Description
Pharmacogenetics aims to study the influence of genetic variation on drug response and drug toxicity, which allows physicians to select a more targeted therapeutic strategy to suit each patient’s genetic profile. Genetic variations in human proteins, such as cytochrome P450 enzymes, Thiopurine methyltransferase (TPMT), Dihydropyrimidine dehydrogenase (DPD), and cell surface proteins, highlights the clinical importance of pharmacogenetic testing.

Cytochrome (CYP) P450 enzymes are a class of enzymes essential in the synthesis and breakdown metabolism of various molecules and chemicals. Found primarily in the liver, these enzymes are also essential for the metabolism of many medications. CYP P450 enzymes, approximately 58 CYP human genes, are essential to producing many biochemical building blocks, such as cholesterol, fatty acids, and bile acids. Additional cytochrome P450 are involved in the metabolism of drugs, carcinogens, and internal substances, such as toxins formed within cells. Mutations in CYP P450 genes can result in the inability to properly metabolize medications and other substances, leading to increased levels of toxic substances in the body.

Thiopurine methyltransferase (TPMT) is an enzyme that methylates azathioprine, mercaptopurine and thioguanine into active thioguanine nucleotide metabolites. Azathioprine and mercaptopurine are used for treatment of nonmalignant immunologic disorders; mercaptopurine is used for treatment of lymphoid malignancies; and thioguanine is used for treatment of myeloid leukemias.

Dihydropyrimidine dehydrogenase (DPD), encoded by the gene DPYD, is a rate-limiting enzyme responsible for fluoropyrimidine catabolism. The fluoropyrimidines (5-fluorouracil and capecitabine) are drugs used in the treatment of solid tumors, such as colorectal, breast, and aerodigestive tract tumors.

A variety of cell surface proteins, such as antigen-presenting molecules and other proteins, are encoded by the human leukocyte antigen genes (HLAs). HLAs are also known as major histocompatibility complex (MHC).

Regulatory Status 
Diagnostic genotyping tests for certain drug metabolizing enzymes are FDA-approved. Additionally, many labs have developed specific tests that they must validate and perform in house. These laboratory-developed tests (LDTs) are regulated by the Centers for Medicare & Medicaid Services (CMS) as high-complexity tests under the Clinical Laboratory Improvement Amendments of 1988 (CLIA ’88). As an LDT, the U.S. Food and Drug Administration has not approved or cleared this test; however, FDA clearance or approval is not currently required for clinical use. 

Currently, there are over 10 other FDA-approved tests for the drug metabolizing enzymes that are nucleic acid-based tests including xTAG CYP2D6 Kit v3 and XTAG CYP2C19 KIT V3 (Luminex Molecular Diagnostics Inc.), Spartan RX CYP2C19 Test System (Spartan Bioscience Inc.), Verigene CYP2C19 Nucleic Acid Test (Nanosphere Inc.), INFINITI CYP2C19 Assay (AutoGenomics Inc.), Invader UGT1A1 (Third Wave Technologies Inc.), eSensor Warfarin Sensitivity Saliva Test (GenMark Diagnostics), eQ-PCR LC Warfarin Genotyping kit (TrimGen Corporation), eSensor Warfarin Sensitivity Test and XT-8 Instrument (Osmetech Molecular Diagnostics), Gentris Rapid Genotyping Assay-CYP2C9&VKORCI (ParagonDx LLC), INFINITI 2C9 & VKORC1 Multiplex Assay for Warfarin (AutoGenomics, Inc) and Verigene Warfarin Metabolism Nucleic Acid Test and Verigene System (Nanosphere, Inc) (FDA, 2018a).

FDA Notes
The Office of Clinical Pharmacology within FDA includes The Genomics and Targeted Therapy Group responsible for applying pharmacogenomics and other biomarkers in drug development and clinical practice. The FDA scientists review current pharmacogenomic information and ensure that pharmacogenomic strategies are utilized appropriately in all phases of drug development (FDA, 2018b).

The current list of pharmacogenomic biomarkers in drug labeling by FDA contains a total of 92 medications that have genotypes related to metabolism dosage recommendations or warnings. These medications are involved in different therapeutic areas and the list includes the following genes and medications:

CYP1A2: Rucaparib
CYP2B6: Efavirenz

CYP2C19 contains 22 different medications: Clopidogrel, Prasugrel, Ticagrelor, Lansoprazole, Omeprazole, Esomeprazole, Rabeprazole, Pantoprazole, Dexlansoprazole, Flibanserin, Drospirenone and Ethinyl Estradiol, Voriconazole, Lacosamide, Brivaracetam, Clobazam, Phenytoin, Diazepam, Citalopram, Escitalopram, Doxepin, Formoterol, Carisoprodol

CYP2C9 contains 9 different medications: Prasugrel, Dronabinol, Flibanserin, Warfarin, Phenytoin, Celecoxib, Piroxicam, Flurbiprofen, Lesinurad

CYP2D6 contains 58 different medications: Codeine, Tramadol, Carvedilol, Metoprolol, Nebivolol, Propafenone, Propranolol, Quinidine, Cevimeline, Ondansetron, Palonosetron, Flibanserin, Eliglustat, Quinine Sulfate, Deutetrabenazine, Dextromethorphan and Quinidine, Galantamine, Tetrabenazine, Valbenazine, Rucaparib, Amitriptyline, Aripiprazole, Aripiprazole Lauroxil, Atomoxetine, Brexpiprazole, Cariprazine, Citalopram, Clomipramine, Clozapine, Desipramine, Desvenlafaxine, Doxepin, Duloxetine, Escitalopram, Fluoxetine, Fluvoxamine, Iloperidone, Imipramine, Modafinil, Nefazodone, Nortriptyline, Paroxetine, Perphenazine, Pimozide, Protriptyline, Risperidone, Thioridazine, Trimipramine, Venlafaxine, Vortioxetine, Arformoterol, Formoterol, Umeclidinium, Darifenacin, Fesoterodine, Mirabegron, Tolterodine. Lofexidine was added in the most recent update of June 2018.

CYP3A5: Prasugrel (FDA, 2018c)
TMPT: Thioguanine
NUDT15: Thioguanine (FDA, 2018c).

FDA Recommendations
The FDA package insert for Plavix (clopidogrel) carries the following “Black Box” warning: “The effectiveness of Plavix results from its antiplatelet activity which is dependent on its conversion to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19. Plavix at recommended doses forms less of the active metabolite and so has a reduced effect on platelet activity in patients who are homozygous for nonfunctional alleles of the CYP2C19 gene, (termed “CYP2C19 poor metabolizers”). Tests are available to identify patients who are CYP2C19 poor metabolizers. Consider another platelet P2Y12 inhibitor in patients identified as CYP2C19 poor metabolizers.” (FDA, 2016)

The FDA package insert for Xenazine (tetrabenazine) indicates “patients who require doses of Xenazine greater than 50 mg per day should be first tested and genotyped to determine if they are poor metabolizers (PMs) or extensive metabolizers (EMs) by their ability to express the drug metabolizing enzyme, CYP2D6. The dose of XENAZINE should then be individualized accordingly to their status as PMs or EMs. (FDA, 2008)

The Coumadin (warfarin) highlights of prescription information notes that “the appropriate initial dosing of COUMADIN varies widely for different patients. Not all factors responsible for warfarin dose variability are known, and the initial dose is influenced by: Genetic factors (CYP2C9 and VKORC1 genotypes).” Although dosage suggestions based on CYP2C9 and VKORC1 genotypes are provided in the package insert, the requirement for genetic testing is not included (FDA).

The eligibility and dosing of Eliglustat is dependent on cytochrome P450 CYP2D6 genotype as eliglustat is extensively metabolized by CYP2D6. The FDA contraindicates this medication in the following patients due “to the risk of cardiac arrhythmias from prolongation of the PR, QTc, and/or QRS cardiac Intervals”:

EMs of CYP2D6

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Moderate or severe hepatic impairment
• Mild hepatic impairment and taking a strong or moderate CYP2D6 inhibitor

IMs

• Taking a strong or moderate CYP2D6 inhibitor concomitantly with a strong or moderate CYP3A inhibitor
• Taking a strong CYP3A inhibitor
• Any degree of hepatic impairment

PMs

• Taking a strong CYP3A inhibitor
• Any degree of hepatic impairment (FDA, 2014) 

Policy
Application of coverage criteria is dependent upon an individual’s benefit coverage at the time of the request.

1. Testing for the CYP2D6 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing:
   1. Amphetamine
   2. Aripiprazole
   3. Aripiprazole Lauroxil
   4. Atomoxetine
   5. Brexpiprazole
   6. Carvedilol
   7. Cevimeline
   8. Clozapine
   9. Codeine
   10. Desipramine
   11. Deutetrabenazine
   12. Eligustat
   13. Fluvoxamine
   14. Gefitinib
   15. Iloperidone
   16. Lofexidine
   17. Meclizine
   18. Metoclopramide
   19. Nortriptyline
   20. Oliceridine
   21. Ondansetron
   22. Paroxetine
   23. Perphenazine
   24. Pimozide
   25. Pitolisant
   26. Propafenone
   27. Tamoxifen
   28. Tetrabenazine
   29. Thioridazine
   30. Tolterodine
   31. Tramadol
   32. Tropisetron
   33. Valbenazine
   34. Venlafaxine
   35. Vortioxetine
2. Testing for the CYP2D6 and CYP2C19 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Amitriptyline
   2. Clomipramine
   3. Doxepin
   4. Imipramine
   5. Trimipramine
3. Testing for the CYP2C19 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Brivaracetam
   2. Citalopram
   3. Clobazam   
   4. Clopidogrel     
   5. Dexlansoprazole (see Note 1)
   6. Escitalopram
   7. Flibanserin
   8. Lansoprazole (see Note 1)
   9. Omeprazole (see Note 1)
   10. Pantoprazole (in pediatric individuals) (see Note 1)
   11. Sertraline  
   12. Voriconazole (see Note 1)
4. Testing for the CYP2C9 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with any of the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Celecoxib
   2. Dronabinol
   3. Erdafitinib
   4. Flurbiprofen
   5. Lornoxicam
   6. Meloxicam
   7. Piroxicam
   8. Siponimod
   9. Tenoxicam
5. Testing for the CYP2C9, CYP4F2, VKORC1, and rs12777823 genotype once per lifetime is considered MEDICALLY NECESSARY for individuals being considered for Warfarin therapy.
6. Testing for the TPMT and NUDT15 genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Azathioprine
   2. Mercaptopurine
   3. Thioguanine
7. Testing for the DPYD genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. Capecitabine
   2. Flucytosine
   3. Fluorouracil
   4. Tegafur
8. Testing for the following Human Leukocyte Antigens (HLAs) genotypes once per lifetime is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
   1. HLA-B*57:01 before treatment with Abacavir
   2. HLA-B*58:01 before treatment with Allopurinol
   3. HLA-B*15:02 for treatment with Oxcarbazepine
   4. HLA-B*15:02 and HLA-A*31:01 for treatment with Carbamazepine
9. Testing for the CYP2C9 and HLA-B*15:02 genotype once per lifetime is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medication, or who are in their course of therapy with this medication, to aid in therapy selection and/or dosing:
   1. Phenytoin/Fosphenytoin
10. Testing for the G6PD genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing:
    1. Pegloticase
    2. Primaquine
    3. Rasburicase
    4. Tafenoquine
11. Testing for the following genotypes once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for therapy with the below medications, or who are in their course of therapy with a medication listed below, to aid in therapy selection and/or dosing:
    1. BCHE for treatment with mivacurium or succinylcholine
    2. CFTR for treatment with Ivacaftor, Elexacaftor and Tezacaftor, Ivacaftor and Lumacaftor, or Ivacaftor and Tezacaftor
    3. CYP2B6 for treatment with Efavirenz
    4. CYP3A5 for treatment with Tacrolimus
    5. IFNL3 treatment with Peginterferon alfa-2a, Peginterferon alfa-2b or Ribavirin
    6. NAT2 for treatment with Amifampridine or Amifampridine Phosphate
    7. UGT1A1 for treatment with Atazanavir, Belinostat, Irinotecan, Nilotinib, Pazopanib, or Sacituzumab govitecan-hziy
12. Testing for the RYR1 and CACNA1S genotype once per lifetime (please see policy guideline)* is considered MEDICALLY NECESSARY for individuals being considered for the use of depolarizing muscle relaxants, such as succinylcholine, or halogenated volatile anesthetics.
13. Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy is considered NOT MEDICALLY NECESSARY.

