Addyi

Name: Addyi

What should I do if I forget a dose?

If a dose is missed at bedtime, take the next dose at bedtime the following day. Do not take a double dose to make up for a missed one.

Brand names

  • Addyi®

What is flibanserin?

Flibanserin is available only from a certified pharmacy under a special program.

Flibanserin is used to treat decreased sexual desire in women who have not gone through menopause and who have never had low sexual desire in the past. Flibanserin is for use only when low sexual desire is NOT caused by a medical condition, a mental disorder, relationship problems, or by using drugs or other medicines.

Flibanserin is not for women who have already gone through menopause. This medicine is also not for use by men.

Flibanserin may also be used for purposes not listed in this medication guide.

What happens if I miss a dose?

Skip the missed dose and take the medicine the following day at bedtime. Do not take flibanserin in the morning, and do not take extra medicine to make up the missed dose.

Stability

Storage

Oral

Tablets

25°C (may be exposed to 15–30°C).1

Before Using Addyi

In deciding to use a medicine, the risks of taking the medicine must be weighed against the good it will do. This is a decision you and your doctor will make. For this medicine, the following should be considered:

Allergies

Tell your doctor if you have ever had any unusual or allergic reaction to this medicine or any other medicines. Also tell your health care professional if you have any other types of allergies, such as to foods, dyes, preservatives, or animals. For non-prescription products, read the label or package ingredients carefully.

Pediatric

Flibanserin should never be used in children for HSDD.

Geriatric

Flibanserin is not recommended for use in the elderly. Safety and efficacy have not been established.

Breast Feeding

There are no adequate studies in women for determining infant risk when using this medication during breastfeeding. Weigh the potential benefits against the potential risks before taking this medication while breastfeeding.

Interactions with Medicines

Although certain medicines should not be used together at all, in other cases two different medicines may be used together even if an interaction might occur. In these cases, your doctor may want to change the dose, or other precautions may be necessary. When you are taking this medicine, it is especially important that your healthcare professional know if you are taking any of the medicines listed below. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following medicines is not recommended. Your doctor may decide not to treat you with this medication or change some of the other medicines you take.

  • Amifampridine
  • Amprenavir
  • Aprepitant
  • Atazanavir
  • Boceprevir
  • Ciprofloxacin
  • Clarithromycin
  • Colchicine
  • Conivaptan
  • Diltiazem
  • Dronedarone
  • Erythromycin
  • Fluconazole
  • Fosamprenavir
  • Fosaprepitant
  • Imatinib
  • Indinavir
  • Itraconazole
  • Ketoconazole
  • Lopinavir
  • Nefazodone
  • Nelfinavir
  • Posaconazole
  • Ritonavir
  • Saquinavir
  • Telaprevir
  • Telithromycin
  • Verapamil
  • Voriconazole

