US Food and Drug Administration Approval of Addyi (Flibanserin) for Treatment of Hypoactive Sexual Desire Disorder

Piroxicam is a nonsteroidal anti-inflammatory drug (NSAID) that is used to relieve the effects of osteoarthritis and rheumatoid arthritis.

Patients with CYP2C9 poor and intermediate metabolizers and an activity score of 1 should select an alternative therapy that is not metabolized by CYP2C9 or is not substantially impacted in vivo by CYP2C9 genetic variants or choose an NSAID that is metabolized by CYP2C9 but has a shorter half-life (Theken et al., 2020). CYP2C9 intermediate or poor metabolizers result in higher systemic concentrations.

Before Using

Higher systemic active metabolite concentrations and a higher risk of adverse reactions are associated with UGT1A1 *28/*28 (poor metabolizers) (severe neutropenia). Starting dose reduction by one level and adjusting the dosage based on individual patient tolerance is recommended (FDA, 2021; Innocenti and Ratain, 2006). Lofexidine is a centrally acting alpha2-adrenergic agonist that has been used to treat high blood pressure in the past but is now most widely used to treat the opioid withdrawal syndrome in adults to assist abrupt opioid discontinuation. Although the pharmacokinetics of lofexidine (LUCEMYRA) have not been routinely tested in patients who do not express CYP2D6, it is probable that sensitivity to the medication will be increased in these patients (Whirl-Carrillo et al., 2012). In CYP2D6 poor metabolizers result in higher systemic concentrations and higher adverse reaction risk.

Activity profile

Orthostatic hypotension and bradycardia monitoring are recommended (FDA, 2021; Mehta and Banerji, 2020). Meclizine is a histamine H1 antagonist that is used to treat motion sickness symptoms including nausea, male enhancement pill vomiting, and dizziness. The FDA-approved drug label for meclizine (ANTIVERT) was indicated that CYP2D6 genetic polymorphism can play a role in meclizine exposure variability as the dominant metabolizing enzyme (Whirl-Carrillo et al., 2012). CYP2D6 ultrarapid, intermediate, or poor metabolizers may influence systemic concentrations. Monitoring the adverse reactions and clinical effects are recommended (FDA, 2021, Hirose et al., 2016).

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Meloxicam is an NSAID that is used for treatment of osteoarthritis, rheumatoid arthritis in adults, and juvenile rheumatoid arthritis in children. According to the FDA-approved drug label for meloxicam (QMIIZ ODT), consideration of dose reduction, and monitoring the adverse effects are recommended in adult patients who are known or suspected poor CYP2C9 metabolizers (Whirl-Carrillo et al., 2012; Bae et al., 2011). CYP2C9 poor metabolizers lead to higher systemic concentrations. Consideration of dose reduction is recommended (FDA, 2021). Metoclopramide used in the treatment of gastroesophageal reflux disorder, inhibition of nausea and vomiting, and to promote gastric emptying as an antiemetic agent and dopamine D2 antagonist. Consideration of reducing the dosage in poor metabolizers is recommended (FDA, 2021; Theken et al., 2020).

• Flibanserin's mechanism involves increasing dopamine and norepinephrine and decreasing serotonin levels.
• It does not address libido caused by relationship issues or physical health problems.
• Flibanserin was once controversial due to debates over its effectiveness.
• It is not suitable for women taking certain antidepressants due to drug interactions.
• The medication has warnings for severe hypotension and syncope.
• Patients are advised to avoid alcohol consumption completely while on the drug.
• Flibanserin's approval was considered a breakthrough for female sexual health.
• Insurance coverage for flibanserin varies and can be limited.
• The drug's marketing emphasizes the importance of patient counseling.

Pitolisant is a histamine H3 receptor antagonist and inverse agonist used to treat narcolepsy in adults (Li and Yang, 2020).

Pitolisant (WAKIX) has an FDA-approved drug label that dose reduction is recommended in patients who are considered to be weak CYP2D6 metabolizers because their pitolisant concentrations are higher than typical CYP2D6 metabolizers.

Warnings & Precautions

For chronic therapy (>12 weeks) and efficacy reached, a 50% reduction in daily dose is recommended for intermediate and low metabolizers (Lima et al., 2020). Using a fivefold higher dose for CYP2C19 ultrarapid metabolizers who are receiving H. pylori eradication therapy is suggested in Dutch Pharmacogenetics Working Group guideline. Awareness of reduced efficacy in CYP2C19 ultrarapid metabolizers with other indications and, if possible, the use a fivefold higher dose is recommended (Whirl-Carrillo et al., 2012). CYP2C19 poor metabolizers lead to higher systemic concentrations.

Breast Feeding

Consideration of dosage reduction in children who are poor metabolizers is recommended and dosage adjustment is not needed for poor metabolizers adult patients (FDA, 2021; El Rouby et al., 2018). Pimozide is an antipsychotic that is used to treat patients with Tourette's Disorder who have crippling motor and phonic tics. Patients who are intermediate metabolizers of CYP2D6 should receive no more than 80% of the standard maximum dose of pimozide, and those who are poor metabolizers of CYP2D6 should receive no more than 50% of the standard maximum dose (Whirl-Carrillo et al., 2012). Poor metabolizers of CYP2D6 result in higher systemic concentrations. Pimozide doses should not be increased more than 14 days and should not exceed 0.05 mg/kg in children or 4 mg/day in adults who are poor metabolizers (FDA, 2021; Rogers et al., 2012; Laje, 2013). For CYP2D6 weak metabolizers, the maximum recommended dose is 17.8 mg once daily (Whirl-Carrillo et al., 2012).