The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness.

1. The following pharmacogenetic testing is considered NOT MEDICALLY NECESSARY:
   1. Genotyping for any medication therapy more than once per lifetime (please see policy guideline).*
   2. Testing for the specific genotype for individuals on medications not listed as meeting coverage criteria for testing.
   3. Testing for all other genotypes including, but not limited to, use of other medication therapy not listed as meeting coverage criteria.
   4. Genotyping the general population.
   5. Pharmacogenetic panel testing for individuals not being considered for any of the above conditions.
2. All other single nucleotide polymorphism (SNP) testing, either as individual SNPs or as a panel of SNPs, is considered NOT MEDICALLY NECESSARY for all indications. The list of SNPs includes, but is not limited to, the following:
   1. 5HT2C (serotonin receptor)
   2. 5HT2A (serotonin receptor)
   3. SLC6A4 (serotonin transporter)
   4. DRD1 (dopamine receptor)
   5. DRD2 (dopamine receptor)
   6. DRD4 (dopamine receptor) 
   7. DAT1 or SLC6A3 (dopamine transporter)
   8. DBH (dopamine beta-hydroxylase)
   9. COMT (catechol-O-methyl-transferase)
   10. MTHFR (methylenetetrahydrofolate reductase)
   11. γ-Aminobutyric acid (GABA) A receptor
   12. OPRM1 (µ-opioid receptor)
   13. OPRK1 (κ-opioid receptor)
   14. TYMS
   15. UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
   16. Cytochrome P450 genes: CYP3A4, CYP1A2

*Policy Guideline
Genotyping once per lifetime

Any gene should be tested once per lifetime regardless of the indication (an exception would be for HLA where a specific variant is tested for the medication). For example, if CYP2C19 was tested for therapy with citalopram, additional testing for CYP2C19 for treatment with clopidogrel is not needed and is considered NOT MEDICALLY NECESSARY. 

Note 1: Pharmacogenetic testing for proton pump inhibitor therapies (PPIs) ONLY MEETS COVERAGE CRITERIA if the patient has an active H. pylori infection.

Table of Terminology 

Term	Definition
AACAP	American Academy of Child and Adolescent Psychiatry
AACC	American Association for Clinical Chemistry
AACF	American College of Cardiology Foundation
AAFP	American Family Physician
AAN	American Academy of Neurology
ACMG	American College of Medical Genetics and Genomics
AHA	American Heart Association
AMP	Association For Molecular Pathology
AS	Activity score
ASCPT	American Society for Clinical Pharmacology and Therapeutics
ASHP	American Society of Health System Pharmacists
BDI	Beck's Depression Inventory
CFTR	Cystic fibrosis transmembrane conductance regulator
COMT	Catechol-O-methyltransferase
CPIC	Clinical Pharmacogenetics Implementation Consortium
CYP	Cytochrome
DBH	Dopamine beta-hydroxylase
DPD	Dihydropyrimidine dehydrogenase
DPWG	Dutch Pharmacogenetics Working Group
DPYD	Dihydropyrimidine dehydrogenase gene
DRD1	Dopamine receptor gene
EMA	European Medicines Agency
FDA	Food and Drug Administration
G6PD	Glucose-6-phosphate dehydrogenase gene
HLAs	Human leukocyte antigen
IM	Intermediate metabolizer
ISPG	The International Society of Psychiatric Genetics
MDD	Major depressive disorder
MHC	Major histocompatibility complex
MP	Mercaptopurine
MTHFR	Methylenetetrahydrofolate reductase
NM	Normal metabolizer
NUDT15	Nudix hydrolase 15
PM	Poor metabolizer
PPIs	Proton pump inhibitor therapies
RM	Rapid metabolizer
RYR1	Ryanodine receptor 1 gene
SJS	Stevens Johnson Syndrome
SLC6A4	Solute carrier family 6 member 4
SNP	Single nucleotide polymorphism
TAU	Treatment as usual
TCAs	Tricyclic antidepressants
TEN	Toxic epidermal necrolysis
TG	Thioguanine
TPMT	Thiopurine methyltransferase
TYMS	Thymidylate synthetase
UGT2B15	Uridine diphosphate glycosyltransferase 2 family, member 15
URM	Ultra-rapid metabolizer

Rationale
Genetic variations play a potentially large role in an individual’s response to medications. However, drug metabolism and responses are affected by many other factors, including age, sex, interactions with other drugs, and disease states (Tantisira & Weiss, 2020). Nonetheless, inherited differences in the metabolism and disposition of drugs and genetic polymorphisms in the targets of drug therapy can have a significant influence on the efficacy and toxicity of medications potentially even more so than clinical variables such as age and organ function (Kapur et al., 2014; Ting & Schug, 2016). Genetic variation can influence pharmacodynamic factors through variations affecting drug target receptors and downstream signal transduction, or pharmacokinetic factors, affecting drug metabolism and/or elimination (Tantisira & Weiss, 2020).

The Cytochrome P450 (CYP 450) system is a group of enzymes responsible for the metabolism of many endogenous and exogenous substances, including many pharmaceutical agents. This system may serve to “activate” an inactive form of a drug, as well as inactivate and/or clear a drug from circulation. The CYP 450 enzymes are responsible for the clearance of over half of all drugs, and their activity can be affected by diet, age and other medications. The genes encoding for the CYP 450 enzymes are highly variable with multiple alleles that confer various levels of metabolic activity for specific substrates. In some cases, alleles can be highly correlated with ethnic background. Generally, there are three categories of metabolizer; ultra-rapid metabolizers, normal metabolizers, and poor metabolizers (Tantisira & Weiss, 2020).

Due to the variations in enzyme activity conferred by allelic differences, some CYP 450 alleles are associated with an increased risk for certain conditions or adverse outcomes with certain drugs. Knowledge of the allele type may assist in the selection of a drug, or in drug dosing. Three CYP 450 enzymes are most often considered regarding clinical use for drug selection and/or dosing. Phenotypes, such as CYP2D6, CYP2C9 and CYP2C19, have been associated with the metabolism of several therapeutic drugs, and various alleles of the CYP450 gene confer differences in metabolic function. For these CYP 450 enzymes, it is thought that “poor metabolizers” could have less efficient elimination of a drug, and therefore may be at risk for side effects due to drug accumulation. For drugs that require activation by a specific CYP 450 enzyme, lower activity may yield less of the biologically active drug, which could result in lower drug efficacy. Individuals considered as “ultra-rapid metabolizers” may clear the drug more quickly than normal, and therefore may require higher doses to yield the desired therapeutic effect. Likewise, for drugs that require activation, these individuals may produce higher levels of the active drug, potentially causing unwanted side effects. Due to these differences in enzyme activity, some alleles are associated with a higher risk of adverse outcomes depending on the drug prescribed (Tantisira & Weiss, 2020).

CYP2C9
Warfarin (brand name Coumadin) is widely used as an anticoagulant in the treatment and prevention of thrombotic disorders. CYP2C9 participates in warfarin metabolism, and several CYP2C9 alleles have reduced activity, resulting in a higher circulating drug concentration. CYP2C9*2 and CYP2C9*3 are the most common variants with reduced activity. Variations in a second gene, VKORC1, also can impact warfarin’s effectiveness. This gene codes for the enzyme that is the target for warfarin. Genotypes resulting in reduced metabolism may need a higher dose to achieve the desired efficacy (Tantisira & Weiss, 2020).

CYP2C19
Clopidogrel (brand name Plavix) is used to inhibit platelet aggregation and is given as a pro-drug that is metabolized to its active form by CYP2C19. Alleles CYP2C19*2 and CYP2C19*3 are associated with reduced metabolism of clopidogrel. Individuals with the “poor metabolizer” alleles may not benefit from clopidogrel treatment at standard doses (Tantry et al., 2021). Tuteja et al. (2020) studied CYP2C19 genotyping to guide antiplatelet therapy. A total of 504 participants contributed to this study, with only 249 participants genotyped. The authors noted that genotyping results “significantly influenced antiplatelet drug prescribing; however, almost half of CYP2C19 LOF [loss-of-function] carriers continued to receive clopidogrel. Interventional cardiologists consider both clinical and genetic factors when selecting antiplatelet therapy following PCI [percutaneous coronary intervention] (Tuteja et al., 2020).”

CYP2D6
Tetrabenazine (brand name Xenazine) is used in the treatment of chorea associated with Huntington disease. This drug is metabolized for clearance primarily by CYP2D6. Poor metabolizers are considered to be those individuals with impaired CYP2D6 function, and dosing is often influenced by how well a patient metabolizes the drug. For example, a poor metabolizer will often have a maximum dose of 50 mg daily whereas an extensive metabolizer has a maximum dose of 100 mg daily (Suchowersky, 2021).

Tamoxifen, a drug commonly used for the treatment and prevention of recurrence of estrogen receptor positive breast cancer, is metabolized by CYP2D6. Polymorphisms of CYP2D6 have been noted to affect the efficacy of tamoxifen by affecting the amount of active metabolite produced. Endoxifen, which is the primary active metabolite of tamoxifen, has a 100-fold affinity for the estrogen receptor compared to tamoxifen, but poor metabolizers have been demonstrated to show lower than expected levels of plasma endoxifen (Ahern et al., 2017).

Codeine, which is commonly used to treat mild to moderate pain, is metabolized to morphine, a much more powerful opioid, by CYP2D6. Individuals with varying CYP2D6 activity may see negative side effects or a shorter duration of pain relief. The effect is significant enough to have caused fatalities in unusual metabolizers; for instance, an ultra-rapid metabolizing toddler was reported to have passed away after being given codeine for a routine dental operation (Kelly et al., 2012; Tantisira & Weiss, 2020).

TPMT
Thiopurine methyltransferase (TPMT) is an enzyme that methylates thiopurines into active thioguanine nucleotides. The TPMT gene is inherited as a monogenic co-dominant trait with ethnic differences in the frequencies of low-activity variant alleles. Individuals who inherit two inactive TPMT alleles will develop severe myelosuppression. Individuals that inherit only one inactive TPMT allele will develop moderate to severe myelosuppression, and those individuals who inherit both active TPMT alleles will have a lower risk of myelosuppression. Therefore, genotyping for TPMT is critical before starting therapy with thiopurine drugs (Relling et al., 2011).

