorrhagia, rash, sedation, vertigo.
In the postmenopausal population, less common adverse reactions included: sleep disorder, bronchitis, edema peripheral, cough, vertigo, palpitations, rash, abnormal dreams. 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. Appendicitis was not reported in trials of postmenopausal women.
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. 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. 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 Alcohol and ADDYI Administration at the Same Time The first alcohol interaction study was conducted in 25 healthy subjects (23 men and 2 premenopausal women). The study excluded subjects who drank fewer than five alcoholic drinks per week and those with a history of orthostatic hypotension, or syncope.
In these four subjects, all of whom were men, the magnitude of the systolic blood pressure reductions ranged from 28 to 54 mmHg and the magnitude of the diastolic blood pressure reductions ranged from 24 to 46 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.
The study excluded subjects with a history of syncope, orthostatic hypotension, hypotensive events, and dizziness, and those with a resting systolic blood pressure less than 110 mmHg or diastolic blood pressure less than 60 mmHg. In this study, no subjects experienced syncope or hypotension requiring therapeutic intervention. However, subjects who were already hypotensive (blood pressure below 90/60 mmHg) or symptomatic (e.g., dizzy) while in the semi-recumbent position were not permitted to stand for orthostatic measurements, and those with blood pressures below 90/40 mmHg while in the semi-recumbent position had blood pressures repeated until it was deemed safe for them to change position.
More subjects had missing or delayed orthostatic measurements (in general, due to hypotension or dizziness) when receiving ADDYI and alcohol, compared to those who received alcohol alone or ADDYI alone. This pattern of missing or delayed orthostatic measurements is concerning for a risk of hypotension and syncope if those subjects had been allowed to stand. In this study, somnolence was reported in 81-89% of subjects administered ADDYI with alcohol, compared to 25-41% of subjects administered alcohol alone and 84% of subjects taking ADDYI alone.
Dizziness was reported in 27-40% of subjects administered ADDYI with alcohol, compared to 6-20% of subjects administered alcohol alone and 31% of subjects taking ADDYI alone. Alcohol Use at Various Time Intervals Before ADDYI Administration In a third alcohol interaction study, 64 healthy premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2 alcoholic drinks in a 70 kg person) two, four or six hours prior to receiving ADDYI 100 mg or placebo in the afternoon. Prior to receiving alcohol, the subjects in the ADDYI arm had taken ADDYI for three days to achieve steady state.
Syncope occurred in one subject who received alcohol alone. The incidences of orthostatic hypotension and hypotension (blood pressure below 90/60 mmHg) at all time points were similar among subjects administered alcohol before ADDYI, subjects administered alcohol alone, and subjects administered ADDYI alone. Three subjects were unable to stand due to feeling dizzy or hypotension; two following alcohol and ADDYI separated by 2 and 6 hours, and one subject who received ADDYI alone.
In this study, somnolence was reported in 35-53% of subjects administered ADDYI and alcohol, compared to 5-8% of subjects taking alcohol alone and 50% of subjects taking ADDYI alone. Dizziness was reported in 5-13% of subjects administered ADDYI and alcohol, compared to 0-3% of subjects taking alcohol alone and 12% of subjects taking ADDYI alone. Alcohol Use in the Evening Before Bedtime ADDYI Administration In another alcohol interaction study, 24 premenopausal women consumed 0.4 g/kg alcohol (equivalent to 2 alcoholic drinks in a 70 kg person) during the evening meal two and a half to four hours prior to taking ADDYI 100 mg at bedtime.
There were no cases of syncope. Upon rising the following morning, the incidence of hypotension was 23% among subjects administered ADDYI after alcohol, 23% among subjects administered alcohol alone and 36% with ADDYI alone. No cases of somnolence or dizziness were reported in this study.
Conclusions are limited because blood pressure and orthostatic measurements were not taken after ADDYI administration until the following morning. Dedicated alcohol-interaction studies were not conducted in postmenopausal women. 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.
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.
