FDA Approval of Flibanserin — Treating Hypoactive Sexual Desire Disorder

Vortioxetine (BRINTELLIX) is an atypical antipsychotic and antidepressant indicated for the treatment of major depressive disorder (MDD) (Gonda et al., 2019).

• Flibanserin's journey from failed antidepressant to HSDD treatment is unique.
• Its development cost hundreds of millions of dollars over two decades.
• The FDA initially rejected it in 2010 and 2013 due to safety/efficacy concerns.
• Final 2015 approval came with the stringent REMS and boxed warning.
• The approval process involved patient testimony and advocacy efforts.
• It is classified as a multifunctional serotonin agonist and antagonist (MSAA).
• Does not bind significantly to dopamine, norepinephrine, or histamine receptors.
• Binding affinity is highest for serotonin 5-HT1A and 5-HT2A receptors.
• Its metabolite, 6-hydroxy-flibanserin, is inactive.

The maximum recommended dose in patients with known CYP2D6 poor metabolizers is 10 mg/day in the FDA-approved drug label for vortioxetine (Whirl-Carrillo et al., 2012).

Higher systemic concentration is associated with CYP2D6 poor metabolizers (FDA, 2021; Chen et al., 2018).

Further reading

Avoid using it if you have a slow metabolizer. To determine sensitivity, administer a test dose and then slowly infuse the medication (FDA, 2021). Tacrolimus is a calcineurin inhibitor that is used to treat mild to serious atopic dermatitis and to prevent organ transplant rejection. Recommendation according to the CPIC dosing guideline for tacrolimus is raising the starting dose by 1.5 to 2 times the recommended starting dose, but the total starting dose does not exceed 0.3 mg/kg/day in patients with CYP3A5 intermediate or extensive metabolizers. Dose changes can also be driven by therapeutic medication control (Birdwell et al., 2015; Zhang et al., 2018).

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Lower systemic concentrations, a lower likelihood of reaching target concentrations, and a higher risk of rejection are all consequences of CYP3A5 intermediate or mild metabolizers. Measurement of drug concentrations and dose regulating based on whole blood tacrolimus concentrations are recommended (FDA, 2021; Staatz and Tett, 2004). Tetrabenazine is a vesicular monoamine transporter 2 (VMAT) inhibitor that is used to treat chorea in Huntington's disease patients. Patients that need doses greater than 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to decide if they are a poor metabolizer (PM) or an extensive metabolizer (EM), according to the FDA-approved drug label for tetrabenazine (XENAZINE) (EM). Low doses should be given to people with CYP2D6 weak metabolizer genotypes (Whirl-Carrillo et al., 2012).

Administration Notes

Poor metabolizers of CYP2D6 lead to higher systemic concentrations. The maximum single dose is 25 mg, and the total daily dose does not exceed 50 mg (FDA, 2021; Mehanna et al., 2013). Tioguanine is a purine analog antineoplastic agent that is used to induce and maintain remission in patients with acute nonlymphocytic anemias (FDA, 2021). Patients who are TPMT or NUDT15 poor metabolizers should consider an alternative agent or a drastic reduction in thioguanine dosage. For patients with intermediate metabolizers of TPMT or NUDT15, starting of 50–80% of the target dose is recommended (Relling et al., 2019). Warfarin is a vitamin K antagonist that is used to treat venous thromboembolism, pulmonary embolism, thromboembolism associated with atrial fibrillation, thromboembolism associated with cardiac valve replacement, and thromboembolic events after a heart attack. The CPIC has released a revised guideline for pharmacogenetics-guided warfarin dosing.

Dosing guidelines are focused on genotypes from CYP2C9, VKORC1, CYP4F2, and rs12777823, and are for adult and pediatric patients with continental ancestry (Johnson et al., 2017). Intermediate and poor metabolizers of CYP2C9 change systemic concentrations and dosage specifications.

Bottom Line

It is possible that dosage reductions are needed (FDA, 2021). Venlafaxine is a selective serotonin and norepinephrine reuptake inhibitor (SNRI) that is used for the treatment of major depression (Singh and Saadabadi, 2022). Selecting an alternative to venlafaxine for CYP2D6 poor (PM) and intermediate metabolizers (IM) or reducing the dose and controlling the patient's plasma metabolite amount is recommended in the Dutch Pharmacogenetics Working Group guideline. The guideline also recommends to raise dosage to 150% of the usual dose for CYP2D6 ultrarapid metabolizers (UM) or choose an alternative to venlafaxine (Whirl-Carrillo et al., 2012). For CYP2D6 poor metabolizers change systemic parent drug and metabolite concentrations (FDA, 2021; Shams et al., 2006). Dosage criteria may be affected by CYP4F2 V433M variant carriers. The VKORC1-1639G>A carriers adjust the dosage specifications.

Flibanserin as a Multifunctional Serotonin Agonist and Antagonist (MSAA): Modulator of Reward in Macrocircuits

The intermediate or weak metabolizers TPMT and/or NUDT15 change the concentration and dosage requirements of systemic active metabolites. As a result, the probability of an adverse reaction is increased (myelosuppression). In poor metabolizers, initial dosages should be reduced; poor metabolizers tolerate 10% or less of the prescribed dose. Tolerability can necessitate dose reductions for intermediate metabolizers (Dean, 2020). Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety disorder and is linked to Torsades de pointes and sudden death.

IN CLINICAL TRIALS1, WOMEN ON ADDYI EXPERIENCED:

Thioridazine is usually reserved for patients who do not respond well to other antipsychotics due to the potentially fatal side effects. Patients with low CYP2D6 activity should avoid the thioridazine (Whirl-Carrillo et al., 2012; Dean, 2017b). Poor metabolizers of CYP2D6 have higher systemic concentrations and a higher risk of adverse reactions (QT prolongation). Patients with poor metabolizers should avoid the thioridazine (FDA, 2021). Tramadol is an SNRI (serotonin/norepinephrine reuptake inhibitor) and a centrally acting opioid agonist used to treat moderate to extreme pain in adults.