DPYD
The dihydropyrimidine dehydrogenase (DPYD) gene encodes for the rate-limiting enzyme dihydropyrimidine dehydrogenase, which is involved in catabolism of fluoropyrimidine drugs used in the treatment of solid tumors. Decreased DPD activity increases the risk for severe or even fatal drug toxicity when patients are being treated with fluoropyrimidine drugs. Numerous genetic variants in the DPYD gene have been identified that alter the protein sequence or mRNA splicing; however, some of these variants have no effect on DPD enzyme activity. The most studied causal variant of DPYD haplotype (HapB3) spans intron 5 to exon 11 and affects protein function. The most common variant in Europeans is HapB3 with a c.1129 – 5923C>G DPYD variant which demonstrates decreased function with carrier frequency of 4.7%, followed by c.190511G>A (carrier frequency: 1.6%) and c.2846A>T (carrier frequency: 0.7%). Approximately 7% of Europeans carry at least one decreased function DPYD variant. In people with African ancestry, the most common variant is c.557A>G (rs115232898, p.Y186C) and is relatively common (3% – 5% carrier frequency). Other DPYD decreased function variants are rare. Therefore, most available genetic tests focus on identifying the most common variants with well-established risk: (c.190511G>A, c.1679T>G, c.2846A>T, c.1129 – 5923C>G) (Amstutz et al., 2018).

TYMS
TYMS (thymidylate synthetase) encodes an enzyme necessary for thymidine production. As with DPYD, TYMS is thought to be involved with the toxicity of fluoropyrimidines. Fluorouracil (FU)’s primary metabolite inhibits thymidylate synthetase by forming a stable complex with thymidylate synthetase and folate, thereby blocking activity of the enzyme. Polymorphisms in the TYMS gene further affect the interaction between TYMS and FU, potentially increasing the toxicity of FU. Genotyping of TYMS prior to treatment with FU or capecitabine has been suggested for clinical practice, but data has been varied (Krishnamurthi & Kamath, 2022).

Castro-Rojas et al. (2017) evaluated TYMS genotypes as predictors of both clinical response and toxicity to fluoropyrimidine-based treatment for colorectal cancer. A total of 105 patients were genotyped. The authors noted that while the 2R/2R genotype was associated with clinical response (odds ratio = 3.45), the genotype was also associated with severe toxicity (odds ratio = 5.21). The genotype was thought to be associated with low TYMS expression. The authors further identified the rs2853542 and rs151264360 alleles to be independent predictors of response failure to chemotherapy (Castro-Rojas et al., 2017).

HLAs
Human Leukocyte antigens (HLAs) are divided into 3 regions, such as class I, class II and class III. Each class has many gene loci, expressed genes and pseudogenes. The class I encodes HLA-A, HLA-B, HLA-C and other antigens. The class II encodes HLA-DP, DQ and DR. The class III region is located between class I and class II and does not encode any HLAs, but other immune response proteins (Viatte, 2021).

An article published by van der Wouden et al. (2019) reports on the development of the new PGx-Passport panel (pre-emptive pharmacogenetics-passport panel), which is able to test “58 germline variant alleles, located within 14 genes (CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, DPYD, F5, HLA-A, HLA-B, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1)”; this standardized panel is based on the Dutch Pharmacogenetics Working Group (DPWG) guidelines and will help physicians to optimize drug prescription in 49 common drugs. It is recommended by the authors that commercial and hospital laboratories utilize this panel for personalized medicinal purposes. Drug optimization in the 49 commonly prescribed drugs includes ten antidepressants, five immunosuppressants, five anti-cancer drugs, four anti-infectives, four anticoagulants, four antiepileptics, four antipsychotics, three proton pump inhibitors, two anti-arrhythmics, two analgesics, two antilipidemics, one antihypertensive, one psychostimulant, one anticontraceptive and one Gaucher disease drug (van der Wouden et al., 2019).

Proprietary Testing
Due to the increase in pharmacogenetic genotyping, proprietary gene panels have become commercially available. Panels encompassing the most common genes that influence drug metabolism have increased in usage. For example, Myriad’s new proprietary panel “GeneSight” proposes it can “predict poorer antidepressant outcomes and to help guide healthcare providers to more genetically optimal medications,” thereby leading to better patient outcomes. The test assesses every known metabolic pathway (CYP450 or otherwise) for a given drug and their metabolites, as well as the pharmacodynamic activity of the compound and its metabolites, any FDA information on that drug, and other validated research on the relevant alleles; this information is then integrated with the genetic test results. This allows the test to categorize the 55 FDA-approved medications into three categories: “green (use as directed), yellow (some moderate gene-drug interaction) and red (significant gene-drug interaction).” Myriad states that this allows every metabolic pathway of a drug to be evaluated instead of the “one gene, one drug” view. Other GeneSight variations, such as GeneSight Psychotropic used for psychotropic medications, exist as well (Myriad, 2016, 2019). Still, other companies such as Mayo Clinic and Sema4 have developed their own pharmacogenetic panels, each with individually chosen analytes (Mayo, 2019; Sema4, 2019).

Benitez et al. (2018) assessed the cost-effectiveness of pharmacogenomics in treating psychiatric disorders. The authors compared 205 members that received guidance from GeneSight’s Psychotropic to 478 members that received “treatment-as-usual” (TAU). Reimbursement costs were calculated over the 12 months pre- and post-index event periods. The authors found a total post-index cost savings of $5,505, which was equivalent to a savings of $0.07 per-member-per-month (PMPM). The authors also evaluated the savings at different adoption rates of the GeneSight test. At 5% adoption, commercial payer savings was calculated at $0.02 PMPM and at 40% adoption, savings was $0.15 PMPM (Benitez et al., 2018).

The AmpliChip^® (Roche Molecular Systems Inc.) is the FDA-cleared test for CYP450 genotyping. This test genotypes CYP2D6 and CYP2C19. From the FDA website: “The AmpliChip CYP4502C19 Test is designed to identify specific nucleic acid sequences and query for the presence of certain known sequence polymorphisms through analysis of the pattern of hybridization to a series of probes that are specifically complementary either to wild-type or mutant sequences (FDA, 2005).” The analytical accuracy was evaluated at 99.6%, or 806 of 809 samples identified correctly. This test assesses a total of 30 alleles, 3 for CYP219 and 27 for CYP2D6 (FDA, 2005).

The OneOme RightMed Pharmacogenomic Test analyzes more than 100 variants in 27 genes to study how a patient may respond to certain medications. The test covers CYP1A2, CYP2B6, CYP2C Cluster, CYP2C9, CYP2C19, CYP2D6, CYP3A4, CYP3A5, CYP4F2, COMT, DPYD, DRD2, F2, F5, GRIK4, HLA-A, HLA-B, HTR2A, HTR2C, IL28B (IFNL4), MTHFR*, NUDT15, OPRM1, SLC6A4, SLCO1B1, TPMT, UGT1A1, and VKORC1 (OneOme, 2021). Analytical validity of the test was assessed by comparing RightMed test results with bi-directional Sanger sequencing results, which resulted in 100% concordance. The RightMed test detects CYP2D6 deletions, duplications, and hybrid alleles, but cannot differentiate duplications in the presence of a deletion (GTR, 2017).

Clinical Utility and Validity
A study evaluating GeneSight Psychotropic’s clinical utility was performed by Greden et al. (2019); a total of 1,167 patients with major depressive disorder were split into two randomized groups: treatment as usual (TAU) and pharmacogenetic-guided. Medications were classified as “congruent” ("use as directed" or "use with caution" test categories) or “incongruent” ("use with increased caution and with more frequent monitoring" test category) with test results. After 8 weeks, the authors found a statistically significant improvement in response and remission; 26% for the pharmacogenetic arm compared 19.9% for TAU and 15.3% for remission compared to 10.1% for TAU (Greden et al., 2019). The authors concluded that pharmacogenetic testing did not improve results, but significantly improved response and remission rates for “difficult-to-treat depression patients over standard of care” (Greden et al., 2019).

Kekic et al. (2020) studied genetic variants that commonly affect supportive care medications, which include, antidepressants, antiemetics, and analgesics, used in oncology practice. 196 cancer patients were genotyped using a multi-gene panel, OneOme RightMed. The panel assessed 27 genes, including CYP2C9, CYP2C19, CYP2D6, CYP3A4, COMT, OPRM1, GRIK4, HTR2A, SLC6A4, associated with pain medications, antidepressants, and antiemetics. Of the 196 patients, 19.9% had prostate cancer, 17.9% had colorectal cancer, 14.8% had melanoma, and 47.4% had other cancer types. All 196 patients had at least one actionable polymorphism related to these supportive care medications, specifically, in CYP2C19 and CYP2D6. 67.3% of the patients had other than normal CYP2D6 metabolizer phenotype and 57.1% had other than normal CYP2C19 metabolizer phenotype. Based on the results, 37 patients were recommended an alternative analgesic, 9 were recommended an alternative antiemetic, and 51 were recommended an alternative anti-depressant (Kekic et al., 2020).

Plumpton et al. (2019) evaluated the cost-effectiveness of panel tests with various pharmacogenes. The constructed multigene panel included HLA-A*31:01, HLA-B*15:02, HLA-B*57:01, HLA-B*58:01, HLA-B (158T), and HLA-DQB1 (126Q), which are involved with various treatments (abacavir, carbamazepine, et al). The constructed multigene panel was found to provide a cost savings of $491 if all findings for all alleles were acted on, regardless of an allele’s individual cost-effectiveness. Testing for patients eligible for abacavir (HLA-B*57:01) and clozapine (HLA-B (158T) and HLA-DQB1 (126Q)) was found to be cost-effective. However, testing for patients eligible for allopurinol (HLA-B*58:01) was not found to be cost-effective. Furthermore, testing for HLA-A*31:01 for carbamazepine was found to be cost-effective, but not testing for HLA-B*15:02 (Plumpton et al., 2019).

Braten et al. (2020) researched the impact of CYP2C19 genotyping on the antidepressant drug sertraline, which is metabolized by the polymorphic CYP2C19 enzyme. A total of 1,202 patients participated and submitted 2190 sertraline serum samples. All patients were categorized based on CYP2C19 genotype-predicted phenotype subgroups; these groups include normal (NM), ultra-rapid (UM), intermediate (IM), and poor metabolizer (PM). Serum samples showed that CYP2C19 IM and PM patients had significantly higher sertraline concentrations compared to NMs; “Based on the relative differences in serum concentrations compared to NMs, dose reductions of 60% and 25% should be considered in PMs and IMs, respectively, to reduce the risk of sertraline overexposure in these patients (Braten et al., 2020).”

Roscizewski et al. (2021) conducted a retrospective observational study to determine what effect pharmacogenomic testing had on “treatment decisions in patients with depressive symptoms in an interprofessional primary care setting.” From April 2019 to March 2021, they identified 78 patients who underwent pharmacogenomic testing for psychotropic medications. They found that 53.8% of patients “experienced a change to their antidepressant regiment after [pharmacogenomic] testing,” with the most cited change being addition of another antidepressant, followed by switching the antidepressant, then increased dose. This demonstrated how pharmacogenomic testing could be useful in informing clinical decision making at the beginning of treatment or “in those who experience an inadequate response to their prescribed regimen” and ensuring optimal patient recovery.

