Flibanserin

Dosage Forms

Excipient information presented when available (limited, particularly for generics); consult specific product labeling.

Tablet, Oral:

Addyi: 100 mg

Pharmacology

Mechanism of Action

The mechanism of action in the treatment of premenopausal women with hypoactive sexual desire disorder is not known. Flibanserin exhibits agonist activity at 5-HT_1A and antagonist activity at 5-HT_2A; moderate antagonist activity is seen at the 5-HT_2B, 5-HT_2C, and dopamine D₄ receptors.

Pharmacokinetics/Pharmacodynamics

Metabolism

Primarily metabolized by CYP3A4 and, to a lesser extent, by CYP2C19 to inactive metabolites.

Excretion

Feces (51%); urine (44%)

Time to Peak

0.75 hours (range: 0.75 to 4 hours)

Half-Life Elimination

Terminal: ~11 hours; mild hepatic impairment: increased to 26 hours; CYP2C19 poor metabolizers: increased to 13.5 hours compared to CYP2C19 extensive metabolizers

Protein Binding

~98%, primarily to albumin

Use in Specific Populations

Special Populations: Renal Function Impairment

Following a single 50 mg dose in patients with renal impairment, the AUC was increased 1.1-fold in patients with mild to moderate impairment (GFR ≤80 mL/minute) and 1.2-fold in patients with severe impairment (GFR <30 mL/minute).

Special Populations: Hepatic Function Impairment

Following a single 50 mg dose in patients with mild hepatic impairment (Child-Pugh class A), the AUC was increased 4.5-fold.

Special Populations Note

CYP2C19 poor metabolizers: In patients who are poor metabolizers of CYP2C19, AUC was increased 1.3-fold, C_max was increased 1.5-fold.

Use: Labeled Indications

Hypoactive sexual desire disorder: 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 not due to a coexisting medical or psychiatric condition, problems within the relationship, or the effects of a medication or other drug substance.

Limitations of use: Flibanserin is not indicated for the treatment of HSDD in postmenopausal women or in men, or to enhance sexual performance.

Contraindications

Concomitant use with moderate or strong CYP3A4 inhibitors; hepatic impairment.

Canadian labeling: Additional contraindications (not in the US labeling): Hypersensitivity to flibanserin or any component of the formulation; patients with a resting systolic blood pressure <110 mm Hg or diastolic blood pressure <60 mm Hg in combination with alcohol; pregnancy; breastfeeding.

Dosage and Administration

Dosing: Adult

Hypoactive sexual desire disorder: Females (premenopausal): Oral: 100 mg once daily at bedtime; assess treatment efficacy at 8 weeks and discontinue if symptoms have not improved.

Missed dose: If a dose is missed, skip the missed dose and resume the normal dosing schedule at bedtime on the next day.

Dosage adjustment for the transition to or from treatment with a moderate or strong CYP3A4 inhibitors: The concomitant use of flibanserin and moderate or strong CYP3A4 inhibitors is contraindicated. The following guidelines are recommended by the manufacturer when transitioning to or from treatment with a moderate or strong CYP3A4 inhibitor:

Initiation of a moderate or strong CYP3A4 inhibitor following the use of flibanserin: Initiate the CYP3A4 inhibitor 2 days after the last dose of flibanserin. If the benefit of starting the CYP3A4 inhibitor within 2 days outweighs the risk of hypotension and syncope, monitor the patient closely.

Initiation of flibanserin following the use of a moderate or strong CYP3A4 inhibitor: Initiate flibanserin therapy 2 weeks after the last dose of the CYP3A4 inhibitor.

Administration

Administer orally once daily at bedtime

Storage

Store at 25°C (77°F); excursions permitted to 15°C to 30°C (59°F to 86°F).

