Flibanserin

The concomitant use of Addyi with digoxin, a drug that is transported by P-glycoprotein (P-gp), increases the digoxin concentration. This may lead to digoxin toxicity.

In this study the functional interaction of the antidepressant drugs amitriptyline, mianserin, maprotiline, imipramine, fluoxetine and the putative antidepressant drug flibanserin has been studied on 5-HT7-mediated responses to 5-carboxamidotryptamine (5-CT) in the guinea-pig ileum. 5-CT induced a concentration-dependent inhibition of the contractile response to substance P (100 nM). Except for fluoxetine and flibanserin, all the antidepressants antagonized by different degrees the 5-CT inhibitory response with the following rank affinity order: mianserin > maprotiline > imipramine > amitriptyline. Mianserin was the only antidepressant to show a profile of competitive antagonism at 5-HT7 receptors in a tenfold range of concentrations (0.1-1 microM), with an affinity (pA2) value of 8.1 +/- 0.6. The antagonism of the other antidepressants was not concentration-dependent (amitriptyline) or was associated with slight or moderate reduction of the maximal 5-CT response (imipramine or maprotiline). The apparent affinity (pKB) values were: amitriptyline, 7.0 +/- 0.2; maprotiline, 7.3 +/- 0.6; imipramine, 7.2 +/- 0.4. Our results show that various +antidepressant drugs belonging to different chemical classes behave as antagonists at enteric 5-HT7 receptors through competitive or allosteric mechanisms. This evidence extends our previous findings demonstrating the interaction of antidepressants with other 5-HT receptors, namely 5-HT3 and 5-HT4 receptors.

The concomitant use of Addyi with CYP3A4 inducers substantially decreases flibanserin exposure compared to the use of Addyi alone. Examples of CYP3A4 inducers: Carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapetine, St. John's Wort.

The concomitant use of Addyi with strong CYP2C19 inhibitors may increase flibanserin exposure which may increase the risk of hypotension, syncope, and CNS depression. Examples of strong CYP2C19 inhibitors: Proton pump inhibitors, selective serotonin reuptake inhibitors, benzodiazepines, antifungals.

For more Interactions (Complete) data for Flibanserin (10 total), please visit the HSDB record page.

In placebo controlled trials, liver test abnormalities were no more common with flibanserin than with placebo treatment, and what abnormalities occurred were mild and resolved spontaneously, usually without need for dose interruption. During these premarketing clinical trials and since its more widespread clinical availability, no instances of acute liver injury with jaundice have been reported attributable to flibanserin. However, the total clinical experience with flibanserin use has been limited. Many other serotonergic agents, such as the SSRIs, have been implicated in rare instances of clinically apparent liver injury. The latency to onset is typically 1 to 8 weeks and the pattern of enzyme elevations varies, ranging from cholestatic to hepatocellular. Mild signs and symptoms of hypersensitivity (rash, fever, eosinophilia) are common, but usually not prominent. Autoantibody formation is rare. The course is generally self-limited and mild-to-moderate in severity, but fatalities have been reported with some SSRIs. However, flibanserin itself has not been implicated in similar cases.

The most frequently reported adverse effects of flibanserin, with an incidence of over 2%, include dizziness, somnolence, nausea, fatigue, insomnia, and dry mouth, listed in descending order of frequency. Hypotension and syncope may manifest if flibanserin is combined with moderate or potent CYP3A4 inhibitors in individuals with hepatic impairment, alcohol, or other medications known for inducing hypotension and syncope. Less frequently reported adverse effects in clinical trials include anxiety, constipation, abdominal pain, sedation, accidental injury, appendicitis, and vertigo.