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The CPIC Guideline recommends libido booster women an alternate non-codeine analgesic for CYP2D6 ultrarapid and poor metabolizers. For CYP2D6 normal and intermediate metabolizers, a label-recommended age- or weight-specific tramadol dose is needed (Crews et al., 2021). Tramadol's efficacy can be decreased in CYP2D6 intermediate or poor metabolizers. If tramadol isn’t working for CYP2D6 intermediate or poor metabolizer patients, consider increasing the dosage or switching to a different pain reliever (not codeine), and keep an eye out for signs of inadequate pain relief. Using an alternative to tramadol (not codeine) for CYP2D6 ultrarapid metabolizers or use 40% of the normal dose and be aware of side effects (Whirl-Carrillo et al., 2012; Dean, 2017c). It should be considered clinical and genetic factors when determining the initial dose. Dosage should be monitored and adjusted based on INR (FDA, 2021; Kumar et al., 2014).

• Flibanserin, a serotonin receptor modulator, was initially investigated for depression.
• Its approval marked a historic moment in treating female sexual dysfunction.
• The medication's side effects necessitate careful patient education.
• Efficacy is often supported by patient-reported improvements in desire.
• It does not function as an aphrodisiac but affects brain chemistry.
• Flibanserin therapy requires adherence to dosing instructions.
• Women with low libido due to other health issues may not benefit from it.
• Its role is to complement behavioral or psychological therapy if needed.
• Research continues into better options for treating female hypoactive sexual desire.

A dietary supplement marketed for sexual enhancement and sold nationwide was officially recalled a month after the Food and Drug Administration (FDA) issued a warning about the dangers of taking it.

What special dietary instructions should I follow?

CYP2D6 ultrarapid metabolizers cause higher active metabolite concentrations in the systemic and breast milk, which can lead to respiratory depression and death. Tramadol is not recommended for children under the age of 12 or adolescents who have had tonsillectomy or adenoidectomy. During therapy, Tramadol is not advised to breastfeed (FDA, 2021). The dosage reduction based on tolerability for CYP2D6 poor metabolizers is recommended in the FDA-approved drug label for valbenazine (INGREZZA) (Whirl-Carrillo et al., 2012). Poor metabolizers of CYP2D6 have higher systemic active metabolite concentrations and a greater risk of adverse reactions (QT prolongation). On Monday, the FDA published the recall by the capsule’s manufacturer, Best Supplements Best Prices, saying that the pills contain three undeclared drugs. Two of them listed in the recall are sildenafil and tadalafil, the active ingredients in Viagra and Cialis, respectively.

Continuing Education Activity

Propafenone doses should be reduced by 70% for CYP2D6 poor metabolizers, and drug plasma concentrations should be monitored or an alternative medication should be used for CYP2D6 intermediate and ultrarapid metabolizers (Whirl-Carrillo et al., 2012; Dean, 2017a). Poor metabolizers of CYP2D6 have higher systemic concentrations and a higher risk of adverse reactions (arrhythmia). Sacituzumab govitecan works by targeting TROP-2-expressing cancer cells with a humanized antibody (RS7), then being internalized and releasing the topoisomerase I inhibitor SN-38 to trigger DNA damage-mediated apoptosis. Patients who are homozygous for the UGT1A1 *28 allele are at an elevated risk of neutropenia after starting sacituzumab govitecan-hziy (TRODELVY) therapy. Patients with low UGT1A1 activity should be closely monitored for serious neutropenia (Whirl-Carrillo et al., 2012; Nelson et al., 2021).

Storage Requirements

Higher systemic concentrations and the chance of adverse reactions are possible with UGT1A1 *28/*28 (poor metabolizers) (neutropenia). Monitoring for adverse reactions and tolerance to treatment are recommended (FDA, 2021). Siponimod is a drug that helps patients with relapsing multiple sclerosis. Lowering the siponimod dose is recommended for CYP2C9 *1/*3, *2/*3 genotypes and avoiding siponimod for the CYP2C9 *3/*3 genotype in the DPWG guideline (Whirl-Carrillo et al., 2012; Abdullah-Koolmees et al., 2020). Higher systemic concentrations are associated with CYP2C9 intermediate or weak metabolizers.

Before taking flibanserin,

Drug dosage is adjusted according to the patient genotype. In patients with the CYP2C9 *3/*3 genotype, do not use the siponimod (FDA, 2021). Succinylcholine is a depolarizing skeletal muscle relaxant that is used to relax skeletal muscles during intubation, mechanical ventilation, and surgical procedures. In people who are susceptible to malignant hyperthermia, the CPIC Dosing Guideline suggests that halogenated volatile anesthetics including desflurane, enflurane, halothane, isoflurane, methoxyflurane, sevoflurane, and the depolarizing muscle relaxants succinylcholine be avoided (MHS) (Gonsalves et al., 2019). Higher systemic concentrations and a higher risk of adverse reactions are associated with BCHE intermediate or weak metabolizers (prolonged neuromuscular blockade). The other drug in question, flibanserin, is the active ingredient in Addyi and is meant to treat low sexual desire in women.

Sildenafil and tadalafil are designed to treat erectile dysfunction, but could interact with nitrates in other prescription drugs and lower blood pressure to dangerous levels, the FDA explained in its statement. Flibanserin, the agency added, can cause drowsiness, sedation, and dangerously low blood pressure and fainting, especially when combined with alcohol.