Drug Interactions

Afatinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Afatinib. Management: Reduce afatinib by 10 mg if not tolerated. Some non-US labeling recommends avoiding combination if possible. If used, administer the P-gp inhibitor simultaneously with or after the dose of afatinib. Consider therapy modification

Alcohol (Ethyl): May enhance the hypotensive effect of Flibanserin. Management: Wait at least 2 hours after consuming 1 or 2 standard alcoholic drinks before taking flibanserin. Skip the flibanserin dose if 3 or more alcoholic drinks were consumed that evening. After taking flibanserin at bedtime, do not drink until the next day. Consider therapy modification

Alizapride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Azelastine (Nasal): CNS Depressants may enhance the CNS depressant effect of Azelastine (Nasal). Avoid combination

Betrixaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Betrixaban. Management: Decrease the adult betrixaban dose to an initial single dose of 80 mg followed by 40 mg once daily if combined with a P-glycoprotein inhibitor. Consider therapy modification

Bilastine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Bilastine. Management: Consider alternatives when possible; bilastine should be avoided in patients with moderate to severe renal insufficiency who are receiving p-glycoprotein inhibitors. Consider therapy modification

Blonanserin: CNS Depressants may enhance the CNS depressant effect of Blonanserin. Consider therapy modification

Brentuximab Vedotin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Brentuximab Vedotin. Specifically, concentrations of the active monomethyl auristatin E (MMAE) component may be increased. Monitor therapy

Brexanolone: CNS Depressants may enhance the CNS depressant effect of Brexanolone. Monitor therapy

Brimonidine (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromopride: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Bromperidol: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

Buprenorphine: CNS Depressants may enhance the CNS depressant effect of Buprenorphine. Management: Consider reduced doses of other CNS depressants, and avoiding such drugs in patients at high risk of buprenorphine overuse/self-injection. Initiate buprenorphine at lower doses in patients already receiving CNS depressants. Consider therapy modification

Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Cannabis: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Celiprolol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Celiprolol. Monitor therapy

Chlormethiazole: May enhance the CNS depressant effect of CNS Depressants. Management: Monitor closely for evidence of excessive CNS depression. The chlormethiazole labeling states that an appropriately reduced dose should be used if such a combination must be used. Consider therapy modification

Chlorphenesin Carbamate: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Clofazimine: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

CNS Depressants: May enhance the adverse/toxic effect of other CNS Depressants. Monitor therapy

Colchicine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Colchicine. Colchicine distribution into certain tissues (e.g., brain) may also be increased. Management: Colchicine is contraindicated in patients with impaired renal or hepatic function who are also receiving a p-glycoprotein inhibitor. In those with normal renal and hepatic function, reduce colchicine dose as directed. See full monograph for details. Consider therapy modification

Conivaptan: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

CYP2C19 Inhibitors (Moderate): May increase the serum concentration of Flibanserin. Monitor therapy

CYP3A4 Inducers (Moderate): May decrease the serum concentration of Flibanserin. Avoid combination

CYP3A4 Inducers (Strong): May decrease the serum concentration of Flibanserin. Avoid combination

CYP3A4 Inhibitors (Moderate): May increase the serum concentration of Flibanserin. Avoid combination

CYP3A4 Inhibitors (Strong): May increase the serum concentration of Flibanserin. Avoid combination

CYP3A4 Inhibitors (Weak): May increase the serum concentration of Flibanserin. Monitor therapy

Dabigatran Etexilate: P-glycoprotein/ABCB1 Inhibitors may increase serum concentrations of the active metabolite(s) of Dabigatran Etexilate. Monitor therapy

Deferasirox: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Digoxin: Flibanserin may increase the serum concentration of Digoxin. Monitor therapy

Dimethindene (Topical): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

DOXOrubicin (Conventional): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of DOXOrubicin (Conventional). Management: Seek alternatives to P-glycoprotein inhibitors in patients treated with doxorubicin whenever possible. One U.S. manufacturer (Pfizer Inc.) recommends that these combinations be avoided. Consider therapy modification

Doxylamine: May enhance the CNS depressant effect of CNS Depressants. Management: The manufacturer of Diclegis (doxylamine/pyridoxine), intended for use in pregnancy, specifically states that use with other CNS depressants is not recommended. Monitor therapy

Dronabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Droperidol: May enhance the CNS depressant effect of CNS Depressants. Management: Consider dose reductions of droperidol or of other CNS agents (eg, opioids, barbiturates) with concomitant use. Exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Consider therapy modification

Edoxaban: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Edoxaban. Management: See full monograph for details. Reduced doses are recommended for patients receiving edoxaban for venous thromboembolism in combination with certain P-gp inhibitors. Similar dose adjustment is not recommended for edoxaban use in atrial fibrillation. Consider therapy modification

Erdafitinib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Erdafitinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Esketamine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Estrogen Derivatives (Contraceptive): May increase the serum concentration of Flibanserin. Monitor therapy

Everolimus: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Everolimus. Monitor therapy

Flunitrazepam: CNS Depressants may enhance the CNS depressant effect of Flunitrazepam. Consider therapy modification

Fosaprepitant: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Fusidic Acid (Systemic): May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

HYDROcodone: CNS Depressants may enhance the CNS depressant effect of HYDROcodone. Management: Avoid concomitant use of hydrocodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

HydrOXYzine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Idelalisib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Avoid combination

Ivosidenib: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Kava Kava: May enhance the adverse/toxic effect of CNS Depressants. Monitor therapy

Larotrectinib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Larotrectinib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Larotrectinib. Monitor therapy

Lemborexant: May enhance the CNS depressant effect of CNS Depressants. Management: Dosage adjustments of lemborexant and of concomitant CNS depressants may be necessary when administered together because of potentially additive CNS depressant effects. Close monitoring for CNS depressant effects is necessary. Consider therapy modification

Lofexidine: May enhance the CNS depressant effect of CNS Depressants. Management: Drugs listed as exceptions to this monograph are discussed in further detail in separate drug interaction monographs. Monitor therapy

Magnesium Sulfate: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Methotrimeprazine: CNS Depressants may enhance the CNS depressant effect of Methotrimeprazine. Methotrimeprazine may enhance the CNS depressant effect of CNS Depressants. Management: Reduce adult dose of CNS depressant agents by 50% with initiation of concomitant methotrimeprazine therapy. Further CNS depressant dosage adjustments should be initiated only after clinically effective methotrimeprazine dose is established. Consider therapy modification

MetyroSINE: CNS Depressants may enhance the sedative effect of MetyroSINE. Monitor therapy

Minocycline (Systemic): May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Nabilone: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Naldemedine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naldemedine. Monitor therapy

Naloxegol: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Naloxegol. Monitor therapy

Opioid Agonists: CNS Depressants may enhance the CNS depressant effect of Opioid Agonists. Management: Avoid concomitant use of opioid agonists and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Orphenadrine: CNS Depressants may enhance the CNS depressant effect of Orphenadrine. Avoid combination

Oxomemazine: May enhance the CNS depressant effect of CNS Depressants. Avoid combination

OxyCODONE: CNS Depressants may enhance the CNS depressant effect of OxyCODONE. Management: Avoid concomitant use of oxycodone and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Palbociclib: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Paraldehyde: CNS Depressants may enhance the CNS depressant effect of Paraldehyde. Avoid combination

PAZOPanib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of PAZOPanib. Avoid combination

Perampanel: May enhance the CNS depressant effect of CNS Depressants. Management: Patients taking perampanel with any other drug that has CNS depressant activities should avoid complex and high-risk activities, particularly those such as driving that require alertness and coordination, until they have experience using the combination. Consider therapy modification

P-glycoprotein/ABCB1 Substrates: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of P-glycoprotein/ABCB1 Substrates. P-glycoprotein inhibitors may also enhance the distribution of p-glycoprotein substrates to specific cells/tissues/organs where p-glycoprotein is present in large amounts (e.g., brain, T-lymphocytes, testes, etc.). Exceptions: Loperamide. Monitor therapy

Piribedil: CNS Depressants may enhance the CNS depressant effect of Piribedil. Monitor therapy

Pramipexole: CNS Depressants may enhance the sedative effect of Pramipexole. Monitor therapy