Using this medicine with any of the following medicines is usually not recommended, but may be required in some cases. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Acepromazine
  • Alfentanil
  • Alprazolam
  • Amisulpride
  • Amobarbital
  • Anileridine
  • Aripiprazole
  • Asenapine
  • Baclofen
  • Benperidol
  • Betrixaban
  • Bromazepam
  • Buprenorphine
  • Buspirone
  • Butabarbital
  • Butorphanol
  • Carbinoxamine
  • Carisoprodol
  • Carphenazine
  • Chloral Hydrate
  • Chlordiazepoxide
  • Chlorpromazine
  • Chlorzoxazone
  • Clobazam
  • Clonazepam
  • Clorazepate
  • Clozapine
  • Codeine
  • Cyclobenzaprine
  • Dabigatran Etexilate
  • Dexmedetomidine
  • Diazepam
  • Dichloralphenazone
  • Difenoxin
  • Dihydrocodeine
  • Diphenhydramine
  • Diphenoxylate
  • Doxylamine
  • Droperidol
  • Eluxadoline
  • Enflurane
  • Estazolam
  • Eszopiclone
  • Ethchlorvynol
  • Ethopropazine
  • Ethylmorphine
  • Fentanyl
  • Fluphenazine
  • Flurazepam
  • Fluspirilene
  • Fospropofol
  • Halazepam
  • Haloperidol
  • Halothane
  • Hexobarbital
  • Hydrocodone
  • Hydromorphone
  • Hydroxyzine
  • Isoflurane
  • Ketamine
  • Ketazolam
  • Ketobemidone
  • Levorphanol
  • Lorazepam
  • Loxapine
  • Meclizine
  • Melperone
  • Meperidine
  • Mephobarbital
  • Meprobamate
  • Meptazinol
  • Mesoridazine
  • Metaxalone
  • Methadone
  • Methdilazine
  • Methocarbamol
  • Methohexital
  • Methotrimeprazine
  • Methylene Blue
  • Midazolam
  • Molindone
  • Moricizine
  • Morphine
  • Morphine Sulfate Liposome
  • Nalbuphine
  • Nicomorphine
  • Nitrazepam
  • Nitrous Oxide
  • Olanzapine
  • Opium
  • Opium Alkaloids
  • Orphenadrine
  • Oxazepam
  • Oxycodone
  • Oxymorphone
  • Papaveretum
  • Paregoric
  • Pentazocine
  • Pentobarbital
  • Perampanel
  • Perazine
  • Periciazine
  • Perphenazine
  • Pimozide
  • Piperacetazine
  • Pipotiazine
  • Piritramide
  • Pitolisant
  • Prazepam
  • Primidone
  • Prochlorperazine
  • Promazine
  • Promethazine
  • Propofol
  • Quazepam
  • Quetiapine
  • Ramelteon
  • Remifentanil
  • Remoxipride
  • Ribociclib
  • Secobarbital
  • Sertindole
  • Sodium Oxybate
  • Sufentanil
  • Sulpiride
  • Suvorexant
  • Tapentadol
  • Temazepam
  • Thiethylperazine
  • Thiopental
  • Thiopropazate
  • Thioridazine
  • Tilidine
  • Tizanidine
  • Tolonium Chloride
  • Topiramate
  • Tramadol
  • Triazolam
  • Trifluoperazine
  • Trifluperidol
  • Triflupromazine
  • Trimeprazine
  • Zaleplon
  • Zolpidem
  • Zopiclone
  • Zotepine

Using this medicine with any of the following medicines may cause an increased risk of certain side effects, but using both drugs may be the best treatment for you. If both medicines are prescribed together, your doctor may change the dose or how often you use one or both of the medicines.

  • Digoxin

Interactions with Food/Tobacco/Alcohol

Certain medicines should not be used at or around the time of eating food or eating certain types of food since interactions may occur. Using alcohol or tobacco with certain medicines may also cause interactions to occur. The following interactions have been selected on the basis of their potential significance and are not necessarily all-inclusive.

Using this medicine with any of the following is not recommended. Your doctor may decide not to treat you with this medication, change some of the other medicines you take, or give you special instructions about the use of food, alcohol, or tobacco.

  • Ethanol
  • Grapefruit Juice

Other Medical Problems

The presence of other medical problems may affect the use of this medicine. Make sure you tell your doctor if you have any other medical problems, especially:

  • Depression or mental illness, history of or
  • Drug or alcohol abuse, or history of or
  • Hypotension (low blood pressure)—Use with caution. May make these conditions worse.
  • Liver problem—Should not be used in patients with this condition.

How is this medicine (Addyi) best taken?

Use Addyi as ordered by your doctor. Read all information given to you. Follow all instructions closely.

  • Take this medicine at bedtime.
  • To gain the most benefit, do not miss doses.
  • Keep taking Addyi as you have been told by your doctor or other health care provider, even if you feel well.

What do I do if I miss a dose?

  • Skip the missed dose and go back to your normal time.
  • Do not take 2 doses at the same time or extra doses.

Contraindications

Addyi is contraindicated:

• With use of alcohol [see Boxed Warning and Warnings and Precautions (5.1, 5.2, 5.4)]. • With concomitant use with moderate or strong CYP3A4 inhibitors [see Boxed Warning and Warnings and Precautions (5.2, 5.4)]. • In patients with hepatic impairment [see Boxed Warning and Warnings and Precautions (5.6)].

Adverse Reactions

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

• Hypotension and syncope [see Warnings and Precautions (5.1, 5.3, 5.5, 5.6)] • CNS depression [see Warnings and Precautions (5.4)]

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 (14.1)]. 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, Placebo-controlled Trials in Premenopausal Women with HSDD
* Adverse reactions leading to discontinuation of ≥1% of patients receiving 100 mg Addyi at bedtime and at a higher incidence than placebo-treated patients.