Postmarketing Experience
The following adverse reactions have been identified during post-approval use 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. • Gastrointestinal disorders: vomiting • General disorders and administration site conditions: asthenia, feeling abnormal, feeling drunk, malaise • Nervous system disorders: headache, presyncope, gait disturbance, vision blurred • Psychiatric disorders: brain fog
| Adverse Reaction | Trials in Premenopausal Women Includes Studies 1-4 | Trials in Postmenopausal Women Includes Studies 6 and 7 | ||
| Placebo (N=1556) | ADDYI (N=1543) | Placebo (N=797) | ADDYI (N=801) | |
| Overall | 6% | 13% | 5% | 9% |
| Dizziness | 0.1% | 1.7% | 0.3% | 0.9% |
| Nausea | 0.1% | 1.2% | 0.3% | 0.5% |
| Insomnia | 0.2% | 1.1% | 0.5% | 1.4% |
| Somnolence | 0.3% | 1.1% | 0.1% | 0.6% |
| Anxiety | 0.3% | 1% | 0.6% | 1.2% |
| Trials in Premenopausal Women | Trials in Postmenopausal Women | |||
|---|---|---|---|---|
| Adverse Reaction | Placebo (N=1556) | ADDYI (N=1543) | Placebo (N=797) | ADDYI (N=801) |
| Dizziness | 2.2% | 11.4% | 3.3% | 7.9% |
| Somnolence | 2.9% | 11.2% | 1.8% | 7.7% |
| Nausea | 3.9% | 10.4% | 3.9% | 6.6% |
| Fatigue | 5.5% | 9.2% | 3.9% | 3.0% |
| Insomnia | 2.8% | 4.9% | 3.4% | 5.7% |
| Dry mouth | 1.0% | 2.4% | 1.3% | 2.4% |
| Urinary tract infection | 2.4% | 2.3% | 3.0% | 3.2% |
| Anxiety | 1.0% | 1.8% | 1.6% | 2.6% |
| Sinusitis | 3.5% | 2.9% | 2.1% | 2.5% |
| Constipation | 0.4% | 1.6% | 1.8% | 2.5% |
| Adverse Reaction | Trials in Premenopausal Women Includes Studies 1-4 | Trials in Postmenopausal Women Includes Studies 6 and 7 | ||
| Placebo (N=1556) | ADDYI (N=1543) | Placebo (N=797) | ADDYI (N=801) | |
| Overall | 6% | 13% | 5% | 9% |
| Dizziness | 0.1% | 1.7% | 0.3% | 0.9% |
| Nausea | 0.1% | 1.2% | 0.3% | 0.5% |
| Insomnia | 0.2% | 1.1% | 0.5% | 1.4% |
| Somnolence | 0.3% | 1.1% | 0.1% | 0.6% |
| Anxiety | 0.3% | 1% | 0.6% | 1.2% |
| Trials in Premenopausal Women | Trials in Postmenopausal Women | |||
|---|---|---|---|---|
| Adverse Reaction | Placebo (N=1556) | ADDYI (N=1543) | Placebo (N=797) | ADDYI (N=801) |
| Dizziness | 2.2% | 11.4% | 3.3% | 7.9% |
| Somnolence | 2.9% | 11.2% | 1.8% | 7.7% |
| Nausea | 3.9% | 10.4% | 3.9% | 6.6% |
| Fatigue | 5.5% | 9.2% | 3.9% | 3.0% |
| Insomnia | 2.8% | 4.9% | 3.4% | 5.7% |
| Dry mouth | 1.0% | 2.4% | 1.3% | 2.4% |
| Urinary tract infection | 2.4% | 2.3% | 3.0% | 3.2% |
| Anxiety | 1.0% | 1.8% | 1.6% | 2.6% |
| Sinusitis | 3.5% | 2.9% | 2.1% | 2.5% |
| Constipation | 0.4% | 1.6% | 1.8% | 2.5% |
Warnings & Cautions for Addyi
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.
After taking ADDYI at bedtime, advise patients to not use alcohol until the following day.
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. 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. Patients should avoid activities requiring full alertness (e.g., driving or operating machinery) 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. In two similarly designed trials in naturally postmenopausal women with acquired, generalized HSDD, there was no difference in the incidence of hypotension between ADDYI-treated patients and placebo-treated patients.
One case of syncope was reported in the ADDYI treatment group. 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 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.
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.
