Side Effects of Addyi (flibanserin)

Addyi (flibanserin) is a multifunctional serotonin agonist and antagonist (MSAA) used to treat low sexual desire in women. The mechanism of action of Addyi is not completely understood. 

Addyi affects the way the brain works by interfering with communication among the brain's nerves in areas of the brain that control sexual desire and other pleasurable sensations. Nerves communicate with each other by making and releasing chemicals called neurotransmitters. 

The neurotransmitters travel to other nearby nerves where they attach to receptors on nerves. The attachment of neurotransmitters either stimulates or inhibits the function of the nearby nerves. 

Addyi blocks several of the receptors on nerves including dopamine type 4, and serotonin type 2A, 2B and 2C receptors. It also stimulates serotonin type 1A. How these effects improve sexual desire in women is unknown. Scientists think Addyi may regulate areas of the brain that control sexual desire in premenopausal women with reduced sexual interest and desire.

Common side effects of Addyi include

• drowsiness and
• reduced alertness.

Serious side effects of Addyi include

• low blood pressure and
• fainting.
• Drug interactions of Addyi include alcohol and other drugs that also cause low blood pressure because Addyi can cause low blood pressure and fainting. Addyi is metabolized or broken down by liver enzymes.
• Drugs that induce the activity of these enzymes such as carbamazepine, rifampin, St. John's wort, phenobarbital, and several other drugs will decrease blood levels of Addyi.
• Addyi should not be combined with drugs that decrease its blood levels.
• Drugs that block the action of enzymes that breakdown Addyi will increase blood levels and side effects of Addyi.
• Therefore, Addyi should not be combined with itraconazole, clarithromycin, ketoconazole, fluconazole, ritonavir, indinavir, telithromycin, diltiazem, verapamil, grapefruit juice, and other drugs that may increase its blood levels. Addyi increases blood levels of digoxin. This may lead to digoxin toxicity. 

Addyi has not been adequately studied in pregnant women. Addyi has not been studied in women who are breastfeeding. It is unknown if Addyi is present in human milk. Consult your doctor before breastfeeding. 

WARNING

Flibanserin may cause low blood pressure and fainting. Patients should lie down and seek medical help if they experience fainting.

Flibanserin causes drowsiness and reduces alertness. Patients should avoid operating machinery, driving, or performing other dangerous activities for at least 6 hours after taking each dose of flibanserin.

The following adverse reactions are discussed in greater detail in other sections of the labeling:

• Hypotension and syncope
• CNS depression

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.

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.
• One of these trials (Study 5) did not evaluate 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.

Table 1. Adverse Reactions* Leading to Discontinuation in Randomized, Double-blind, Placebocontrolled Trials in 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. The majority of these adverse reactions began within the first 14 days of treatment.

Table 2. Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD

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

• Anxiety (Addyi 1.8%; placebo 1.0%),
• Constipation (Addyi 1.6%; placebo 0.4%),
• Abdominal pain (Addyi 1.5%; placebo 0.9%),
• Metrorrhagia (Addyi 1.4%; placebo 1.4%),
• Rash (Addyi 1.3%; placebo 0.8%),
• Sedation (Addyi 1.3%; placebo 0.2%), and
• Vertigo (Addyi 1%; placebo 0.3%).

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.

Accidental Injury

• In five trials of premenopausal women with HSDD, accidental injury was reported in 42/1543 (2.7%) Addyi-treated patients and 47/1905 (2.5%) placebo-treated patients.
• Among these 89 patients who experienced injuries, 9/42 (21%) Addyi-treated patients and 3/47 (6%) placebo-treated patients reported adverse reactions consistent with CNS depression (e.g., somnolence, fatigue, or sedation) within the preceding 24 hours.

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 9.9% in HC non-users, 13.4% in HC users; somnolence 10.6% in HC non-users, 12.3% in HC users; fatigue 7.5% in HC non-users, 11.4% 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 (Addyi is not approved for the treatment of postmenopausal women with HSDD).
• 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.
• A single dose of 100 mg Addyi was administered concurrently with 0.4 g/kg or 0.8 g/kg alcohol in the morning; alcohol was consumed over 10 minutes.
• 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 100 mg Addyi and 0.4 g/kg alcohol (equivalent to 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).
• 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.
• In addition, 6 (25%) of the 24 subjects co-administered 100 mg Addyi and 0.8 g/kg alcohol (equivalent to four 12 ounce cans of beer containing 5% alcohol content, four 5 ounce glasses of wine containing 12% alcohol content, or four 1.5 ounce shots of 80-proof spirit in a 70 kg person) experienced orthostatic hypotension when standing from a sitting position.
• The magnitude of the systolic blood pressure reduction 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.
• In this study, somnolence was reported in 67%, 74%, and 92% of subjects who received Addyi alone, Addyi in combination with 0.4 g/kg alcohol, and Addyi in combination with 0.8 g/kg alcohol, respectively.
• In the second alcohol interaction study, 96 healthy premenopausal women received a single dose of 100 mg Addyi concurrently with 0.2 g/kg, 0.4 g/kg, or 0.6 g/kg alcohol (equivalent to one, two or three alcoholic drinks in a 70 kg person, respectively) in the morning.
• 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.
• The study excluded subjects with a history or presence of orthostatic hypotension, history of hypotension, syncope, or dizziness.
• 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.

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.

Syncope With Ketoconazole

• In a pharmacokinetic drug interaction study of 50 mg flibanserin and 400 mg ketoconazole, a strong CYP3A4 inhibitor, syncope occurred in 1/24 (4%) healthy subjects treated with concomitant flibanserin and ketoconazole, 1/24 (4%) receiving flibanserin alone, and no subjects receiving ketoconazole alone.
• 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.

Table 3 contains clinically significant drug interactions (DI) with Addyi.

Table 3: Clinically Significant Drug Interactions with Addyi