 

Placebo (N=1556)

Addyi (N=1543)

   Dizziness

0.1%

1.7%

   Nausea

0.1%

1.2%

   Insomnia

0.2%

1.1%

   Somnolence

 0.3%

1.1% 

   Anxiety

 0.3%

 1%

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.

Table 2. Common Adverse Reactions* in Randomized, Double-blind, Placebo-controlled Trials in Premenopausal Women with HSDD
* Adverse reactions reported in ≥2% of patients receiving 100 mg Addyi at bedtime and at a higher incidence than placebo-treated patients.

 

Placebo
(N=1556)

Addyi
(N=1543)

   Dizziness

2.2%

11.4%

   Somnolence

2.9%

11.2%

   Nausea

3.9%

10.4%

   Fatigue

 5.5%

9.2%

   Insomnia

 2.8%

4.9%

   Dry mouth

 1.0%

2.4%

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:

• 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 [see Drug Interactions (7)].

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) [see Indications and Usage (1)]. 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 [see Boxed Warning and Warnings and Precautions (5.1)].

Hypotension, Syncope, and CNS Depression in Studies of Healthy Subjects

Hypotension, Syncope, and CNS Depression with Alcohol
In a cross-over alcohol interaction study of 100 mg Addyi and alcohol in 25 healthy subjects dosed in the morning [see Clinical Pharmacology (12.2)], somnolence was reported in 67%, 74%, and 92% of subjects who received Addyi alone, Addyi in combination with 0.4 g/kg ethanol, and Addyi in combination with 0.8 g/kg ethanol, respectively. In the group receiving Addyi in combination with 0.4 g/kg ethanol, 4/23 (17%) subjects had substantial reductions in blood pressure, resulting in hypotension and/or syncope requiring medical intervention. In the group receiving Addyi in combination with 0.8 g/kg ethanol, 6/24 (25%) subjects experienced orthostatic hypotension [see Boxed Warning, Contraindications (4), Warnings and Precautions (5.1, 5.3)].

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 [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)].

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 [see Warnings and Precautions (5.3), Drug Interactions (7) and Clinical Pharmacology (12.3)].

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 [see Drug Interactions (7), Use in Specific Populations (8.7) and Clinical Pharmacology (12.5)].

Drug Interactions

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

Table 3: Clinically Significant Drug Interactions with Addyi

Alcohol

Clinical Implications

The concomitant use 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

The concomitant use of Addyi with alcohol is contraindicated.

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 (5.3), 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).  

Overdosage

Overdosage of Addyi may cause an increase in the incidence or severity of any of the reported adverse reactions [see Warnings and Precautions (5.4,5.5) and Adverse Reactions (6.1)].  In the event of overdosage, treatment should address the symptoms and supportive measures, as needed. There is no known specific antidote for flibanserin.

Nonclinical Toxicology

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 (adenoacanthoma 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).

Clinical Studies

Trials in Premenopausal HSDD Patients

The efficacy of Addyi for the treatment of HSDD in premenopausal women was established in three 24-week, randomized, double-blind, placebo-controlled trials (Studies 1, 2, and 3). The three trials included premenopausal women with acquired, generalized HSDD of at least 6 months duration. In the clinical trials, 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 mean age of study participants was 36 years old (range 19 to 55 years old); the mean duration in the monogamous, heterosexual relationship was 11 years, and the mean duration of HSDD was approximately 5 years. 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 Study 3: • 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. • 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).

The efficacy results from Studies 1, 2, and 3 are summarized in Table 6. In all 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.

Table 6 Efficacy Results in Premenopausal HSDD Patients in Studies 1, 2, and 3
  Study 1 Study 21 Study 3
  Addyi
Placebo Addyi
Placebo Addyi
Placebo
Full Analysis Set    n=280 n=290 n=365 n=372 n=532 n=536

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)

 

0.6 (-0.03, 1.2)

 

1.0 (0.4, 1.5)

 

    Change from baseline (Median)

1.0

 0.0

1.0

0.5 

1.0

0.5 

    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/A2

 

   N/A2

 

p<0.0001

 

FSDS-R Question 133   

 

 

 

 

 

 

    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/A2

 