Stevenson et al. (2021) aimed to assess the potential impact of multigene pharmacogenomic testing among those hospitalized with COVID-19 in the United States. Through a cross-sectional analysis with electronic health records, researchers “characterized medication orders, focusing on medications with actionable guidance related to 14 commonly assayed genes (CYP2C19, CYP2C9, CYP2D6, CYP3A5, DPYD, G6PD, HLA-A, HLA-B, IFNL3, NUDT15, SLCO1B1, TPMT, UGT1A1, and VKORC1).” From their cohort, they found that 64 unique medications with pharmacogenomic guidance were ordered at least once, and about 89.7% of patients “had at least one order for a medication with PGx guidance and … (23.1%) had orders for 4 or more actionable medications.” Through a simulation analysis, they estimated that “17 treatment modifications per 100 patients would be enabled if [pharmacogenomic] results were available,” and that the genes CYP2D6 and CYP2C19 were responsible for most of the treatment modifications. Medications most affected included ondansetron, oxycodone, and clopidogrel. With additional investigations that support these findings, pharmacogenomic testing would better inform the curation of individualized treatment plans for patients suffering from severe COVID-19.

Clinical Pharmacogenetics Implementation Consortium (CPIC)
CPIC guidelines provide guidance to physicians on how to use genetic testing to help them to optimize drug therapy. The guidelines and projects were endorsed by several professional societies including The Association for Molecular Pathology (AMP), The American Society for Clinical Pharmacology and Therapeutics (ASCPT) and The American Society of Health-System Pharmacists (ASHP) (CPIC, 2019).

In their list of guidelines, CPIC provides specific therapeutic recommendations for drugs metabolized by Cytochrome P450 enzymes and other important metabolic enzymes.

CYP2C9 Genotypes 

Drug	CYP2C9/ Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Phenytoin/ fosphenytoin based on HLA-B*15:02	HLA-B*15:02 Positive- Normal Metabolizer (NM), Intermediate Metabolizer (EM), and Poor Metabolism (M)	If patient is phenytoin-naïve, do not use phenytoin/fosphenytoin. Avoid carbamazepine and oxcarbazepine. If the patient has previously used phenytoin continuously for longer than three months without incidence of cutaneous adverse reactions, cautiously consider use of phenytoin in the future.	Strong	(Caudle et al., 2014; Karnes et al., 2021)
	HLA-B*15:02 Negative-Normal Metabolizer (NM)	No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.	Strong
	HLA-B*15:02 Negative-Intermediate Metabolizer (IM)	No adjustments needed from typical dosing strategies. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice. For first dose, use typical initial or loading dose. For subsequent doses, use approximately 25% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response and side effects.	Moderate
	HLA-B*15:02 Negative-Poor Metabolizer (PM)	For first dose, use typical initial or loading dose. For subsequent doses use approximately 50% less than typical maintenance dose. Subsequent doses should be adjusted according to therapeutic drug monitoring, response, and side effects. An HLA-B*15:02 negative test does not eliminate the risk of phenytoin-induced SJS/TEN, and patients should be carefully monitored according to standard practice.	Strong
Warfarin	Various phenotypes	Genotype-guided warfarin dosing is very complex and involves a combination of CYP2C9, VKORC1, CYP4F2 and rs12777823 as well as an algorithm including ancestry information.	Multiple	(Johnson et al., 2017)
Celecoxib, flurbiprofen, ibuprofen, lornoxicam	NM	“In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals”	Strong	(Theken et al., 2020)
	IM (Activity Score [AS] = 1.5)	“Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.”	Moderate
	IM (AS = 1)	“Initiate therapy with lowest recommended starting dose. Titrate dose upward to clinical effect or maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Carefully monitor adverse events, such as blood pressure and kidney function during course of therapy.”	Moderate
	PM	“Initiate therapy with 25% – 50% of the lowest recommended starting dose. Titrate dose upward to clinical effect or 25% – 50% of the maximum recommended dose with caution. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady-state is reached (at least 8 days for celecoxib and 5 days for ibuprofen, flurbiprofen, and lornoxicam after first dose in PMs). Carefully monitor adverse events such as blood pressure and kidney function during course of therapy. Alternatively, consider an alternate therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo.”	Moderate
Meloxicam	NM	“Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.”	Strong	(Theken et al., 2020)
	IM, AS 1.5	See NM	Moderate
	IM, AS 1	“Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals. Upward dose titration should not occur until after steady-state is reached (at least 7 days). Carefully monitor adverse events, such as blood pressure and kidney function during course of therapy. Alternatively, consider alternative therapy. Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life.”	Moderate
	PM	“Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life.”	Moderate
Piroxicam/Tenoxicam	NM	“Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.”	Strong	(Theken et al., 2020)
	IM AS 1.5	“Initiate therapy with recommended starting dose. In accordance with the prescribing information, use the lowest effective dosage for shortest duration consistent with individual patient treatment goals.”	Moderate
	IM AS 1	“Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life.”	Moderate (Optional for Tenoxicam)
	PM	“Choose an alternative therapy not metabolized by CYP2C9 or not significantly impacted by CYP2C9 genetic variants in vivo or choose an NSAID metabolized by CYP2C9 but with a shorter half-life.”	Moderate (Optional for Tenoxicam)

CYP2D6 Genotype 

Drug	CYP2D6 Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Amitriptyline and Nortripyline   Other TCAs (tricyclic antidepressants): clomipramine, desipramine, doxepin, imipramine, and trimipramine	Ultra-rapid Metabolizer (UM)	Avoid tricyclic use due to potential lack of efficacy. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider titrating to a higher target dose (compared to normal metabolizers). Utilize therapeutic drug monitoring to guide dose adjustments.	Strong (recommendation for other TCAs is Optional)	(Hicks et al., 2017)
	Normal Metabolizer (NM)	Initiate therapy with recommended starting dose.	Strong (recommendation for other TCAs is Strong)
	IM	Consider a 25% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.	Moderate (recommendation for other TCAs is Optional)
	PM	Avoid tricyclic use due to potential for side effects. Consider alternative drug not metabolized by CYP2D6. If a TCA is warranted, consider a 50% reduction of recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.	Strong (recommendation for other TCAs is Optional)
Codeine	URM	Avoid codeine use due to potential for toxicity.	Strong	(Crews et al., 2021)
	EM	Use label-recommended age or weight-specific dosing.	Strong
	IM	Use label-recommended age or weight-specific dosing. If no response, consider alternative analgesics such as morphine or a nonopioid.	Moderate
	PM	Avoid codeine use due to lack of efficacy.	Strong
Paroxetine	URM	Select alternative drug not predominantly metabolized by CYP2D6	Strong	(Hicks et al., 2015)
	EM	Initiate therapy with recommended starting dose.	Strong
	IM	Initiate therapy with recommended starting dose.	Moderate
	PM	Select alternative drug not predominantly metabolized by CYP2D6b or if paroxetine use warranted, consider a 50% reduction of recommended starting dose and titrate to response.	Optional
Fluvoxamine	UM	No recommendation due to lack of evidence.	Optional	(Hicks et al., 2015)
	EM	Initiate therapy with recommended starting dose.	Strong
	IM	Initiate therapy with recommended starting dose.	Moderate
	PM	Consider a 25% – 50% reduction of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6.	Optional
Ondansetron and Tropisetron	URM	Select alternative drug not predominantly metabolized by CYP2D6 (i.e., granisetron).	Moderate	(Bell et al., 2017)
	NM	Initiate therapy with recommended starting dose.	Strong
	IM	Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.	No recommendation
	PM	Insufficient evidence demonstrating clinical impact based on CYP2D6 genotype. Initiate therapy with recommended starting dose.	No recommendation
Tamoxifen	URM	Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).	Strong	(Goetz et al., 2018)
	NM	Avoid moderate and strong CYP2D6 inhibitors. Initiate therapy with recommended standard of care dosing (tamoxifen 20 mg/day).	Strong
	NM/IM	Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day).45 Avoid CYP2D6 strong to weak inhibitors.	Optional (Controversy remains)
	IM	Consider hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women, given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype. If aromatase inhibitor use is contraindicated, consideration should be given to use a higher but FDA approved tamoxifen dose (40 mg/day). Avoid CYP2D6 strong to weak inhibitors.	Moderate
	PM	Recommend alternative hormonal therapy such as an aromatase inhibitor for postmenopausal women or aromatase inhibitor along with ovarian function suppression in premenopausal women given that these approaches are superior to tamoxifen regardless of CYP2D6 genotype and based on knowledge that CYP2D6 poor metabolizers switched from tamoxifen to anastrozole do not have an increased risk of recurrence. Note, higher dose tamoxifen (40 mg/day) increases but does not normalize endoxifen concentrations and can be considered if there are contraindications to aromatase inhibitor therapy.	Strong
Atomoxetine (for children)	URM	Initiate with a dose of 0.5 mg/kg/day and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 – 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.	Moderate	(Brown et al., 2019)
	NM	Initiate with a dose of 0.5 mg/kg and increase to 1.2 mg/kg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a peak plasma concentration (1 – 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.	Moderate
	IM	Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 2 – 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL.b,c. If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
	PM	Initiate with a dose of 0.5 mg/kg/day and if no clinical response and in the absence of adverse events after 2 weeks, consider obtaining a plasma concentration 4 hours after dosing. If response is inadequate and concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL.b,c. If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
Atomoxetine (for adults)	URM	Initiate with a dose of 40 mg/day and increase to 80 mg/ day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 – 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.b,c. Dosages > 100 mg/day may be needed to achieve target concentrations.	Moderate
	NM	Initiate with a dose of 40 mg/day and increase to 80 mg/day after 3 days. If no clinical response and in the absence of adverse events after 2 weeks, consider increasing dose to 100 mg/day. If no clinical response observed after 2 weeks, consider obtaining a peak plasma concentration (1 – 2 hours after dose administered). If < 200 ng/mL, consider a proportional increase in dose to approach 400 ng/mL.b,c. Dosages > 100 mg/day may be needed to achieve target concentrations.	Moderate
	IM	Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks consider obtaining a plasma concentration 2 – 4 hours after dosing. If concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL.b,c. If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate
	PM	Initiate with a dose of 40 mg/day and if no clinical response and in the absence of adverse events after 2 weeks increase dose to 80 mg/day. If response is inadequate after 2 weeks, consider obtaining a plasma concentration 2 – 4 hours after dosing. If concentration is < 200 ng/mL, consider a proportional dose increase to achieve a concentration to approach 400 ng/mL.b,c. If unacceptable side effects are present at any time, consider a reduction in dose.	Moderate

CYP2B6 Genotypes 

Drug	CYP2B6 Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Efavirenz (for children > 40 kg and adults)	URM	Initiate efavirenz with standard dosing (600 mg/day)	Strong	(Desta et al., 2019)
	Rapid Metabolizer (RM)	Initiate efavirenz with standard dosing (600 mg/day)	Strong
	NM	Initiate efavirenz with standard dosing (600 mg/day)	Strong
	IM	Consider initiating efavirenz with decreased dose of 400 mg/day	Moderate
	PM	Consider initiating efavirenz with decreased dose of 400 or 200 mg/day.	Moderate