Hypersensitivity Reactions
Hypersensitivity reactions, including anaphylaxis, reactions consistent with angioedema (e.g., swelling of the face, lips, and mouth), pruritus, and urticaria have been reported with ADDYI. ADDYI is contraindicated in women with known hypersensitivity to ADDYI or any of its components. Immediately discontinue ADDYI and initiate appropriate treatment if a hypersensitivity reaction occurs.
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 flibanserin exposures 3 and 10 times the recommended clinical dose of ADDYI. No such increases were seen in male mice or in male or female rats. The clinical significance of these findings is unknown.
Drug Interactions with Addyi
- 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. 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. The risk of hypotension and syncope is increased with concomitant use of ADDYI and moderate or strong CYP3A4 inhibitors. 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).
- Oral Contraceptives and Other Weak CYP3A4 Inhibitors: Increases flibanserin exposures and incidence of adverse reactions
- Strong CYP2C19 Inhibitors: Increases flibanserin exposure which may increase risk of hypotension, syncope, and CNS depression
- CYP3A4 Inducers: Use of ADDYI not recommended; flibanserin concentrations substantially reduced
- Digoxin: Increases digoxin concentrations, which may lead to digoxin toxicity. Increase monitoring of digoxin concentrations
| 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). |
Pregnancy Safety for Addyi
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. In pregnant rats and rabbits, 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. The estimated background risk of major birth defects and miscarriage for the indicated population is unknown. All pregnancies have a background risk of birth defect, loss, or other adverse outcomes.
In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is respectively. Data Animal Data Pregnant rats were administered flibanserin at doses of 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 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). 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.
Pediatric Use of Addyi
Pediatric Use ADDYI is not indicated for use in pediatric patients.
Contraindications for Addyi
- ADDYI is contraindicated in patients:
- Using concomitant moderate or strong CYP3A4 inhibitors.
- With hepatic impairment.
- 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.
- Moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors
- Hepatic impairment
- Known hypersensitivity to ADDYI or its components
Overdosage Information for Addyi
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.
Clinical Studies of Addyi
Trials in Premenopausal Patients with HSDD
The efficacy of ADDYI for the treatment of acquired, generalized HSDD in premenopausal women was established in three 24-week, randomized, double-blind, placebo-controlled trials (Study 1, NCT00360529; Study 2, NCT00360555; and Study 3, NCT00996164). The clinical trials enrolled premenopausal women with acquired, generalized HSDD of at least 6 months duration as evidenced by low sexual desire that caused marked distress or interpersonal difficulty and was not due to: a co-existing medical or psychiatric condition, problems with the relationship, or the effects of a medication or other drug substance. Acquired HSDD was defined as HSDD that developed in patients who previously had no problems with sexual desire.
Generalized HSDD was defined as HSDD that was not limited to certain types of stimulation, situations or partners. The patients were treated with ADDYI 100 mg once daily at bedtime (n = 1187) or placebo (n = 1188). Most of the trial participants were Caucasian (88.6%); the remainder were Black (9.6%) and Asian (1.5%).
The completion rate across these three trials was 69% and 78% for the ADDYI and placebo groups, respectively. These trials each had two co-primary efficacy endpoints, one for satisfying sexual events (SSEs) and the other for sexual desire: • The change from baseline to Week 24 in the number of monthly SSEs (i.e., sexual intercourse, oral sex, masturbation, or genital stimulation by the partner). The SSEs were based on patient responses to the following questions: “Did you have a sexual event?” and “Was the sex satisfying for you?” • Studies 1 and 2 had a different sexual desire endpoint than Studies 3: o In Studies 1 and 2, the sexual desire co-primary endpoint was the change from baseline to Week 24 in the calculated monthly sexual desire score and was based on patient responses to the question: “Indicate your most intense level of sexual desire.” Every day, patients rated their sexual desire level from 0 (no desire) to 3 (strong desire) and recorded their response in an electronic Diary (eDiary).
These responses were summed over a 28-day period to yield the calculated monthly sexual desire score, which ranged from 0 to 84. o In Study 3, the desire domain of the Female Sexual Function Index (FSFI Desire) was the sexual desire co-primary endpoint. The desire domain of the FSFI has two questions. The first question asks patients “Over the past 4 weeks, how often did you feel sexual desire or interest?”, with responses ranging from 1 (almost never or never) to 5 (almost always or always).
