Veterans Health Library

For CYP2D6 poor metabolizers change systemic parent drug

Property	Description	Status
Approved Uses	Hypoactive Sexual Desire Disorder (HSDD) in women	Yes
Mechanism of Action	Serotonin receptor modulator	Partial agonist & antagonist
FDA Approval Year	2015
Common Brand Name	Addyi

and metabolite concentrations (FDA, 2021; Shams et al., 2006).

• The chemical name is 1,2,3,4-tetrahydro-1-{[2-(1,2,3,4-tetrahydro-8-quinolyl)ethyl]amino}methyl-6-fluorobenz[cd]indol-5(6H)-one.
• Molecular formula is C₂₀H₂₁F₃N₄O.
• It is a white to off-white powder that is slightly soluble in water.
• The tablet contains inactive ingredients: microcrystalline cellulose, croscarmellose sodium.
• Also contains magnesium stearate, hypromellose, titanium dioxide, and iron oxide red.
• Manufactured under strict Good Manufacturing Practice (GMP) standards.
• Distributed in bottles or blister packs, typically containing 30 tablets.
• National Drug Code (NDC) for Addyi 100 mg is 0187-XXXX-XX (varies by pack).
• Keep out of reach of children and pets.

Vortioxetine (BRINTELLIX) is an atypical antipsychotic and antidepressant indicated for

Dosing & Uses

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). 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. Consideration of reducing the dosage in poor metabolizers is recommended (FDA, 2021; Theken et al., 2020).

Ask her, and start the conversation.

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. For CYP2D6 weak metabolizers, the maximum recommended dose is 17.8 mg once daily (Whirl-Carrillo et al., 2012). CYP2D6 poor metabolizers result in higher systemic concentrations. Using the lowest starting dosage is recommended (FDA, 2021).

What are some things I need to know or do while I take this drug?

It is used to treat paroxysmal atrial fibrillation/flutter and ventricular arrhythmias. 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. the treatment of major depressive disorder (MDD) (Gonda et al., 2019).

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The maximum recommended dose in patients with known CYP2D6 poor metabolizers is

• Flibanserin should be discontinued if no benefit is observed after several weeks.
• The medication's influence on mental health conditions is still being studied.
• Flibanserin was recognized as a breakthrough therapy for female sexual desire issues.
• Its use is guided by strict medical protocols due to safety concerns.
• Women are encouraged to report any adverse effects during treatment.
• Continued research aims to improve treatment options for female sexual health.
• Flibanserin is one of a few FDA-approved drugs for Female Sexual Desire Disorder.
• Clinical improvements may include increased frequency of satisfying sexual events.
• The drug's use should be combined with counseling when appropriate.

10 mg/day in the FDA-approved drug label for vortioxetine (Whirl-Carrillo et al., 2012).

Further information

Dose changes can best ed treatments also be driven by therapeutic medication control (Birdwell et al., 2015; Zhang et al., 2018). 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).

Missed Dose Instructions

Low doses should be given to people with CYP2D6 weak metabolizer genotypes (Whirl-Carrillo et al., 2012). 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.

Administration Notes

For patients with intermediate metabolizers of TPMT or NUDT15, starting of 50–80% of the target dose is recommended (Relling et al., 2019). The intermediate or weak metabolizers TPMT and/or NUDT15 change the concentration and dosage requirements cenforce 150mg tablets 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). Higher systemic concentration is associated with CYP2D6 poor metabolizers (FDA, 2021; Chen et al., 2018).

What special dietary instructions should I follow?

Patients with low UGT1A1 activity should be closely monitored for serious neutropenia (Whirl-Carrillo et al., 2012; Nelson et al., 2021). 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).

Features and Benefits

Higher systemic concentrations are associated with CYP2C9 intermediate or weak metabolizers. 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).

What do I need to tell my doctor BEFORE I take this drug?

Higher systemic concentrations and a higher risk of adverse reactions are associated with BCHE intermediate or weak metabolizers (prolonged neuromuscular blockade). 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. Warfarin is a vitamin K antagonist that is used to treat venous thromboembolism, pulmonary embolism, thromboembolism

Before using flibanserin

Thioridazine is a phenothiazine antipsychotic used to treat schizophrenia and generalized anxiety disorder and is linked to Torsades de pointes and sudden death. 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).

What should I do if I miss a dose of Addyi?

Tramadol is an SNRI (serotonin/norepinephrine reuptake inhibitor) and a centrally acting opioid agonist used to treat moderate to extreme pain in adults. The CPIC Guideline recommends 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.

General drug facts

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). 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). associated with atrial fibrillation, thromboembolism associated with cardiac

• Flibanserin's side effects need to be balanced against its benefits.
• It is not recommended for use in women who are pregnant or planning pregnancy.
• The medication's pharmacodynamics involve complex neurotransmitter interactions.
• Some women may experience relapse of symptoms after discontinuation.
• The drug must be prescribed with appropriate patient counseling regarding risks.
• Its approval sparked discussions about gender disparities in drug development.
• Flibanserin’s impact on sexual desire has led to increased research interest.
• Proper patient selection is critical for optimal outcomes.
• It represents one of the few pharmacological options for HSDD.

valve replacement, and thromboembolic events after a heart attack.

Feature	Flibanserin	Bremelanotide	Vyleesi
Approved for HSDD	Yes	No	Yes
Administration Route	Oral	Injectable	Injectable
Usage Frequency	Daily	As needed	As needed
Main Side Effects	Dizziness, nausea	Nausea, flushing	Nausea, reactions at injection site

The CPIC has released a revised guideline for pharmacogenetics-guided warfarin dosing.

Side effects of Addyi (flibanserin)

Poor metabolizers of CYP2D6 have higher systemic active metabolite concentrations and a greater risk of adverse reactions (QT prolongation). 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).