CYP2C19 Genotype 

Drug	Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations for amitriptyline	Reference
Amitriptyline and Nortripyline   Other TCAs: clomipramine, doxepin, imipramine, and trimipramine	URM, RM	Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. If a tertiary amine is warranted, utilize therapeutic drug monitoring to guide dose adjustments.	Optional (recommendation for other TCAs is Optional)	(Hicks et al., 2017)
	NM	Initiate therapy with recommended starting dose.	Strong (recommendation for other TCAs is Strong)
	IM	Initiate therapy with recommended starting dose.	Strong (recommendation for other TCAs is Optional)
	PM	Avoid tertiary amine use due to potential for sub-optimal response. Consider alternative drug not metabolized by CYP2C19. TCAs without major CYP2C19 metabolism include the secondary amines nortriptyline and desipramine. For tertiary amines, consider a 50% reduction of the recommended starting dose. Utilize therapeutic drug monitoring to guide dose adjustments.	Moderate (recommendation for other TCAs is Optional)
Citalopram and Escitalopram	URM	Consider an alternative drug not predominantly metabolized by CYP2C19.	Moderate	(Hicks et al., 2015)
	EM	Initiate therapy with recommended starting dose.	Strong
	IM	Initiate therapy with recommended starting dose.	Strong
	PM	Consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.	Moderate
Sertraline	URM	Initiate therapy with recommended starting dose. If patient does not respond to recommended maintenance dosing, consider alternative drug not predominantly metabolized by CYP2C19.	Optional	(Hicks et al., 2015)
	EM	Initiate therapy with recommended starting dose.	Strong
	IM	Initiate therapy with recommended starting dose.	Strong
	PM	Consider a 50% reduction of recommended starting dose and titrate to response or select alternative drug not predominantly metabolized by CYP2C19.	Optional
Clopidogrel	URM, RM, NM	If considering clopidogrel, use at standard dose (75 mg/day)	Strong	(Lee et al., 2022)
	IM, Likely IM	Avoid standard dose clopidogrel (75 mg) if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.	Strong
	PM, Likely PM	Avoid clopidogrel if possible. Use prasugrel or ticagrelor at standard dose if no contraindication.	Strong
Voriconazole	URM	Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.	Moderate	(Moriyama et al., 2017)
	RM	Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole.	Moderate
	NM	Initiate therapy with recommended starting dose.	Strong
	IM	Initiate therapy with recommended starting dose.	Moderate
	PM	Choose an alternative agent that is not dependent on CYP2C19 metabolism as primary therapy in lieu of voriconazole. Such agents include isavuconazole, liposomal amphotericin B, and posaconazole. In the event that voriconazole is considered to be the most appropriate agent, based on clinical advice, for a patient with poor metabolizer genotype, voriconazole should be administered at a preferably lower than standard dosage with careful therapeutic drug monitoring.	Moderate
Proton Pump Inhibitors (omeprazole, lansoprazole, and pantoprazole)   All recommendations here are “Optional” for dexlansoprazole	URM	“Increase starting daily dose by 100%. Daily dose may be given in divided doses. Monitor for efficacy.”	Optional	(Lima et al., 2020)
	RM	“Initiate standard starting daily dose. Consider increasing dose by 50% – 100% for the treatment of Helicobacter pylori infection and erosive esophagitis. Daily dose may be given in divided doses. Monitor for efficacy”	Moderate
	Normal	“Initiate standard starting daily dose. Consider increasing dose by 50% – 100% for the treatment of H. pylori infection and erosive esophagitis. Daily dose may be given in divided doses. Monitor for efficacy.”	Moderate
	Likely IM/IM	“Initiate standard starting daily dose. For chronic therapy (> 12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.”	Optional
	Likely PM/PM	“Initiate standard starting daily dose. For chronic therapy (> 12 weeks) and efficacy achieved, consider 50% reduction in daily dose and monitor for continued efficacy.”	Moderate

CYP2D6 and CYP2C19 Genotypes (Caudle et al., 2020; Hicks et al., 2017) for Amitriptyline, Clomipramine, Doxepin, Imipramine, and Trimipramine

Phenotype	CYP2D6	CYP2D6	CYP2D6	CYP2D6
CYP2C19	UM	NM	IM	PM
URM	Avoid amitriptyline use Recommendation: Optional	Consider alternative drug not metabolized by CYP2C19. Recommendation: Optional	Consider alternative drug not metabolized by CYP2C19. Recommendation: Optional	Avoid amitriptyline use Recommendation: Optional
NM	Avoid amitriptyline use. If amitriptyline is warranted, consider titrating to a higher target dose (compared to normal metabolizers) Recommendation: Strong	Initiate therapy with recommended starting dose. Recommendation: Strong	Consider a 25% reduction of recommended starting dose. Recommendation: Moderate	Avoid amitriptyline use. If Amitriptyline is warranted, consider a 50% reduction of recommended starting dose. Recommendation: Strong
IM	Avoid amitriptyline use Recommendation: Optional	Initiate therapy with recommended starting dose. Recommendation: Strong	Consider a 25% reduction of recommended starting dose. Recommendation: Optional This recommendation may also be considered for diplotypes with an activity score of 1.	Avoid amitriptyline use. If Amitriptyline is warranted, consider a 50% reduction of recommended starting dose. Recommendation: Optional
PM	Avoid amitriptyline use Recommendation: Optional	Avoid amitriptyline use. If Amitriptyline is warranted, consider a 50% reduction of recommended starting dose. Recommendation: Moderate	Avoid amitriptyline use Recommendation: Optional	Avoid amitriptyline use Recommendation: Optional

TPMT Genotype 

Drug	TPMT Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Mercaptopurine (MP)	NM	Start with normal starting dose (e.g., 75 mg/m2/d or 1.5 mg/kg/d) and adjust doses of MP (and of any other myelosuppressive therapy) without any special emphasis on MP compared to other agents. Allow 2 weeks to reach steady state after each dose adjustment. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.	Strong	(Relling et al., 2018)
	IM	Start with reduced doses (start at 30% – 70% of full dose: e.g., at 50 mg/m2/d or 0.75 mg/kg/d) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 2 – 4 weeks to reach steady state after each dose adjustment. In those who require a dosage reduction based on myelosuppression, the median dose may be ~ 40% lower (44 mg/m2) than that tolerated in wild-type patients (75 mg/m2). In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing MP over other agents. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.	Strong
	PM	For malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and reduce frequency to thrice weekly instead of daily, e.g., 10 mg/m2/d given just 3 days/week) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 4 – 6 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing MP over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy. Consider evaluating TPMT erythrocyte activity to assess TPMT phenotype. If thiopurines are required and either TPMT or NUDT15 status is unknown, monitor closely for toxicity.	Strong
Azathioprine	NM	Start with normal starting dose (e.g., 2 – 3 mg/kg/d) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady state after each dose adjustment. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Strong	(Relling et al., 2018)
	IM	Start with reduced starting doses (30% – 80% of normal dose) if normal starting dose is 2 – 3 mg/kg/day, (e.g., 0.6 – 2.4 mg/kg/day), and adjust doses of azathioprine based on degree of myelosuppression and disease-specific guidelines. Allow 2 – 4 weeks to reach steady-state after each dose adjustment. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Strong
	PM	For non-malignant conditions, consider alternative-nonthiopurine immunosuppressant therapy or malignancy, start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of azathioprine based on degree of myelosuppression and disease specific guidelines. Allow 4 – 6 weeks to reach steady state after each dose adjustment. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Strong
Thioguanine	NM	Start with normal starting dose (e.g., 40 – 60 mg/m2 /day). Adjust doses of thioguanine (TG) and of other myelosuppressive therapy without any special emphasis on TG. Allow 2 weeks to reach steady state after each dose adjustment. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Strong	(Relling et al., 2011; Relling et al., 2018)
	IM	Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40 – 60 mg/m2 /day (e.g. 20-48 mg/m2 /day) and adjust doses of TG based on degree of myelosuppression and disease-specific guidelines. Allow 2 – 4 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, and depending on other therapy, emphasis should be on reducing TG over other agents. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Moderate
	PM	Start with drastically reduced doses (reduce daily dose by 10-fold and dose thrice weekly instead of daily) and adjust doses of TG based on degree of myelosuppression and disease-specific guidelines. Allow 4 – 6 weeks to reach steady state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing TG over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy. Consider evaluating erythrocyte TPMT activity to assess TPMT phenotype. If thiopurines are required and TPMT status is unknown, monitor closely for toxicity.	Strong

NUDT15 Genotype

Drug	NUDT15 Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Mercaptopurine	NM	Start with normal starting dose (e.g., 75 mg/m2/day or 1.5 mg/kg/day) and adjust doses of MP (and of any other myelosuppressive therapy) without any special emphasis on MP compared to other agents. Allow 2 weeks to reach steady state after each dose adjustment.	Strong	(Relling et al., 2018)
	IM	Start with reduced doses (start at 30% – 80% of normal dose: if normal starting dose is ≥ 75 mg/m2 /day or ≥ 1.5 mg/kg/day (e.g., start at 25 – 60 mg/m2/day or 0.45 – 1.2 mg/kg/day) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 2 – 4 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing mercaptopurine over other agents. If normal starting dose is already < 1.5mg/kg/day, dose reduction may not be recommended.	Strong
	PM	For malignancy, initiate dose at 10 mg/m2/day and adjust dose based on myelosuppression and disease specific guidelines. Allow 4 – 6 weeks to reach steady state after each dose adjustment. If myelosuppression occurs, emphasis should be on reducing mercaptopurine over other agents. For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy.	Strong
Azathioprine	NM	Start with normal starting dose (e.g., 2 – 3 mg/kg/day) and adjust doses of azathioprine based on disease-specific guidelines. Allow 2 weeks to reach steady state after each dose adjustment.	Strong	(Relling et al., 2018)
	IM	Start with reduced doses (start at 30% – 80% of normal dose: if normal starting dose is 2 – 3 mg/kg/day, (e.g., 0.6 – 2.4 mg/kg/day) and adjust doses of MP based on degree of myelosuppression and disease-specific guidelines. Allow 2 – 4 weeks to reach steady state after each dose adjustment.	Strong
	PM	For nonmalignant conditions, consider alternative nonthiopurine immunosuppressant therapy. For malignant conditions, start with drastically reduced normal daily doses (reduce daily dose by 10-fold) and adjust doses of azathioprine based on degree of myelosuppression and disease specific guidelines. Allow 4 – 6 weeks to reach steady-state after each dose adjustment.	Strong
Thioguanine	NM	Start with normal starting dose (40 – 60 mg/day). Adjust doses of thioguanine and of other myelosuppressive therapy without any special emphasis on thioguanine. Allow 2 weeks to reach steady-state after each dose adjustment.	Strong	(Relling et al., 2018)
	IM	Start with reduced doses (50% to 80% of normal dose) if normal starting dose is ≥ 40 – 60 mg/m2 /day (e.g., 20 – 48 mg/m2 /day) and adjust doses of thioguanine based on degree of myelosuppression and disease specific guidelines. Allow 2 – 4 weeks to reach steady-state after each dose adjustment. If myelosuppression occurs, and depending on other therapy, emphasis should be on reducing thioguanine over other agents.	Moderate
	PM	Reduce doses to 25% of normal dose and adjust doses of thioguanine based on degree of myelosuppression and disease specific guidelines. Allow 4 – 6 weeks to reach steady-state after each dose adjustment. In setting of myelosuppression, emphasis should be on reducing thioguanine over other agents. For non-malignant conditions, consider alternative nonthiopurine immunosuppressant therapy.	Strong