The second question asks patients “Over the past 4 weeks, how would you rate your level (degree) of sexual desire or interest?”, with responses ranging from 1 (very low or none at all) to 5 (very high). The FSFI Desire score was calculated by adding the patient’s responses to these two questions then multiplying that sum by 0.6. The FSFI Desire domain score ranged from 1.2 to 6.
The desire domain of the Female Sexual Function Index (FSFI Desire) was also used as a secondary endpoint in Studies 1 and 2. The three trials had a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 of the Female Sexual Distress Scale-Revised (FSDS-R). This question asks “How often did you feel: Bothered by low sexual desire?” Patients assessed their sexual distress over a 7-day recall period and responded on a scale of 0 (never) to 4 (always).
In the three trials, ADDYI resulted in statistically significant improvement compared to placebo in the change from baseline in monthly SSEs at Week 24. In Study 1 and 2, there were no statistically significant differences between ADDYI and placebo for the eDiary sexual desire endpoint (change in baseline to Week 24). In contrast, in Study 3 there was statistically significant improvement in the change from baseline to Week 24 in sexual desire (using the FSFI Desire Domain) with ADDYI compared to placebo.
The FSFI Desire Domain findings were consistent across all three trials as were the findings for the secondary endpoint that assessed distress using Question 13 of the FSDS-R. No notable differences were identified among these subgroups. Supportive analyses were conducted to help interpret the clinical meaningfulness of the observed treatment effects.
These analyses defined responders for each efficacy endpoint by anchoring change from baseline to end of treatment with the Patient's Global Impression of Improvement (PGI‑I). The second analysis considered responders to be those who reported being at least "minimally improved". The trial included postmenopausal women with acquired, generalized HSDD of at least 6 months duration.
The study completion rate for the ADDYI and placebo groups less than 65 years of age was 79% and 83%, respectively. In this trial, postmenopausal patients with significant comorbidities such as uncontrolled hypertension, uncontrolled diabetes mellitus (Hgb A1C > 7%), cardiovascular disease, uncorrected thyroid disorders, psychiatric disorders, etc., were excluded. The trial had two co-primary efficacy endpoints - one for SSEs counts and one for desire domain of the Female Sexual Function Index (FSFI Desire) (similar to Study 3) - and a secondary endpoint that measured bother (a component of distress) related to sexual desire using Question 13 FSDS-R.
These endpoints are defined in Section 14.1. The efficacy results for patients less than 65 years of age from Study 6 are summarized in Table 7. ADDYI resulted in statistically significant improvement compared to placebo in the co-primary and secondary endpoints.
Table 7 Efficacy Results in Postmenopausal HSDD Patients in Study 6 (<65 Years of Age)
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). The effect of ADDYI on driving performance in postmenopausal women was not evaluated.
| Study 1 | Study 2 Excludes subjects from two study sites that had data integrity issues | Study 3 | ||||
|---|---|---|---|---|---|---|
| ADDYI | Placebo | ADDYI | Placebo | ADDYI | Placebo | |
| Full Analysis Set | n=280 | n=290 | n=365 | n=372 | n=532 | n=536 |