Progestins (Contraceptive): May increase the serum concentration of Flibanserin. Monitor therapy

Prucalopride: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Prucalopride. Monitor therapy

Ranolazine: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ranolazine. Monitor therapy

RifAXIMin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of RifAXIMin. Monitor therapy

ROPINIRole: CNS Depressants may enhance the sedative effect of ROPINIRole. Monitor therapy

Rotigotine: CNS Depressants may enhance the sedative effect of Rotigotine. Monitor therapy

Rufinamide: May enhance the adverse/toxic effect of CNS Depressants. Specifically, sleepiness and dizziness may be enhanced. Monitor therapy

Sarilumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Selective Serotonin Reuptake Inhibitors: CNS Depressants may enhance the adverse/toxic effect of Selective Serotonin Reuptake Inhibitors. Specifically, the risk of psychomotor impairment may be enhanced. Monitor therapy

Silodosin: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Silodosin. Monitor therapy

Siltuximab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Simeprevir: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Monitor therapy

Sodium Oxybate: May enhance the CNS depressant effect of CNS Depressants. Management: Consider alternatives to combined use. When combined use is needed, consider minimizing doses of one or more drugs. Use of sodium oxybate with alcohol or sedative hypnotics is contraindicated. Consider therapy modification

Stiripentol: May increase the serum concentration of CYP3A4 Substrates (High risk with Inhibitors). Management: Use of stiripentol with CYP3A4 substrates that are considered to have a narrow therapeutic index should be avoided due to the increased risk for adverse effects and toxicity. Any CYP3A4 substrate used with stiripentol requires closer monitoring. Consider therapy modification

Suvorexant: CNS Depressants may enhance the CNS depressant effect of Suvorexant. Management: Dose reduction of suvorexant and/or any other CNS depressant may be necessary. Use of suvorexant with alcohol is not recommended, and the use of suvorexant with any other drug to treat insomnia is not recommended. Consider therapy modification

Talazoparib: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Talazoparib. Management: These listed exceptions are discussed in detail in separate interaction monographs. Monitor therapy

Tapentadol: May enhance the CNS depressant effect of CNS Depressants. Management: Avoid concomitant use of tapentadol and benzodiazepines or other CNS depressants when possible. These agents should only be combined if alternative treatment options are inadequate. If combined, limit the dosages and duration of each drug. Consider therapy modification

Tegaserod: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Tegaserod. Monitor therapy

Tetrahydrocannabinol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Tetrahydrocannabinol and Cannabidiol: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Thalidomide: CNS Depressants may enhance the CNS depressant effect of Thalidomide. Avoid combination

Tocilizumab: May decrease the serum concentration of CYP3A4 Substrates (High risk with Inducers). Monitor therapy

Topotecan: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Topotecan. Avoid combination

Trimeprazine: May enhance the CNS depressant effect of CNS Depressants. Monitor therapy

Ubrogepant: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Ubrogepant. Management: Use an initial ubrogepant dose of 50 mg and second dose (if needed) of 50 mg when used with a P-gp inhibitor. Consider therapy modification

Venetoclax: P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of Venetoclax. Management: Consider a venetoclax dose reduction by at least 50% in patients requiring concomitant treatment with P-glycoprotein (P-gp) inhibitors. Consider therapy modification

VinCRIStine (Liposomal): P-glycoprotein/ABCB1 Inhibitors may increase the serum concentration of VinCRIStine (Liposomal). Avoid combination

Zolpidem: CNS Depressants may enhance the CNS depressant effect of Zolpidem. Management: Reduce the Intermezzo brand sublingual zolpidem adult dose to 1.75 mg for men who are also receiving other CNS depressants. No such dose change is recommended for women. Avoid use with other CNS depressants at bedtime; avoid use with alcohol. Consider therapy modification

Adverse Reactions

>10%: Central nervous system: Dizziness (11%), drowsiness (11%)

1% to 10%:

Central nervous system: Fatigue (9%), insomnia (5%), anxiety (2%), sedation (1%), vertigo (1%)