DPYD Genotypes 

Drug	Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
5-Fluorouracil Capecitabine	NM	Based on genotype, there is no indication to change dose or therapy. Use label recommended dosage and administration.	Strong	(Amstutz et al., 2018)
	IM	Reduce starting dose based on activity score followed by titration of dose based on toxicity or therapeutic drug monitoring (if available). Activity score 1: Reduce dose by 50% Activity score 1.5: Reduce dose by 25% to 50%.	Activity score 1: Strong Activity score 1.5: Moderate
	PM	Activity score 0.5: Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens. In the event, based on clinical advice, alternative agents are not considered a suitable therapeutic option, 5-fluorouracil should be administered at a strongly reduced dosed with early therapeutic drug monitoring. Activity score 0: Avoid use of 5-fluorouracil or 5-fluorouracil prodrug-based regimens.	Strong

HLA-B Genotypes 

Drug	Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
Abacavir	Noncarrier of HLA-B*57:01	Low or reduced risk of abacavir hypersensitivity	Strong	(Martin et al., 2014)
	Carrier of HLA-B*57:01	Abacavir is not recommended.	Strong
Allopurinol	Noncarrier of HLA-B*5801 (*X/*X)	Use allopurinol per standard dosing guidelines.	Strong	(Hershfield et al., 2013; Saito et al., 2016)
	Carrier of HLA-B*5801 (HLA-B*5801/*X,b HLA-B*5801/HLA-B*5801)	Allopurinol is contraindicated.	Strong
Oxcarbazepine	HLA-B*15:02 negative	Use oxcarbazepine per standard dosing guidelines.	Strong	(Phillips et al., 2018)
	HLA-B*15:02 positive	If patient is oxcarbazepine-naive, do not use oxcarbazepine.	Strong
Carbamazepine	HLA-B*15:02 negative and HLA-A*31:01 negative	Use carbamazepine per standard dosing guidelines.	Strong	(Phillips et al., 2018)
	HLA-B*15:02 negative and HLA-A*31:01 positive	If patient is carbamazepine-naive and alternative agents are available, do not use carbamazepine.	Strong
	HLA-B*15:02 positive and any HLA-A*31:01 genotype (or HLA-A*31:01 genotype unknown)	If patient is carbamazepine-naive, do not use carbamazepine.	Strong

Additional Genotypes 

Drug/Genotype	Phenotype	Summary of CPIC Therapeutic Recommendations	Level of Recommendations	Reference
UGT1A1 for Atazanavir	EM	There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice).	Strong	(Gammal et al., 2016)
	IM	There is no need to avoid prescribing of atazanavir based on UGT1A1 genetic test result. Inform the patient that some patients stop atazanavir because of jaundice (yellow eyes and skin), but that this patient’s genotype makes this unlikely (less than about a 1 in 20 chance of stopping atazanavir because of jaundice).	Strong
	PM	Consider an alternative agent particularly where jaundice would be of concern to the patient. If atazanavir is to be prescribed, there is a high likelihood of developing jaundice that will result in atazanavir discontinuation (at least 20% and as high as 60%).	Strong
UGT1A1 for Irinotecan	N/A	N/A	A, 1A level of evidence	(CPIC, 2021)
CFTR for Ivacaftor	Homozygous or heterozygous G551D-CFTR — e.g., G551D/ F508del, G551D/G551D, rs75527207 genotype AA or AG	Use ivacaftor according to the product label (e.g., 150 mg every 12h for patients aged 6 years and older without other diseases; modify dose in patients with hepatic impairment).	Strong	(Clancy et al., 2014)
	Noncarrier of G551D-CFTR — e.g., F508del/R553X, rs75527207 genotype GG	Ivacaftor is not recommended.	Moderate
	Homozygous for F508del-CFTR (F508del/F508del), rs113993960, or rs199826652 genotype del/ del	Ivacaftor is not recommended.	Moderate
G6PD for Rasburicase	Normal	No reason to withhold rasburicase based on G6PD status.	Strong	(Relling et al., 2014)
	Deficient or deficient with CNSHA	Rasburicase is contraindicated; alternatives include allopurinol.	Strong
	Variable	To ascertain that G6PD status is normal, enzyme activity must be measured; alternatives include allopurinol.	Moderate
SLCO1B1 for Simvastatin	Normal function	Prescribe desired starting dose and adjust doses of simvastatin based on disease-specific guidelines.	Strong	(Ramsey et al., 2014)
	Intermediate function	Prescribe a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine CK surveillance.	Strong
	Low function	Prescribe a lower dose or consider an alternative statin (e.g., pravastatin or rosuvastatin); consider routine CK surveillance.	Strong
CYP3A5 for treatment with Tacrolimus	EM	Increase starting dose 1.5 – 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.	Strong	(Birdwell et al., 2015)
	IM	Increase starting dose 1.5 – 2 times recommended starting dose. Total starting dose should not exceed 0.3 mg/kg/day. Use therapeutic drug monitoring to guide dose adjustments.	Strong
	PM	Initiate therapy with standard recommended dose. Use therapeutic drug monitoring to guide dose adjustments.	Strong
IFNL3 treatment with Peginterferon alfa-2a, Peginterferon alfa-2b or Ribavirin	Favorable response genotype	Approximately 90% chance for SVR after 24 – 48 weeks of treatment. Approximately 80% – 90% of patients are eligible for shortened therapy (24 – 28 weeks vs. 48 weeks). Weighs in favor of using PEG-IFN-α- and RBV- containing regimens.	Strong	(Muir et al., 2014)
	Unfavorable response genotype	Approximately 60% chance of SVR after 24 – 48 weeks of treatment. Approximately 50% of patients are eligible for shortened therapy regimens (24 – 28 weeks). Consider implications before initiating PEG-IFN-α- and RBV-containing regimens.	Strong
RYR1 and CACNA1S genotypes for Potent Volatile Anesthetic Agents and Succinylcholine	Malignant Hyperthermia Susceptible	Halogenated volatile anesthetics or depolarizing Halogenated volatile anesthetics or depolarizing muscle relaxants succinylcholine are relatively contraindicated in persons with MHS. They should not be used, except in extraordinary circumstances in which the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.	Strong	(Gonsalves et al., 2019)
	Uncertain susceptibility	Clinical findings, family history, further genetic testing and other laboratory data should guide use of halogenated volatile anesthetics or depolarizing muscle relaxants.	Strong

CPIC notes that evidence for TYMS testing is unclear or weak and have assigned TYMS a “D” level recommendation. CPIC does not recommend any change in prescription based on TYMS genotype (CPIC, 2021).

American College of Medical Genetics and Genomics (ACMG)
ACMG notes that CYP2C9 and VKORC1 testing may be useful for assessing unusual responses to warfarin, but cannot recommend for or against routine genotyping (ACMG, 2007).

American College of Cardiology Foundation (AACF) and the American Heart Association (AHA) Joint Guidelines
A report by the ACCF and the AHA on genetic testing for selection and dosing of clopidogrel provided the following recommendations for practice: 

• “Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes in registry experiences and clinical trials.”
• “The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined (e.g., the importance of CYP2C19*2 versus *3 or *4 for a specific patient), and the frequency of genetic variability differs among ethnic groups.”
• “Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies.”
• “The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time. There is no information that routine testing improves outcome in large subgroups of patients. In addition, the clinical course of the majority of patients treated with clopidogrel without either genetic testing or functional testing is excellent. Clinical judgment is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism (“poor metabolizers”) may be considered before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, among others, patients undergoing elective high-risk PCI procedures (e.g., treatment of extensive and/or very complex disease). If such testing identifies a potential poor metabolizer, other therapies, particularly prasugrel for coronary patients, should be considered. (Holmes et al., 2010).

American Academy of Neurology (AAN)
The AAN published a position paper on the use of opioids for chronic non-cancer pain. Regarding pharmacogenetic testing, the guidelines state “genotyping to determine whether response to opioid therapy can/should be more individualized will require critical original research to determine effectiveness and appropriateness of use” (Franklin, 2014).

American Association for Clinical Chemistry (AACC) Academy Laboratory Medicine Practice Guidelines
AACC Academy issued laboratory medicine practice guidelines on using clinical laboratory tests to monitor drug therapy in pain management. Their guidelines have a total of 26 recommendations and 7 expert opinions. Regarding pharmacogenetic testing for pain management, they stated in the recommendation #20 (Level A, II) that “while the current evidence in the literature doesn’t support routine genetic testing for all pain management patients, it should be considered to predict or explain variant pharmacokinetics, and/ or pharmacodynamics of specific drugs as evidenced by repeated treatment failures, and/or adverse drug reactions/toxicity (AACC, 2017).”

American Family Physician (AAFP)
The AAFP has published guidelines on pharmacogenetics: using genetic information to guide drug therapy. CPIC guidelines are cited for many medication/allele combinations in this article. The recommendations by the AAFP are listed in the table below taken from Chang et al. (2015):

Allele	Medications	Test Results and Clinical Implications	Comments
CYP2D6	Codeine, hydrocodone, oxycodone, tramadol	Ultrarapid metabolizer: Avoid codeine because of potential for toxicity. Poor metabolizer: Avoid codeine and possibly tramadol because of possible lack of effectiveness.	CPIC guidance limits genotype-guided dosing recommendations to codeine. Alternative analgesics not affected by CYP2D6 variability include morphine, oxymorphone, and nonopioid analgesics. Oxycodone may also have reduced effectiveness in poor CYP2D6 metabolizers.
CYP2C19	Clopidogrel (Plavix)	Intermediate metabolizer: Use alternative antiplatelet therapy if no contraindications Poor metabolizer: Use alternative antiplatelet therapy if no contraindications.	Clopidogrel prescribing information states that CYP2C19 tests can be used as an aid to determine therapeutic strategy in patients with acute coronary syndromes who are undergoing percutaneous coronary intervention. CPIC guidance limits genotype-guided dosing recommendations to patients undergoing percutaneous coronary intervention for acute coronary syndromes (excluding medical management of acute coronary syndromes, stroke, and peripheral artery disease). ACCF/AHA guidelines state that genotyping may be considered in patients with unstable angina/non-ST segment elevation myocardial infarction (or after percutaneous coronary intervention for acute coronary syndromes) if test results could alter management. Alternative antiplatelet therapy not affected by CYP2C19 variability includes prasugrel (Effient) and ticagrelor (Brilinta).
CYP2C19	Amitriptyline	Poor metabolizer: Consider 50% reduction in recommended starting dose.	CPIC guidance is available for CYP2D6- and CYP2C19-genotype guided tricyclic antidepressant therapy. Although limited data exist for other tricyclic antidepressants, most supporting evidence of clinically relevant gene-drug effects is for amitriptyline and nortriptyline (Pamelor).
CYP2C19	Citalopram (Celexa), escitalopram (Lexapro)	Ultrarapid metabolizer: Consider alternative. Poor metabolizer: Consider 50% starting dose reduction and titrate to response, or use alternative.	CPIC guidance is available for CYP2C19-genotype guided citalopram and escitalopram therapy. FDA label for citalopram states that 20 mg per day is the maximum recommended dosage for patients older than 60 years, patients with hepatic impairment, and CYP2C19 poor metabolizers or patients taking cimetidine (Tagamet) or another CYP2C19 inhibitor.
CYP2C19	Sertraline (Zoloft)	Ultrarapid metabolizer: If patient does not respond to recommended dose, consider alternative. Poor metabolizer: Consider 50% dose reduction or alternative.	CPIC guidance is available for CYP2C19-genotype guided sertraline therapy.
CYP2D6	Amitriptyline, nortriptyline	Ultrarapid metabolizer: Avoid because of possible lack of effectiveness. Poor metabolizer: Avoid because of possible adverse effects; if use is warranted, consider 50% reduction in recommended starting dose.	CPIC guidance is available for CYP2D6- and CYP2C19-genotype guided tricyclic antidepressant therapy. Although limited data exist for other tricyclic antidepressants, most supporting evidence of clinically relevant gene-drug effects is for amitriptyline and nortriptyline.
CYP2D6	Aripiprazole (Abilify)	Poor metabolizer: Decrease dose.	Quality of supporting evidence is classified as low by PharmGKB. FDA label for aripiprazole states that in poor metabolizers, the usual dose should initially be reduced to 50% and then adjusted to achieve a favorable clinical response; in poor metabolizers receiving a strong CYP3A4 inhibitor, the usual dose should be reduced to 25%.
CYP2D6	Atomoxetine (Strattera)	Poor metabolizer: Adjust dose.	Quality of supporting evidence is classified as moderate (Level 2a) by PharmGKB. FDA label for atomoxetine states that in poor metabolizers, the initial dosage should be 0.5 mg per kg per day and then increased to the the usual target dosage of 1.2 mg per kg per day only if symptoms do not improve after 4 weeks and the initial dose is well tolerated.
CYP2D6	Paroxetine (Paxil)	Ultrarapid metabolizer: Select alternative because of possible lack of effectiveness. Poor metabolizer: Select alternative or if use is warranted, consider 50% starting dose reduction.	CPIC guidance is available for CYP2D6-genotype guided paroxetine therapy.