| CI = Confidence Interval; NS = not statistically significant; N/A = not applicable Shaded cells show the results for the co-primary efficacy endpoints for each trial. e-Diary desire was evaluated as a co-primary endpoint in Studies 1 and 2; FSFI desire was evaluated as a co-primary endpoint in Study 3. The efficacy results are based on the full analysis set comprised of all randomized patients who took at least one dose of study medication and had at least one on-treatment efficacy assessment. Missing values were imputed using last-observation-carried-forward. The unadjusted means are presented for the baseline values. For satisfying sexual events, p-values are based on the Wilcoxon rank sum test stratified by pooled center. Median change from baseline is shown because the data are not normally distributed. For FSFI-desire, e-Diary desire, and FSDS-R Question 13, reported p-values are based on an ANCOVA model using baseline as a covariate with treatment and pooled center as main effect terms. For the change from baseline, the adjusted least squares mean (standard error) are presented. | ||||||
| Number of satisfying sexual events (per 28 days) | ||||||
| Baseline (Mean) | 3.0 | 2.7 | 2.6 | 2.7 | 2.5 | 2.7 |
| Change from baseline (Mean) | 1.6 | 0.8 | 1.8 | 1.1 | 2.5 | 1.5 |
| Treatment diff. (95% CI) | 0.9 (0.3, 1.4) | 0.0 | 0.6 (-0.03, 1.2) | 0.5 | 1.0 (0.4, 1.5) | 0.5 |
| Change from baseline (Median) | 1.0 | 1.0 | 1.0 | |||
| Median treatment difference | 1.0 | 0.5 | 0.5 | |||
| p-value vs placebo | p<0.01 | p<0.01 | p<0.0001 | |||
| e-Diary Desire | ||||||
| Baseline (Mean) | 12.9 | 11.8 | 12.1 | 10.2 | Not Used | Not Used |
| Change from baseline at Week 24 (Mean) | 9.1 | 6.9 | 8.3 | 6.7 | ||
| Treatment diff. (95% CI) | 2.3 (-0.1, 4.7) | 1.7 (-0.5, 4.0) | ||||
| p-value vs placebo | NS | NS | ||||
| FSFI Desire | ||||||
| Baseline (Mean) | 1.9 | 1.9 | 1.8 | 1.8 | 1.9 | 1.9 |
| Change from baseline at Week 24 (Mean) | 0.9 | 0.5 | 0.9 | 0.5 | 1.0 | 0.7 |
| Treatment diff. (95% CI) | 0.4 (0.2, 0.5) | 0.3 (0.2, 0.5) | 0.3 (0.2, 0.4) | |||
| p-value vs placebo | N/A p-value not reported for secondary endpoints because the trial failed on the eDiary Desire co-primary efficacy endpoint | N/A | p<0.0001 | |||
| FSDS-R Question 13 A decrease in score represents improvement | ||||||
| Baseline (Mean) | 3.2 | 3.2 | 3.2 | 3.2 | 3.4 | 3.4 |
| Change from baseline at Week 24 (Mean) | -0.8 | -0.5 | -0.8 | -0.5 | -1.0 | -0.7 |
| Treatment diff. (95% CI) | -0.4 (-0.5, -0.2) | -0.3 (-0.4, -0.1) | -0.3 (-0.4, -0.1) | |||
| p-value vs placebo | N/A | N/A | p=0.0001 | |||
| Full Analysis Set <65 years of age | ADDYI n=430 | Placebo n=451 |
|---|---|---|
| CI = Confidence Interval | ||
| The efficacy results are based on the full analysis set <65 years of age comprised of all randomized patients <65 years of age who took at least one dose of study medication and had at least one post-baseline efficacy assessment. Missing values were imputed using last-observation-carried-forward. | ||
| For satisfying sexual events, p-values are based on the Wilcoxon rank sum test. For FSFI-desire and FSDS-R Question 13, reported p-values are based on an ANCOVA model using baseline as a covariate with treatment and pooled center as main effect terms. | ||
| The unadjusted means are presented for the baseline values. For the change from baseline, the adjusted least squares means are presented. | ||
| Number of satisfying sexual events (count) per 28 days | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 2.0 0.9 0.4 (-0.0, 0.8) p < 0.025 | 2.0 0.6 |
| FSFI Desire | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 1.8 0.7 0.3 (0.2, 0.5) p < 0.0001 | 1.8 0.4 |
| FSDS-R Question 13 A decreased in scope represents improvement | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 3.3 -0.8 -0.2 (-0.4, -0.1) p < 0.01 | 3.3 -0.6 |
| Study 1 | Study 2 Excludes subjects from two study sites that had data integrity issues | Study 3 | ||||
|---|---|---|---|---|---|---|
| ADDYI | Placebo | ADDYI | Placebo | ADDYI | Placebo | |
| Full Analysis Set | n=280 | n=290 | n=365 | n=372 | n=532 | n=536 |