N/A2

 

p=0.0001

 

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.
1Excludes subjects from two study sites that had data integrity issues
2p-value not reported for secondary endpoints because the trial failed on the eDiary Desire co-primary efficacy endpoint
3A decrease in score represents improvement

Exploratory analyses were conducted to assess whether the treatment effects varied depending on baseline number of SSEs, FSFI Desire score, and FSDS-R Question 13 distress score. 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 first analysis considered responders to be those who reported being “much improved” or “very much improved.” In this analysis, the absolute difference in the percentage of responders with Addyi and the percentage of responders with placebo across the three trials was 8-9% for SSEs (29-39% for Addyi; 21-31% for placebo), 10-13% for FSFI desire domain (43-48% for Addyi; 31-38% for placebo), and 7-13% for FSDS-R Question 13 (21-34% for Addyi; 14-25% for placebo). The second analysis considered responders to be those who reported being at least minimally improved. The absolute difference in the percentage of responders with Addyi and the percentage of responders with placebo across the three trials was 10-15% for SSEs (44-48% for Addyi; 33-36% for placebo), 12-13% for FSFI desire domain (43-51% for Addyi; 31-39% for placebo), and 9-12% for FSDS-R Question 13 (50-60% for Addyi; 41-48% for placebo).

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 (5.4)].

Warnings

Black Box Warnings

Contraindicated with alcohol

  • Use with alcohol increases risk of severe hypotension and syncope; therefore, alcohol use is contraindicated
  • Before prescribing flibanserin, assess the likelihood of the patient abstaining from alcohol, taking into account the patient’s current and past drinking behavior, and other pertinent social and medical history
  • Counsel patients who are prescribed flibanserin about the importance of abstaining from alcohol use
  • Because of the increased risk of hypotension and syncope is due to an interaction with alcohol, flibanserin is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called the ADDYI REMS Program

Contraindicated with moderate or strong CYP3A4 inhibitors

  • Coadministration with moderate or strong CYP3A4 inhibitors increases flibanserin concentrations, which can cause severe hypotension and syncope
  • Therefore, the use of moderate or strong CYP3A4 inhibitors is contraindicated

Contraindicated in patients with hepatic impairment

  • Contraindicated for use with any degree of hepatic impairment
  • Flibanserin exposure increased 4.5-fold in patients with hepatic impairment, compared with those with normal hepatic function, increasing the risk of hypotension, syncope, and CNS depression

Contraindications

Use with alcohol

Coadministration with moderate or strong CYP3A4 inhibitors

Any degree of hepatic impairment

Cautions

Coadministration with alcohol increases the risk of severe hypotension and syncope (also see Contraindications and Black Box Warnings)

Coadministration with moderate or strong CYP3A4 inhibitors is significantly increases flibanserin concentrations, which can lead to hypotension and syncope (also see Contraindications, Black Box Warnings, and Dosing)

Concomitant use of multiple weak CYP3A4 inhibitors that may include herbal supplements (eg, ginkgo, resveratrol) or nonprescription drugs (eg, cimetidine) could also lead to clinically relevant increases in flibanserin concentrations that may increase the risk of hypotension and syncope

Causes CNS depression (eg, somnolence, sedation); risk of CNS depression is increased if taken during waking hours, or with alcohol or other CNS depressants, or with medications that increase flibanserin concentrations (eg, CYP3A4 inhibitors)

Hypotension and syncope can also occur with flibanserin taken alone

The use in patients with any degree of hepatic impairment is contraindicated; hepatic impairment significantly increases flibanserin concentrations, which can lead to hypotension and syncope

What happens if I overdose?

Seek emergency medical attention or call the Poison Help line at 1-800-222-1222.

What other drugs will affect Addyi?

Taking this medicine with other drugs that make you sleepy or lower your blood pressure can worsen this effect. Ask your doctor before taking Addyi with a sleeping pill, narcotic pain medicine, muscle relaxer, or medicine for anxiety, depression, or seizures.

Tell your doctor about all your current medicines and any you start or stop using, especially:

  • cimetidine;

  • gingko biloba;

  • resveratrol; or

  • St. John's wort.

This list is not complete. Other drugs may interact with flibanserin, including prescription and over-the-counter medicines, vitamins, and herbal products. Not all possible interactions are listed in this medication guide.

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