Dutch Pharmacogenetics Working Group (DPWG)
The DPWG has published guidelines for the gene-drug interaction of DPYD and fluoropyrimidines. Conclusions state that “four variants have sufficient evidence to be implemented into clinical care: DPYD*2A (c.1905+1G>A, IVS14+1G>A), DPYD*13 (c.1679T>G), c.2846A>T and c.1236G>A (in linkage disequilibrium with c.1129–5923C>G). The current guideline only reports recommendations for these four variants; no recommendations are provided for other variants in DPYD or other genes (Lunenburg et al., 2019).”

Food and Drug Administration
The FDA published several tables of pharmacogenetic associations with “sufficient scientific evidence to suggest that subgroups of patients with certain genetic variants, or genetic variant-inferred phenotypes (i.e., affected subgroup in the table below), are likely to have altered drug metabolism, and in certain cases, differential therapeutic effects, including differences in risks of adverse events”.

The table below lists associations “for which the data support therapeutic management recommendations” (FDA, 2021b).

Drug	Gene	Affected Subgroups	Description of Gene-Drug Interaction
Abacavir	HLA-B	*57:01 allele positive	Results in higher adverse reaction risk (hypersensitivity reactions). Do not use abacavir in patients positive for HLA-B*57:01.
Amifampridine	NAT2	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Use lowest recommended starting dosage and monitor for adverse reactions. Refer to FDA labeling for specific dosing recommendations.
Amifampridine Phosphate	NAT2	poor metabolizers	Results in higher systemic concentrations. Use lowest recommended starting dosage (15 mg/day) and monitor for adverse reactions.
Amphetamine	CYP2D6	poor metabolizers	May affect systemic concentrations and adverse reaction risk. Consider lower starting dosage or use alternative agent.
Aripiprazole	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations.
Aripiprazole Lauroxil	CYP2D6	poor metabolizers	Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations.
Atomoxetine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Adjust titration interval and increase dosage if tolerated. Refer to FDA labeling for specific dosing recommendations.
Azathioprine	TPMT and/or NUDT15	intermediate or poor metabolizers	Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Consider alternative therapy in poor metabolizers. Dosage reduction is recommended in intermediate metabolizers for NUDT15 or TPMT. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations.
Belinostat	UGT1A1	*28/*28 (poor metabolizers)	May result in higher systemic concentrations and higher adverse reaction risk. Reduce starting dose to 750 mg/m2 in poor metabolizers.
Brexpiprazole	CYP2D6	poor metabolizers	Results in higher systemic concentrations. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations.
Brivaracetam	CYP2C19	intermediate or poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Consider dosage reductions in poor metabolizers.
Capecitabine	DPYD	intermediate or poor metabolizers	Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers, and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity.
Carbamazepine	HLA-B	*15:02 allele positive	Results in higher adverse reaction risk (severe skin reactions). Avoid use unless potential benefits outweigh risks and consider risks of alternative therapies. Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance.
Celecoxib	CYP2C9	poor metabolizers	Results in higher systemic concentrations. Reduce starting dose to half of the lowest recommended dose in poor metabolizers. Consider alternative therapy in patients with juvenile rheumatoid arthritis.
Citalopram	CYP2C19	poor metabolizers	Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dose is 20 mg.
Clobazam	CYP2C19	intermediate or poor metabolizers	Results in higher systemic active metabolite concentrations. Poor metabolism results in higher adverse reaction risk. Dosage adjustment is recommended. Refer to FDA labeling for specific dosing recommendations.
Clopidogrel	CYP2C19	intermediate or poor metabolizers	Results in lower systemic active metabolite concentrations, lower antiplatelet response, and may result in higher cardiovascular risk. Consider use of another platelet P2Y12 inhibitor.
Clozapine	CYP2D6	poor metabolizers	Results in higher systemic concentrations. Dosage reductions may be necessary.
Codeine	CYP2D6	ultrarapid metabolizers	Results in higher systemic active metabolite concentrations and higher adverse reaction risk (life-threatening respiratory depression and death). Codeine is contraindicated in children under 12 years of age.
Deutetrabenazine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and adverse reaction risk (QT prolongation). The maximum recommended dosage should not exceed 36 mg (maximum single dose of 18 mg).
Dronabinol	CYP2C9	intermediate or poor metabolizers	May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions.
Eliglustat	CYP2D6	ultrarapid, normal, intermediate, or poor metabolizers	Alters systemic concentrations, effectiveness, and adverse reaction risk (QT prolongation). Indicated for normal, intermediate, and poor metabolizer patients. Ultrarapid metabolizers may not achieve adequate concentrations to achieve a therapeutic effect. The recommended dosages are based on CYP2D6 metabolizer status. Coadministration with strong CYP3A inhibitors is contraindicated in intermediate and poor CYP2D6 metabolizers. Refer to FDA labeling for specific dosing recommendations.
Erdafitinib	CYP2C9	*3/*3 (poor metabolizers)	May result in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions.
Flibanserin	CYP2C19	poor metabolizers	May result in higher systemic concentrations and higher adverse reaction risk. Monitor patients for adverse reactions.
Flurbiprofen	CYP2C9	poor metabolizers	Results in higher systemic concentrations. Use a reduced dosage.
Fluorouracil	DPYD	intermediate or poor metabolizer	Results in higher adverse reaction risk (severe, life-threatening, or fatal toxicities). No dosage has proven safe in poor metabolizers and insufficient data are available to recommend a dosage in intermediate metabolizers. Withhold or discontinue in the presence of early-onset or unusually severe toxicity.
Fosphenytoin	CYP2C9	Intermediate or poor metabolizers	May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Consider starting at the lower end of the dosage range and monitor serum concentrations. Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding fosphenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management.
Fosphenytoin	HLA-B	*15:02 allele positive	May result in higher adverse reaction risk (severe cutaneous reactions). Patients positive for HLA-B*15:02 may be at increased risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Consider avoiding fosphenytoin as an alternative to carbamazepine in patients who are positive for HLA-B*15:02. Genotyping is not a substitute for clinical vigilance and patient management.
Gefitinib	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Monitor for adverse reactions.
Iloperidone	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Reduce dosage by 50%.
Irinotecan	UGT1A1	*28/*28 (poor metabolizers)	Results in higher systemic active metabolite concentrations and higher adverse reaction risk (severe neutropenia). Consider reducing the starting dosage by one level and modify the dosage based on individual patient tolerance.
Lofexidine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. Monitor for orthostatic hypotension and bradycardia.
Meclizine	CYP2D6	ultrarapid, intermediate, or poor metabolizers	May affect systemic concentrations. Monitor for adverse reactions and clinical effect.
Meloxicam	CYP2C9	Poor metabolizers or *3 carriers	Results in higher systemic concentrations. Consider dose reductions in poor metabolizers. Monitor patients for adverse reactions.
Metoclopramide	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk. The recommended dosage is lower. Refer to FDA labeling for specific dosing recommendations.
Mercaptopurine	TPMT and/or NUDT15	intermediate or poor metabolizers	Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations.
Mivacurium	BCHE	intermediate or poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (prolonged neuromuscular blockade). Avoid use in poor metabolizers.
Oliceridine	CYP2D6	Poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (respiratory depression and sedation). May require less frequent dosing.
Pantoprazole	CYP2C19	poor metabolizers	Results in higher systemic concentrations. Consider dosage reduction in children who are poor metabolizers. No dosage adjustment is needed for adult patients who are poor metabolizers.
Phenytoin	CYP2C9	Intermediate or poor metabolizers	May result in higher systemic concentrations and higher adverse reaction risk (central nervous system toxicity). Refer to FDA labeling for specific dosing recommendations. Carriers of CYP2C9*3 alleles may be at increased risk of severe cutaneous adverse reactions. Consider avoiding phenytoin as an alternative to carbamazepine in patients who are CYP2C9*3 carriers. Genotyping is not a substitute for clinical vigilance and patient management.
Phenytoin	HLA-B	*15:02 allele positive	May result in higher adverse reaction risk (severe cutaneous reactions). Patients positive for HLA-B*15:02 may be at increased risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Consider avoiding phenytoin as an alternative to carbamazepine in patients who are positive for HLA-B*15:02. Genotyping is not a substitute for clinical vigilance and patient management.
Pimozide	CYP2D6	poor metabolizers	Results in higher systemic concentrations. Dosages should not exceed 0.05 mg/kg in children or 4 mg/day in adults who are poor metabolizers and dosages should not be increased earlier than 14 days.
Piroxicam	CYP2C9	intermediate or poor metabolizers	Results in higher systemic concentrations. Consider reducing dosage in poor metabolizers.
Pitolisant	CYP2D6	Poor metabolizers	Results in higher systemic concentrations. Use lowest recommended starting dosage. Refer to FDA labeling for specific dosing recommendations.
Propafenone	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (arrhythmia). Avoid use in poor metabolizers taking a CYP3A4 inhibitor.
Sacituzumab Govitecan-hziy	UGT1A1	*28/*28 (poor metabolizers)	May result in higher systemic concentrations and adverse reaction risk (neutropenia). Monitor for adverse reactions and tolerance to treatment.
Siponimod	CYP2C9	intermediate or poor metabolizers	Results in higher systemic concentrations. Adjust dosage based on genotype. Do not use in patients with CYP2C9 *3/*3 genotype. Refer to FDA labeling for specific dosing recommendations.
Succinylcholine	BCHE	intermediate or poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (prolonged neuromuscular blockade). Avoid use in poor metabolizers. May administer test dose to assess sensitivity and administer cautiously via slow infusion.
Tacrolimus	CYP3A5	intermediate or normal metabolizers	Results in lower systemic concentrations and lower probability of achieving target concentrations. Measure drug concentrations and adjust dosage based on trough whole blood tacrolimus concentrations.
Tetrabenazine	CYP2D6	poor metabolizers	Results in higher systemic concentrations. The maximum recommended single dose is 25 mg and should not exceed 50 mg/day.
Thioguanine	TPMT and/or NUDT15	intermediate or poor metabolizers	Alters systemic active metabolite concentration and dosage requirements. Results in higher adverse reaction risk (myelosuppression). Initial dosages should be reduced in poor metabolizers; poor metabolizers generally tolerate 10% or less of the recommended dosage. Intermediate metabolizers may require dosage reductions based on tolerability. Intermediate metabolizers for both genes may require more substantial dosage reductions. Refer to FDA labeling for specific dosing recommendations.
Thioridazine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation). Predicted effect based on experience with CYP2D6 inhibitors. Contraindicated in poor metabolizers.
Tramadol	CYP2D6	Ultrarapid metabolizers	Results in higher systemic and breast milk active metabolite concentrations, which may result in respiratory depression and death. Contraindicated in children under 12 and in adolescents following tonsillectomy/adenoidectomy. Breastfeeding is not recommended during treatment.
Valbenazine	CYP2D6	poor metabolizers	Results in higher systemic active metabolite concentrations and higher adverse reaction risk (QT prolongation). Dosage reductions may be necessary.
Venlafaxine	CYP2D6	poor metabolizers	Alters systemic parent drug and metabolite concentrations. Consider dosage reductions.
Vortioxetine	CYP2D6	poor metabolizers	Results in higher systemic concentrations. The maximum recommended dose is 10 mg.
Warfarin	CYP2C9	intermediate or poor metabolizers	Alters systemic concentrations and dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR.
Warfarin	CYP4F2	V433M variant carriers	May affect dosage requirements. Monitor and adjust doses based on INR.
Warfarin	VKORC1	-1639G>A variant carriers	Alters dosage requirements. Select initial dosage, taking into account clinical and genetic factors. Monitor and adjust dosages based on INR.