• The pharmacology of flibanserin demonstrates a complex serotonin-dopamine interplay.
• The medication is not a substitute for addressing relationship or psychological factors.
• It is essential to evaluate contraindications before prescribing flibanserin.
• The drug's societal impact includes increased awareness of female sexual health.
• Use during pregnancy is contraindicated due to unknown risks.
• Flibanserin requires healthcare provider supervision due to its safety profile.
• Its effectiveness varies, necessitating personalized treatment approaches.
• Ongoing studies seek to expand understanding of its benefits and risks.
• The medication represents a milestone in female sexual medicine advancements.

CYP2D6 poor metabolizers result in higher systemic concentrations. Using the lowest starting dosage is recommended (FDA, 2021).

Medical uses

Patients with an activity score of 1 to 1.5 who are intermediate metabolizers should achieve a 50% dosage reduction. Patients with the 2846A>T and 2846A>T genotypes can require a dose reduction of more than 50% (Amstutz et al., 2018). DPYD intermediate or poor metabolizer leads to raising the adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and there is insufficient evidence to make a dosage recommendation in intermediate metabolizers. If you experience early-onset or unusually high toxicity, stop taking it (FDA, 2021; Matsusaka and Lenz, 2015).

generalized hypoactive sexual desire disorder, acquired

Gefitinib (IRESSA) is recommended for the first treatment of patients with metastatic non-small cell lung cancer (NSCLC) with exon 19 deletions or exon 21 (L858R) replacement mutations of epidermal growth factor receptor (EGFR) according to the FDA-approved drug label. The label also mentions the relevance of understanding the CYP2D6 phenotype in clinical practice, though CYP2D6 testing is not listed (Whirl-Carrillo et al., 2012). CYP2D6 poor metabolizer is led to higher systemic concentrations and higher adverse reaction risk. Monitoring the adverse reactions is recommended (FDA, 2021; Hirose et al., 2016). Iloperidone is an atypical antipsychotic drug used for acute treatment of adults with schizophrenia (Buckley et al., 2010).

Biochem/physiol Actions

According to the FDA-approved medication label for iloperidone (FANAPT), CYP2D6 poor metabolizers are exposed to more iloperidone than extensive metabolizers, and their dosage should be cut in half (Whirl-Carrillo et al., 2012). CYP2D6 poor metabolizers lead to higher systemic concentrations and higher adverse reaction risk (QT prolongation). Reducing the dose by half is recommended (FDA, 2021; Nnadi and Malhotra, 2008; De Leon, 2009). Irinotecan is an antineoplastic enzyme inhibitor primarily used in the treatment of colorectal cancer. Irinotecan dose reductions are recommended for UGT1A1 *28/*28 or UGT1A1 PM patients, beginning at 70% of the starting dose and increasing as tolerated, driven by neutrophil count (Whirl-Carrillo et al., 2012). It is used to treat paroxysmal atrial fibrillation/flutter and ventricular arrhythmias.

What women are saying

Metoclopramide (REGLAN) is used as a short-term treatment option in gastroesophageal reflux in adult patients who have not responded to conventional therapy. Drug elimination is decreased in patients with CYP2D6 poor metabolizers, potentially raising the risk of adverse reactions, a reduced dose of the metoclopramide should prescribed to the patients (Whirl-Carrillo et al., 2012; Bae et al., 2020). Higher systemic concentrations and adverse reaction risk could associate with CYP2D6 poor metabolizers (FDA, 2021). Mercaptopurine is an antineoplastic agent used to treat acute lymphocytic leukemia. The CPIC Dosing Guideline states that patients with TPMT or NUDT15 poor metabolizers should consider a different agent or a drastic reduction in mercaptopurine dosage.

Does Addyi interact with other medicines (drug interactions)?

Patients who are intermediate metabolizers of TPMT or NUDT15 should start at 30–80% of the target dose (Relling et al., 2019; Zgheib et al., 2017). According to the Dutch Pharmacogenetics Working Group, choosing an alternative drug or decreasing the initial dose of mercaptopurine for patients with NUDT15 poor metabolizers, and reducing the initial dose for NUDT15 intermediate metabolizer patients are recommended (Whirl-Carrillo et al., 2012). The guideline also recommends choosing an alternative drug or decreasing the initial dose of mercaptopurine for patients with TPMT low metabolizers and reducing the initial dose for patients who are TPMT intermediate metabolizers (Whirl-Carrillo et al., 2012; Dean and Kane, 2012). According to the FDA guideline, TPMT and/or NUDT15 intermediate or poor metabolizers alter systemic active metabolite concentration and dosage requirements and lead to higher adverse reaction risk (myelosuppression). Initial dosages should be decreased in poor metabolizers; poor metabolizers tolerate 10% or less of the prescribed dose.

Dosage Forms & Strengths

Tolerability can necessitate dose reductions for intermediate metabolizers. For both genes, intermediate metabolizers may necessitate more drastic dosage reductions (FDA, 2021). Increasing the starting daily dose and to monitoring efficacy in CYP2C19 ultrarapid metabolizer is recommended in the CPIC Dosing Guideline for omeprazole, lansoprazole, pantoprazole. In the treatment of gel erectile dysfunction Helicobacter pylori (H. pylori) infection and erosive esophagitis with CYP2C19 rapid and natural metabolizers, increasing the dose after initiation with the usual starting daily dose may be considered. 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).

• 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.

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.