Gastrointestinal: Nausea (10%), abdominal pain (2%), constipation (2%), xerostomia (2%)

<1%, postmarketing, and/or case reports: Appendicitis

Warnings/Precautions

Concerns related to adverse effects:

• CNS depression: May cause CNS depression, which may impair physical or mental abilities. Patients must be cautioned about performing tasks that require mental alertness (eg, operating machinery or driving); wait ≥6 hours before performing these tasks. The risk of CNS depression is increased with administration during waking hours, in patients with hepatic impairment, or with concomitant use of alcohol or other CNS depressants, or with medications that increase flibanserin concentrations (eg, CYP3A4 inhibitors).
• Hypotension/syncope: Use may result in hypotension and syncope; the risk is increased with administration during waking hours or if higher than the recommended dose is taken. Use with caution in patients predisposed to hypotension. Patients who experience pre-syncope should immediately lie supine and seek medical help if the symptoms do not resolve; patients who experience syncope should seek prompt medical attention.

Disease-related concerns:

• Hepatic impairment: [US Boxed Warning]: Use in patients with hepatic impairment results in increased flibanserin concentrations and a subsequent increased risk of severe hypotension and syncope; use in this patient population is contraindicated.

Concurrent drug therapy issues:

• Alcohol: [US Boxed Warning]: The use of flibanserin and alcohol together close in time increases the risk of severe hypotension and syncope. Counsel patients to wait ≥2 hours after consuming 1 or 2 standard alcoholic drinks before taking flibanserin at bedtime or to skip their flibanserin dose if they have consumed ≥3 standard alcoholic drinks that evening. One standard alcoholic drink contains 14 g pure alcohol and is equivalent to one 12 oz regular beer (5% alcohol), 5 oz wine (12% alcohol), or 1.4 oz of distilled spirits/shot (40% alcohol).
• CYP3A4 inhibitors: [US Boxed Warning]: Concomitant use of moderate or strong CYP3A4 inhibitors results in increased flibanserin concentrations and subsequent increased risk of severe hypotension and syncope; concomitant use is contraindicated. If the patient requires treatment with a moderate or strong CYP3A4 inhibitor, discontinue flibanserin at least 2 days prior to the initiation of therapy. If the benefit of starting the CYP3A4 inhibitor outweighs the risk of hypotension and syncope, monitor the patient closely. Re-initiation of flibanserin should occur at least 2 weeks after the last dose of the CYP3A4 inhibitor. Concomitant use of multiple weak CYP3A4 inhibitors (eg, ginkgo, cimetidine) may increase the risk of hypotension and syncope; use with caution.

Special populations:

• CYP2C19 poor metabolizers: Use of flibanserin in patients who are CYP2C19 poor metabolizers results in increased flibanserin concentrations and may increase the risk of hypotension and syncope; monitor these patients closely for adverse reactions.

Monitoring Parameters

Monitor for signs of hypotension and syncope

Pregnancy

Pregnancy Considerations

Adverse events were observed in some animal reproduction studies.

Patient Education

• Discuss specific use of drug and side effects with patient as it relates to treatment. (HCAHPS: During this hospital stay, were you given any medicine that you had not taken before? Before giving you any new medicine, how often did hospital staff tell you what the medicine was for? How often did hospital staff describe possible side effects in a way you could understand?)
• Patient may experience nausea, loss of strength and energy, trouble sleeping, or dry mouth. Have patient report immediately to prescriber dizziness, passing out, or severe fatigue (HCAHPS).
• Educate patient about signs of a significant reaction (eg, wheezing; chest tightness; fever; itching; bad cough; blue skin color; seizures; or swelling of face, lips, tongue, or throat). Note: This is not a comprehensive list of all side effects. Patient should consult prescriber for additional questions.

Intended Use and Disclaimer: Should not be printed and given to patients. This information is intended to serve as a concise initial reference for health care professionals to use when discussing medications with a patient. You must ultimately rely on your own discretion, experience, and judgment in diagnosing, treating, and advising patients.