- ACRONYMS AND DEFINITIONS
- CNS - Central nervous system
- HSDD - Hypoactive sexual desire disorder
- 5-HT - Serotonin
- DRUGS IN CLASS
- Serotonergic drugs
- Flibanserin (Addyi®)
- Other drugs for female hyposexuality
- MECHANISM OF ACTION
- Flibanserin
- The mechanism by which flibanserin supposedly increases sexual desire is not known
- Flibanserin was initially developed as a serotonergic antidepressant, but it was not found to be effective. During antidepressant trials, patients taking flibanserin gave more positive responses to the question "How strong is your sex drive?" when compared to placebo. This led to its development as a treatment for low sex drive. [1]
- Flibanserin is a serotonergic agonist/antagonist with the following properties:
- Agonist activity at 5-HT1A
- Antagonist activity at 5-HT2A
- Moderate antagonist activities at the 5-HT2B, 5-HT2C, and dopamine D4 receptors
- FDA-APPROVED INDICATION
- Indication
- Flibanserin (Addyi®) - treatment of premenopausal women with acquired, generalized hypoactive sexual desire disorder (HSDD), as characterized by low sexual desire that causes marked distress or interpersonal difficulty and is NOT due to:
- A co-existing medical or psychiatric condition
- Problems within the relationship
- The effects of a medication or other drug substance
- Restrictions
- Addyi is not indicated in postmenopausal women or in men
- Addyi does not enhance sexual performance
- Flibanserin can only be prescribed by providers who have been certified and completed training in the ADDYI REMS program. Pharmacies must also be certified to dispense ADDYI. See ADDYI REMS program for more.
- Definitions
- 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
- SEXUAL DESIRE
- Overview
- The effects of flibanserin were evaluated in three trials
- In the original application to the FDA, trials 1 and 2 were submitted. These trials included a primary endpoint where sexual desire was measured with a daily electronic diary. These 2 trials failed to show a significant improvement in sexual desire. The FDA rejected the drug based on these 2 trials.
- A third trial was then performed where sexual desire was measured with a monthly recall (as opposed to daily recall). This trial found a significant difference from placebo and the drug was eventually approved.
- An outcome that measured "number of sexually satisfying events" per month showed flibanserin to be significantly better than placebo in all 3 trials
| Number of satisfying sexual events over past 28 days (24 week study) | ||
|---|---|---|
| STUDY 1 | Flibanserin 100 mg at bedtime (n=280) |
Placebo (n=290) |
| Baseline | 3 | 2.7 |
| Change from baseline | 1.6 | 0.8 |
| Treatment difference (95% CI) |
0.9 (0.3 to 1.4) |
|
| STUDY 2 | Flibanserin 100 mg at bedtime (n=365) |
Placebo (n=372) |
| Baseline | 2.6 | 2.7 |
| Change from baseline | 1.8 | 1.1 |
| Treatment difference (95% CI) |
0.6 (0.1 to 1.2) |
|
| STUDY 3 | Flibanserin 100 mg at bedtime (n=532) |
Placebo (n=536) |
| Baseline | 2.5 | 2.7 |
| Change from baseline | 2.5 | 1.5 |
| Treatment difference (95% CI) |
1.0 (0.4 to 1.5) |
|
| Sexual desire outcomes (24 week study) | ||
|---|---|---|
| STUDY 1 | Flibanserin 100mg at bedtime (n=280) |
Placebo (n=290) |
| Baseline | 12.9 | 11.8 |
| Change from baseline | 9.1 | 6.9 |
| Treatment difference (95% CI) |
2.2 (-0.1 to 4.6) |
|
| STUDY 2 | Flibanserin 100mg at bedtime (n=365) |
Placebo (n=372) |
| Baseline | 12.1 | 10.2 |
| Change from baseline | 8.3 | 6.7 |
| Treatment difference (95% CI) |
0.8 (-0.3 to 4.0) |
|
| STUDY 3 | Flibanserin 100mg at bedtime (n=532) |
Placebo (n=536) |
| Baseline | 1.9* | 1.9* |
| Change from baseline | 1.0* | 0.7* |
| Treatment difference (95% CI) |
0.3* (0.2 to 0.4) |
|
- Summary
- In the 3 studies submitted to the FDA, flibanserin was shown to have a slight effect on female sexual desire
- Flibanserin trials had the following issues:
- When patients recorded their sexual desire on a daily basis (studies 1 and 2), there was no significant effect. When a 28-day recall was used (study 3), the effect became significant. Daily assessment is more accurate and less susceptible to recall bias.
