FLIBANSERIN Drug Interactions: What You Need to Know

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Drug Interactions (FDA Label)

INTERACTIONS 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 [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).

Oral Contraceptives and Other Weak CYP3A4 Inhibitors : Increases flibanserin exposures and incidence of adverse reactions (6.1, 7)
Strong CYP2C19 Inhibitors : Increases flibanserin exposure which may increase risk of hypotension, syncope, and CNS depression (7)
CYP3A4 Inducers : Use of ADDYI not recommended; flibanserin concentrations substantially reduced (7)
Digoxin : Increases digoxin concentrations, which may lead to digoxin toxicity. Increase monitoring of digoxin concentrations (7)

Contraindications

ADDYI is contraindicated in patients:

Using concomitant moderate or strong CYP3A4 inhibitors [see Boxed Warning and Warnings and Precautions (5.2) ] .
With hepatic impairment [see Boxed Warning and Warnings and Precautions (5.5) ] .
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 [see Adverse Reactions (6.2) ] .
Moderate or strong cytochrome P450 3A4 (CYP3A4) inhibitors (4, 5.2)
Hepatic impairment (4, 5.5)
Known hypersensitivity to ADDYI or its components ( 4 , 5.6 , 6.2 )

Related Warnings

AND PRECAUTIONS

Hypotension and Syncope due to an Interaction with Alcohol : After taking ADDYI at bedtime, advise patients to avoid alcohol until the following day. (5.1)
Central Nervous System (CNS) Depression (e.g., Somnolence, Sedation) : Can occur with ADDYI alone. Exacerbated by other CNS depressants, and in settings where flibanserin concentrations are increased. Patients should avoid activities requiring full alertness (e.g., driving or operating machinery) until at least six hours after each dose and until they know how ADDYI affects them. (5.3)
Hypotension and Syncope with ADDYI Alone : Patients with pre-syncope should immediately lie supine and promptly seek medical help if symptoms do not resolve. (5.4)
Hypersensitivity Reactions, including anaphylaxis, angioedema, pruritus, urticaria : Avoid in women with known hypersensitivity to ADDYI or any of its components ( 5.6 )

5.1 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 [see Boxed Warning and Adverse Reactions (6.1) ] . Patients who drink three or more standard alcoholic drinks should skip their ADDYI dose that evening. One standard alcoholic drink contains 14 grams of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol). After taking ADDYI at bedtime, advise patients to not use alcohol until the following day.

5.2 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 [see Adverse Reactions (6.1) ]. 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 [see Drug Interactions (7) ].

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 [see Drug Interactions (7) ] .

5.3 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 [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . 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 [see Contraindications (4), Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1) , and Drug Interactions (7) ]. 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 [see Clinical Studies (14.3) ].

5.4 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 [see Warnings and Precautions (5.1, 5.3) , Adverse Reactions (6.1) , Drug Interactions (7) , and Use in Specific Populations (8.7) ]. 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.

5.5 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 [see Contraindications (4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

5.6 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 [see Adverse Reactions (6.2) ] . Immediately discontinue ADDYI and initiate appropriate treatment if a hypersensitivity reaction occurs.

5.7 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 [see Nonclinical Toxicology (13.1)] . The clinical significance of these findings is unknown.

5.1 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 [see Boxed Warning and Adverse Reactions (6.1) ] . Patients who drink three or more standard alcoholic drinks should skip their ADDYI dose that evening. One standard alcoholic drink contains 14 grams of pure alcohol and is equivalent to one 12-ounce regular beer (5% alcohol), 5-ounces wine (12% alcohol), or 1.5 ounces of distilled spirits/shot (40% alcohol). After taking ADDYI at bedtime, advise patients to not use alcohol until the following day.

5.2 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 [see Adverse Reactions (6.1) ]. 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 [see Drug Interactions (7) ].

Multiple Concomitant

5.3 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 [see Adverse Reactions (6.1) and Clinical Studies (14.1) ] . 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 [see Contraindications (4), Warnings and Precautions (5.1, 5.2), Adverse Reactions (6.1) , and Drug Interactions (7) ]. 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 [see Clinical Studies (14.3) ].

5.4 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 [see Warnings and Precautions (5.1, 5.3) , Adverse Reactions (6.1) , Drug Interactions (7) , and Use in Specific Populations (8.7) ]. 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.

5.5 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 [see Contraindications (4), Use in Specific Populations (8.6) and Clinical Pharmacology (12.3) ].

5.6 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 [see Adverse Reactions (6.2) ] . Immediately discontinue ADDYI and initiate appropriate treatment if a hypersensitivity reaction occurs.

5.7 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 [see Nonclinical Toxicology (13.1)] . The clinical significance of these findings is unknown.

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