| CI = Confidence Interval; NS = not statistically significant; N/A = not applicable Shaded cells show the results for the co-primary efficacy endpoints for each trial. e-Diary desire was evaluated as a co-primary endpoint in Studies 1 and 2; FSFI desire was evaluated as a co-primary endpoint in Study 3. The efficacy results are based on the full analysis set comprised of all randomized patients who took at least one dose of study medication and had at least one on-treatment efficacy assessment. Missing values were imputed using last-observation-carried-forward. The unadjusted means are presented for the baseline values. For satisfying sexual events, p-values are based on the Wilcoxon rank sum test stratified by pooled center. Median change from baseline is shown because the data are not normally distributed. For FSFI-desire, e-Diary desire, and FSDS-R Question 13, reported p-values are based on an ANCOVA model using baseline as a covariate with treatment and pooled center as main effect terms. For the change from baseline, the adjusted least squares mean (standard error) are presented. | ||||||
| Number of satisfying sexual events (per 28 days) | ||||||
| Baseline (Mean) | 3.0 | 2.7 | 2.6 | 2.7 | 2.5 | 2.7 |
| Change from baseline (Mean) | 1.6 | 0.8 | 1.8 | 1.1 | 2.5 | 1.5 |
| Treatment diff. (95% CI) | 0.9 (0.3, 1.4) | 0.0 | 0.6 (-0.03, 1.2) | 0.5 | 1.0 (0.4, 1.5) | 0.5 |
| Change from baseline (Median) | 1.0 | 1.0 | 1.0 | |||
| Median treatment difference | 1.0 | 0.5 | 0.5 | |||
| p-value vs placebo | p<0.01 | p<0.01 | p<0.0001 | |||
| e-Diary Desire | ||||||
| Baseline (Mean) | 12.9 | 11.8 | 12.1 | 10.2 | Not Used | Not Used |
| Change from baseline at Week 24 (Mean) | 9.1 | 6.9 | 8.3 | 6.7 | ||
| Treatment diff. (95% CI) | 2.3 (-0.1, 4.7) | 1.7 (-0.5, 4.0) | ||||
| p-value vs placebo | NS | NS | ||||
| FSFI Desire | ||||||
| Baseline (Mean) | 1.9 | 1.9 | 1.8 | 1.8 | 1.9 | 1.9 |
| Change from baseline at Week 24 (Mean) | 0.9 | 0.5 | 0.9 | 0.5 | 1.0 | 0.7 |
| Treatment diff. (95% CI) | 0.4 (0.2, 0.5) | 0.3 (0.2, 0.5) | 0.3 (0.2, 0.4) | |||
| p-value vs placebo | N/A p-value not reported for secondary endpoints because the trial failed on the eDiary Desire co-primary efficacy endpoint | N/A | p<0.0001 | |||
| FSDS-R Question 13 A decrease in score represents improvement | ||||||
| Baseline (Mean) | 3.2 | 3.2 | 3.2 | 3.2 | 3.4 | 3.4 |
| Change from baseline at Week 24 (Mean) | -0.8 | -0.5 | -0.8 | -0.5 | -1.0 | -0.7 |
| Treatment diff. (95% CI) | -0.4 (-0.5, -0.2) | -0.3 (-0.4, -0.1) | -0.3 (-0.4, -0.1) | |||
| p-value vs placebo | N/A | N/A | p=0.0001 | |||
| Full Analysis Set <65 years of age | ADDYI n=430 | Placebo n=451 |
|---|---|---|
| CI = Confidence Interval | ||
| The efficacy results are based on the full analysis set <65 years of age comprised of all randomized patients <65 years of age who took at least one dose of study medication and had at least one post-baseline efficacy assessment. Missing values were imputed using last-observation-carried-forward. | ||
| For satisfying sexual events, p-values are based on the Wilcoxon rank sum test. For FSFI-desire and FSDS-R Question 13, reported p-values are based on an ANCOVA model using baseline as a covariate with treatment and pooled center as main effect terms. | ||
| The unadjusted means are presented for the baseline values. For the change from baseline, the adjusted least squares means are presented. | ||
| Number of satisfying sexual events (count) per 28 days | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 2.0 0.9 0.4 (-0.0, 0.8) p < 0.025 | 2.0 0.6 |
| FSFI Desire | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 1.8 0.7 0.3 (0.2, 0.5) p < 0.0001 | 1.8 0.4 |
| FSDS-R Question 13 A decreased in scope represents improvement | ||
| Baseline (Mean) Change from baseline at Week 24 (Mean) Treatment difference (95% CI) | 3.3 -0.8 -0.2 (-0.4, -0.1) p < 0.01 | 3.3 -0.6 |
Drug information sourced from the FDA. This content is for informational purposes only and does not constitute medical advice. Consult a healthcare professional before making any medication decisions.
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