RX FOCUS DRUG INTERACTIONS Flibanserin: Hypotension and Syncope with Drug Interactions John R. Horn, PharmD, FCCP, and Philip D. Hansten, PharmD

a heart rate of 50 beats per minute. The flibanserin. Alcohol administration did subject responded to fluid administration. not alter the pharmacokinetics of fliban- Other drugs that inhibit both CYP3A4 serin. However, patients taking flibanserin and CYP2C19 (delavirdine, fluvoxamine, should be counseled to avoid alcohol. INH, and voriconazole) would likely pro- duce similarly large increases in flibanserin Oral Contraceptives plasma concentrations. Patients who are poor Based on a meta-analysis of pharmacoki- metabolizers of CYP2C19 may demonstrate netic data, patients taking oral contracep- an exaggerated response to CYP3A4 inhibi- tives (OCs) had an average 40% increase John R. Horn, PharmD, Philip D. Hansten, FCCP PharmD tors. Grapefruit juice (8 oz regular strength) in flibanserin concentration compared with increased the AUC of flibanserin by 40%. patients not taking OCs. Pending a con- libanserin (Addyi) has been approved With all of these interactions, inhibition of the trolled trial, patients on OCs should be by the FDA for the treatment of CYP3A4 metabolism of flibanserin resulted monitored for increased flibanserin AEs. hypoactive sexual desire disorder in in increased serum concentrations. It would F 1 premenopausal women. Primarily metabo- be prudent to avoid administering CYP3A4 Digoxin lized by CYP3A4 and, to a smaller extent, inhibitors (eg, clarithromycin, erythromy- The administration of flibanserin 100 mg by CYP2C19, flibanserin appears to be an cin, cyclosporine, imatinib, miconazole, daily for 5 days increased the AUC of inhibitor of P-glycoprotein and perhaps posaconazole, ritonavir, and voriconazole) a single 0.5-mg dose of digoxin almost CYP3A4. Adverse effects (AEs) associ- to patients taking flibanserin. 2-fold. Based on this study’s results, it ated with the administration of flibanserin appears that flibanserin has P-glycoprotein- include sedation, hypotension, and syn- CYP3A4 Inducers blocking activity. Patients taking digoxin cope. These AEs can be Rifampin 600 mg daily for should be monitored for AEs (arrhyth- exacerbated by drug inter- 7 days reduced the mean mia, bradycardia, anorexia) if flibanserin is actions with flibanserin. Flibanserin AUC of flibanserin by added to their dosage regimen. (Addyi) has 95%. Etravirine, a mod- CYP3A4 Inhibitors est CYP3A4 inducer and Simvastatin The administration of keto- been approved weak CYP2C19 inhibitor, In a study of 12 subjects, flibanserin 50 conazole 400 mg daily for reduced the AUC of fliban- mg twice daily for 4 days caused the 5 days increased the mean by the FDA to serin by about 20%. Based mean AUC of simvastatin, following a area under the concentra- treat hypoactive on these study results, other single 40-mg dose, to increase 2.6-fold. tion time curve (AUC) by inducers of CYP3A4— Lovastatin and atorvastatin plasma concen- more than 4.5-fold. The sexual desire such as barbiturates, car- trations would be expected to increase with half-life of flibanserin was bamazepine, bosentan, flibanserin administration. Monitor patients increased from a mean disorder in phenytoin, rifabutin, and receiving these statins plus flibanserin for 11 hours to more than premenopausal St. John’s wort—are like- complaints of muscle weakness or pain. 18 hours following keto- ly to reduce the efficacy conazole administration. women. of flibanserin. CYP3A4 Summary Itraconazole 200 mg daily inducers should also be Patients taking flibanserin are at risk of for 8 days produced a 2.6-fold increase in avoided in patients taking flibanserin. a number of potential drug interactions. the AUC of flibanserin. Full therapeutic The hypotension and syncope outcomes doses of itraconazole would likely produce Alcohol prompted the FDA to require a risk evalua- a larger increase in AUC. Fluconazole In several studies, the administration of tion and mitigation strategy for flibanserin inhibits both CYP3A4 and CYP2C19. alcohol with flibanserin resulted in hypo- patients. Pharmacists should be vigilant in When a fluconazole 400-mg loading dose tensive episodes or syncope. The reduction monitoring for potential interactions with followed by 200 mg daily for 3 days was in systolic blood pressure exceeded 45 flibanserin to mitigate the risk of AEs in administered with flibanserin, the mean mm Hg in some subjects. Doses of alcohol patients taking the drug. n AUC increased 7-fold and its half-life ranged from 0.4 to 0.8 g/kg (about 2 to increased by 13 hours. During this study, 4 drinks); higher doses of alcohol tended Drs. Horn and Hansten are both professors of pharmacy at the University of Washington several subjects became hypotensive, with to increase the hypotensive response. As School of Pharmacy. For an electronic version one of the subjects becoming unresponsive expected, alcohol also increased the central of this article, including references, if any, visit with a blood pressure of 64/41 mm Hg and nervous system depression associated with www.hanstenandhorn.com.

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