IDENTIFICATION AND USE: Flibanserin (trade name Addyi) is a non-hormonal drug approved for the treatment of generalized hypoactive sexual desire disorder (HSDD) in pre- and postmenopausal women. HUMAN EXPOSURE AND TOXICITY: The adverse event profile of flibanserin is similar to that of other centrally acting drugs. In human exposure studies, the most common reported adverse event was sedation/ drowsiness. Dizziness, nausea, fatigue and somnolence were also reported. Flibanserin can cause CNS depression. The use of flibanserin in patients with hepatic impairment increases flibanserin concentrations, which can cause severe hypotension and syncope. Hypotension and syncope are also an increased risk for patients taking moderate to strong CYP3A4 inhibitors. Concomitant alcohol use also increases the risk of severe hypotension and syncope in patients taking flibanserin. Flibanserin has preferential affinity for serotonin 5-HT(1A), dopamine D(4k), and serotonin 5-HT(2A) receptors. In vitro and in microiontophoresis, flibanserin behaves as a 5-HT(1A) agonist, a very weak partial agonist on dopamine D(4) receptors, and a 5-HT(2A) antagonist. Flibanserin does not display consistent effects in animal models of anxiety and seems to exert potential antipsychotic effects. Flibanserin may induce some sedation but does not induce observable toxic effects at pharmacologically relevant doses. ANIMAL STUDIES: In carcinogenicity studies, mammary tumors were observed in female mice. Hepatocellular carcinomas were reported in female and male mice, however, these effects were only noted in animals exposed to flibanserin at 3-10 x the clinically recommended dose.

Research conducted on animals has revealed that female rats developed mammary tumors when exposed to flibanserin within 2 years and at doses exceeding recommendations 3 to 10 times. Although the clinical significance in human studies has not been determined, it has been included in package labeling as a warning. Patients should not exceed the prescribed daily dosage of 100 mg of flibanserin. Doses exceeding 250 mg/d may be intolerable and can further exacerbate the noted effects. Currently, no known antidotes are available to reverse the effects of toxicity caused by flibanserin.

/HUMAN EXPOSURE STUDIES/ Flibanserin is being developed for treating hypoactive sexual desire disorder in women; the main side effect is sedation. The analysis objective was to relate flibanserin plasma concentrations with acute sedative effects using a population pharmacokinetic/pharmacodynamic (PK/PD) model. The population model was developed with NONMEM based on data from 24 healthy volunteers. "Drowsiness" was serially assessed by a Visual Analogue Scale (VAS) on a baseline day and after morning oral administration of 100 mg flibanserin together with PK sampling. PK was best described by a three-compartment disposition model and transit compartments accounting for the lag time in absorption. VAS "drowsiness" baseline profiles were modeled using linear splines with three breakpoints located at clock times at first and last observation, and at the median of the observation time across subjects. The drug effect followed a sigmoidal E(MAX) model using predicted effect site concentrations (C(e)). The VAS vs. C(e) relationship was very steep and effect site and plasma concentration-time profiles were very similar thus suggesting little delay between the occurrence of maximum flibanserin plasma concentrations and drowsiness. At effect site concentrations lower than approximately 200 ng/mL that are reached approximately 4 hr after administration, flibanserin shows hardly any effect on the VAS "drowsiness" scale.

/OTHER TOXICITY INFORMATION/ Flibanserin works by correcting an imbalance of the levels of the neurotransmitters that affect sexual desire. More specifically, flibanserin increases dopamine and norepinephrine, both responsible for sexual excitement, and decreases serotonin, responsible for sexual inhibition.

Drug Induced Liver Injury Rank (DILIrank 2.0)

Flibanserin

vNo-DILI-concern

0

No match

DOI:10.1016/j.drudis.2016.02.015

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ There were no significant increases in tumor incidence in a two year carcinogenicity study conducted in 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).

/LABORATORY ANIMALS: Chronic Exposure or Carcinogenicity/ A two-year carcinogenicity study was conducted in mice with dietary administration of 0, 10, 80, 200 and 1000/1200 mg/kg/day of flibanserin. Statistically significant increases in combined mammary tumors (adenocanthomas 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 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).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ 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).