- Flibanserin has significant side effects which may have led to unblinding. Given its modest effects, any amount of unblinding could have biased the results.
- It's conceivable that the serotonergic activity of flibanserin may have improved another disorder (e.g. mood, anxiety, depression) which secondarily improved sex life
- Based on the available evidence, patients and providers can expect the following when flibanserin is prescribed for 6 months:
- 31% of patients will discontinue the medication
- On average, patients will experience 0.6 - 1 additional satisfying sexual events per month than if they were taking a placebo
- On average, sexual desire will improve by about 6% more than if they were taking a placebo
- SIDE EFFECTS
- Common
- The most common side effects seen in clinical trials are listed in the table below
| Side effect | Flibanserin (N=1556) |
Placebo (N=1543) |
|---|---|---|
| Dizziness | 11.4% | 2.2% |
| Somnolence | 11.2% | 2.9% |
| Nausea | 10.4% | 3.9% |
| Fatigue | 9.2% | 5.5% |
| Insomnia | 4.9% | 2.8% |
| Dry mouth | 2.4% | 1.0% |
- Hypotension
- Flibanserin may cause hypotension in some patients
- The potential for hypotension is greatly increased when flibanserin is taken with alcohol (see use with alcohol below) and certain medications (see drug interactions below). Liver disease also increases the risk.
- In trials, 0.2% of flibanserin-treated patients experienced hypotension compared to < 0.1% of placebo-treated patients. Syncope was reported in 0.4% of flibanserin-treated patients and 0.2% of placebo-treated patients [2]
- Hypersensitivity reactions
- Hypersensitivity reactions, including anaphylaxis, angioedema, pruritus, and urticaria, have been reported with flibanserin. If a reaction occurs, patients should immediately discontinue flibanserin and seek appropriate medical care.
- CONTRAINDICATIONS
- Concomitant alcohol - see use with alcohol below
- Concomitant moderate or strong CYP3A4 inhibitors
- Liver disease (any degree)
- History of hypersensitivity to flibanserin or any of its components
- PRECAUTIONS
- Kidney disease
- CrCl 30 - 80 ml/min: exposure is increased 1.1-fold
- CrCl < 30 ml/min: exposure is increased 1.2-fold
- Manufacturer makes no dose adjustment recommendations
- Liver disease
- Flibanserin is contraindicated in patients with any degree of liver disease
- In trials, patients with mild liver disease had a 4.5-fold increase in exposure to flibanserin [2]
- Use with alcohol
- Taking flibanserin with alcohol may increase the risk of severe hypotension and syncope. Patients should wait at least two hours after consuming one or two standard alcoholic drinks before taking flibanserin at bedtime, and they should skip their flibanserin dose if they have consumed three or more standard alcoholic drinks that evening. Standard alcoholic drink is defined as 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol).
- In alcohol interaction studies, 17% of patients who took flibanserin 100 mg with the equivalent of 2 alcohol drinks experienced hypotension and/or syncope. In patients receiving 4 drinks with flibanserin, 25% of subjects experienced orthostatic hypotension.