/LABORATORY ANIMALS: Developmental or Reproductive Toxicity/ Pregnant rats were administered flibanserin at doses of 0, 20, 80 and 200 mg/kg/day (3, 15 and approximately 20 times clinical exposures at the recommended human dose) from day 6 of pregnancy until day 21 of lactation to assess for effects on peri- and postnatal development. The highest dose was associated with clinical signs of toxicity in pregnant and lactating rats. All doses resulted in sedation and decreases in body weight gain during pregnancy. Flibanserin prolonged gestation in some dams in all dose groups and decreased implantations, number of fetuses and fetal weights at 200 mg/kg/day. Dosing dams with 200 mg/kg also decreased pup weight gain and viability during the lactation period and delayed opening of the vagina and auditory canals. Flibanserin had no effects on learning, reflexes, fertility or reproductive capacity of the F1 generation. The no adverse effect level for maternal toxicity and peri/postnatal effects was 20 mg/kg/day.

For more Non-Human Toxicity Excerpts (Complete) data for Flibanserin (9 total), please visit the HSDB record page.

CYP2C19 poor metabolizers had increased flibanserin exposures compared to CYP2C19 extensive metabolizers. Additionally, syncope occurred in a subject who was a CYP2C19 poor metabolizer. Therefore, increase monitoring for adverse reactions (e.g., hypotension) in patients who are CYP2C19 poor metabolizers. The frequencies of poor CYP2C19 metabolizers are approximately 2-5% among Caucasians and Africans and approximately 2-15% among Asians.

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.

/SRP:/ Immediate first aid: Ensure that adequate decontamination has been carried out. If patient is not breathing, start artificial respiration, preferably with a demand valve resuscitator, bag-valve-mask device, or pocket mask, as trained. Perform CPR if necessary. Immediately flush contaminated eyes with gently flowing water. Do not induce vomiting. If vomiting occurs, lean patient forward or place on the left side (head-down position, if possible) to maintain an open airway and prevent aspiration. Keep patient quiet and maintain normal body temperature. Obtain medical attention. /Poisons A and B/

/SRP:/ Basic treatment: Establish a patent airway (oropharyngeal or nasopharyngeal airway, if needed). Suction if necessary. Watch for signs of respiratory insufficiency and assist ventilations if needed. Administer oxygen by nonrebreather mask at 10 to 15 L/min. Monitor for pulmonary edema and treat if necessary ... . Monitor for shock and treat if necessary ... . Anticipate seizures and treat if necessary ... . For eye contamination, flush eyes immediately with water. Irrigate each eye continuously with 0.9% saline (NS) during transport ... . Do not use emetics. For ingestion, rinse mouth and administer 5 mL/kg up to 200 mL of water for dilution if the patient can swallow, has a strong gag reflex, and does not drool ... . Cover skin burns with dry sterile dressings after decontamination ... . /Poisons A and B/

/SRP:/ Advanced treatment: Consider orotracheal or nasotracheal intubation for airway control in the patient who is unconscious, has severe pulmonary edema, or is in severe respiratory distress. Positive-pressure ventilation techniques with a bag valve mask device may be beneficial. Consider drug therapy for pulmonary edema ... . Consider administering a beta agonist such as albuterol for severe bronchospasm ... . Monitor cardiac rhythm and treat arrhythmias as necessary ... . Start IV administration of D5W TKO /SRP: "To keep open", minimal flow rate/. Use 0.9% saline (NS) or lactated Ringer's (LR) if signs of hypovolemia are present. For hypotension with signs of hypovolemia, administer fluid cautiously. Watch for signs of fluid overload ... . Treat seizures with diazepam or lorazepam ... . Use proparacaine hydrochloride to assist eye irrigation ... . /Poisons A and B/

The Approved Drug Products with Therapeutic Equivalence Evaluations identifies currently marketed prescription drug products, including flibanserin, approved on the basis of safety and effectiveness by FDA under sections 505 of the Federal Food, Drug, and Cosmetic Act.