- Systolic blood pressure drops up to 54 mmHg and diastolic blood pressure drops up to 46 mmHg were seen in affected patients [2]
- CNS depression
- Flibanserin causes somnolence and sedation
- The effect is increased when flibanserin is taken with certain medications (see drug interactions below)
- Flibanserin should only be taken at bedtime
- Patients should not drive or engage in activities that require mental alertness within 6 hours of taking flibanserin. Some patients may need to wait longer depending on how the drug affects them. [2]
- CYP2C19 poor metabolizers
- Flibanserin is primarily metabolized by CYP3A4. CYP2C19 is a minor pathway of flibanserin metabolism.
- Patients who are poor CYP2C19 metabolizers may have increased exposure to flibanserin and be at increased risk of side effects. [2]
- Mammary tumors
- In mice studies lasting 2 years, there was an increased risk of mammary tumors in mice receiving 3 and 10 times the recommended clinical dose of flibanserin
- The significance of this finding in humans is unknown [2]
- DRUG INTERACTIONS
- NOTE: Drug interactions presented here are NOT all-inclusive. Other interactions may exist. The interactions presented here are meant to encompass commonly prescribed medications and/or interactions that are well-documented. Always consult your physician or pharmacist before taking medications concurrently. CLICK HERE for more information on drug interactions.
- Flibanserin
- Alcohol - see use with alcohol above
- CYP3A4 inhibitors and inducers - flibanserin is a CYP3A4 sensitive substrate
- Moderate or strong CYP3A4 inhibitors - DO NOT COMBINE. High risk of hypotension and syncope. See dosing for recommendations on starting flibanserin after stopping a CYP3A4 inhibitor.
- Weak CYP3A4 inhibitors - may increase the risk of side effects
- CYP3A4 inducers - CYP3A4 inducers may decrease the effectiveness of flibanserin
- CNS depressants (e.g. benzodiazepines, opioids, antihistamines, sleep aids) - flibanserin may potentiate the sedation seen with other CNS drugs. Use caution.
- Hormonal contraceptives = The hormones in some contraceptives are weak CYP3A4 inhibitors. In trials, patients taking flibanserin with hormonal contraceptives had a slightly higher incidence of side effects
- Strong CYP2C19 inhibitors - Strong CYP2C19 inhibitors may increase exposure to flibanserin and increase the risk of side effects
- P-glycoprotein substrates - flibanserin may increase exposure to drugs that are substrates for p-glycoprotein
- Digoxin - Digoxin is a p-glycoprotein substrate. Flibanserin increases exposure to digoxin. Use caution when prescribing together.
- DOSING
- Special prescribing requirements
- Flibanserin can only be prescribed by providers who have completed training and been certified in the ADDYI REMS program
- Pharmacies must also be certified to dispense ADDYI
- See ADDYI REMS program for more.
- Dosage forms
- 100 mg tablet
- No generic. Costs > $400 for 30 tablets
- Dosing
- Standard
- 100 mg once daily at bedtime
- Discontinue after 8 weeks if no effect is seen
- Following CYP3A4 moderate or strong inhibitors
- If starting flibanserin after stopping a CYP3A4 moderate or strong inhibitor, start flibanserin 2 weeks after the last dose of the inhibitor
- If starting a CYP3A4 moderate or strong inhibitor after stopping flibanserin, start the inhibitor 2 days after the last dose of flibanserin
- Missed doses
- If a dose is missed, the next dose should be taken at bedtime on the following day
- Do not double the dose
- Food
- High fat meals increase the extent of absorption and slow the rate of absorption
- Manufacturer makes no specific dosing recommendations regarding food
- Pharmacokinetics
- Time to max concentration (Tmax): median of 0.75 hours; range of 0.75 to 4 hours
- Half-life: 11 hours
- Protein binding: 98%, mainly albumin
- LONG-TERM SAFETY
- Flibanserin was FDA-approved in 2015. It has no long-term safety data.
- BIBLIOGRAPHY
- 1 - 26148201 JAMA editorial
- 2 - Addyi PI