The table below lists associations “for which the data indicate a potential impact on safety or response” (FDA, 2021b).  

Drug	Gene	Affected Subgroups	Description of Gene-Drug Interaction
Allopurinol	HLA-B	*58:01 allele positive	Results in higher adverse reaction risk (severe skin reactions).
Carbamazepine	HLA-A	*31:01 allele positive	Results in higher adverse reaction risk (severe skin reactions). Consider risk and benefit of carbamazepine use in patients positive for HLA-A*31:01. Genotyping is not a substitute for clinical vigilance.
Carvedilol	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (dizziness).
Cevimeline	CYP2D6	poor metabolizers	May result in higher adverse reaction risk. Use with caution.
Codeine	CYP2D6	poor metabolizers	Results in lower systemic active metabolite concentrations and may result in reduced efficacy.
Efavirenz	CYP2B6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation).
Isoniazid	Nonspecific (NAT)	poor metabolizers	May result in higher systemic concentrations and adverse reaction risk.
Lapatinib	HLA-DRB1	*07:01 allele positive	Results in higher adverse reaction risk (hepatotoxicity). Monitor liver function tests regardless of genotype.
Lapatinib	HLA-DQA1	*02:01 allele positive	Results in higher adverse reaction risk (hepatotoxicity). Monitor liver function tests regardless of genotype.
Nilotinib	UGT1A1	*28/*28 (poor metabolizers)	Results in higher adverse reaction risk (hyperbilirubinemia).
Oxcarbazepine	HLA-B	*15:02 allele positive	Results in higher adverse reaction risk (severe skin reactions). Patients positive for HLA-B*15:02 may be at increased risk of severe skin reactions with other drugs that are associated with a risk of Stevens Johnson Syndrome/Toxic Epidermal necrolysis (SJS/TEN). Genotyping is not a substitute for clinical vigilance.
Pazopanib	HLA-B	*57:01 allele positive	May result in higher adverse reaction risk (liver enzyme elevations). Monitor liver function tests regardless of genotype.
Pazopanib	UGT1A1	*28/*28 (poor metabolizers)	Results in higher adverse reaction risk (hyperbilirubinemia).
Perphenazine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk.
Procainamide	Nonspecific (NAT)	poor metabolizers	Alters systemic parent drug and metabolite concentrations. May result in higher adverse reaction risk.
Simvastatin	SLCO1B1	521 TC or 521 CC (intermediate or poor function transporters)	Results in higher systemic concentrations and higher adverse reaction risk (myopathy). The risk of adverse reaction (myopathy) is higher for patients on 80 mg than for those on lower doses.
Sulfamethoxazole and Trimethoprim	Nonspecific (NAT)	poor metabolizers	May result in higher adverse reaction risk.
Sulfasalazine	Nonspecific (NAT)	poor metabolizers	Results in higher systemic metabolite concentrations and higher adverse reaction risk.
Tolterodine	CYP2D6	poor metabolizers	Results in higher systemic concentrations and higher adverse reaction risk (QT prolongation).

The International Society of Psychiatric Genetics
The International Society of Psychiatric Genetics (ISPG) released recommendations on the use of pharmacogenetic testing to guide psychiatric treatment. ISPG recommends that pharmacogenetic testing should be used as a decision-support tool. HLA-A and HLA-B testing is recommended before the use of carbamazepine and oxcarbazepine. CYP2C19 and CYP2D6 testing would be beneficial for those who experienced an inadequate response or adverse reaction to a previous antidepressant or antipsychotic medication (ISPG, 2019).

The American Academy of Child and Adolescent Psychiatry
AACAP does not recommend the use of pharmacogenetic testing to select psychotropic medications for children and adolescents (AACAP, 2020)

Association for Molecular Pathology PGx Working Group (AMP)
AMP released clinical practice guidelines to define a minimum set of CYP2C19 allele variants that should be included in the pharmacogenomic genotyping assay. Tier 1 represents alleles that have been shown to affect drug response and should be included, while Tier 2 represents alleles which meet at least one but not all the criteria for inclusion in Tier 1 and are considered optional for inclusion in expanded clinical genotyping panels. Those in Tier 1 include alleles *2, *3, and *17. The following CYP2C19 alleles were recommended as Tier 2: *4A, *4B, *5, *6, *7, *8, *9, *10, and *35 (Pratt et al., 2018). Regarding CYP2C9 variant alleles, Tier 1 alleles include CYP2C9 *2, *3, *5, *6, *8, and *11. The following CYP2C9 alleles are recommended for inclusion in Tier 2: CYP2C9*12, *13, and *15 (Pratt et al., 2019). For testing genes and alleles specific to warfarin, AMP recommends including VKORC1 c.-1639G>Ain Tier 1 and VKORC1 c.196G>A and c.106G>A in Tier 2 (Pratt et al., 2020). In a joint recommendation endorsed by the AMP, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy, CYP2D6 variant alleles were elucidated. Tier 1 alleles include CYP2D6 *2 to *6, *9, *10, *17, *29, and *41. Tier 2 CYP2D6 alleles include CYP2D6 *7, *8, *12, *14, *15, *21, *31, *40, *42, *49, *56, and *59, and hybrid genes containing portions of CYP2D6 and CYP2D7 (Pratt et al., 2021). These recommendations should help to standardize testing and genotyping concordance among laboratories.

European Medicines Agency
EMA released recommendations on DPD testing before treatment with fluorouracil, capecitabine, tegafur, and flucytosine. EMA recommends testing for the lack of DPD before starting cancer treatment with fluorouracil, capecitabine, or tegafur. Patients who completely lack DPD should not be given these medications. For patients with partial deficiency, the physician may consider beginning treatment at a lower dose and terminating treatment if severe side effects occur. These recommendations do not apply to fluorouracil medications used for skin conditions or flucytosine used for fungal infection (EMA, 2020).

References 

1. AACAP. (2020). Clinical Use of Pharmacogenetic Tests in Prescribing Psychotropic Medications for Children and Adolescents. https://www.aacap.org/aacap/Policy_Statements/2020/Clinical-Use-Pharmacogenetic-Tests-Prescribing-Psychotropic-Medications-for-Children-Adolescents.aspx
2. AACC. (2017, 01/01/2017). Using Clinical Laboratory Tests to Monitor Drug Therapy in Pain Management Patients. https://www.aacc.org/science-and-practice/practice-guidelines/using-clinical-laboratory-tests-to-monitor-drug-therapy-in-pain-management-patients
3. ACMG. (2007). Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. http://www.acmg.net/PDFLibrary/CYP2C9-VKORC1-Parmacogenetic-Testing.pdf
4. Ahern, T. P., Hertz, D. L., Damkier, P., Ejlertsen, B., Hamilton-Dutoit, S. J., Rae, J. M., Regan, M. M., Thompson, A. M., Lash, T. L., & Cronin-Fenton, D. P. (2017). Cytochrome P-450 2D6 (CYP2D6) Genotype and Breast Cancer Recurrence in Tamoxifen-Treated Patients: Evaluating the Importance of Loss of Heterozygosity. Am J Epidemiol, 185(2), 75-85. https://doi.org/10.1093/aje/kww178
5. Aka, I., Bernal, C. J., Carroll, R., Maxwell-Horn, A., Oshikoya, K. A., & Van Driest, S. L. (2017). Clinical Pharmacogenetics of Cytochrome P450-Associated Drugs in Children. J Pers Med, 7(4). https://doi.org/10.3390/jpm7040014
6. Amstutz, U., Henricks, L. M., Offer, S. M., Barbarino, J., Schellens, J. H. M., Swen, J. J., Klein, T. E., McLeod, H. L., Caudle, K. E., Diasio, R. B., & Schwab, M. (2018). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther, 103(2), 210-216. https://doi.org/10.1002/cpt.911
7. Bains, R. K. (2013). African variation at Cytochrome P450 genesEvolutionary aspects and the implications for the treatment of infectious diseases. Evolution, Medicine, and Public Health, 2013(1), 118-134. https://doi.org/10.1093/emph/eot010
8. Bell, G. C., Caudle, K. E., Whirl-Carrillo, M., Gordon, R. J., Hikino, K., Prows, C. A., Gaedigk, A., Agundez, J., Sadhasivam, S., Klein, T. E., & Schwab, M. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6 genotype and use of ondansetron and tropisetron. Clin Pharmacol Ther, 102(2), 213-218. https://doi.org/10.1002/cpt.598
9. Benitez, J., Cool, C. L., & Scotti, D. J. (2018). Use of combinatorial pharmacogenomic guidance in treating psychiatric disorders. Per Med, 15(6), 481-494. https://doi.org/10.2217/pme-2018-0074
10. Birdwell, K. A., Decker, B., Barbarino, J. M., Peterson, J. F., Stein, C. M., Sadee, W., Wang, D., Vinks, A. A., He, Y., Swen, J. J., Leeder, J. S., van Schaik, R., Thummel, K. E., Klein, T. E., Caudle, K. E., & MacPhee, I. A. (2015). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP3A5 Genotype and Tacrolimus Dosing. Clin Pharmacol Ther, 98(1), 19-24. https://doi.org/10.1002/cpt.113
11. Braten, L. S., Haslemo, T., Jukic, M. M., Ingelman-Sundberg, M., Molden, E., & Kringen, M. K. (2020). Impact of CYP2C19 genotype on sertraline exposure in 1200 Scandinavian patients. Neuropsychopharmacology, 45(3), 570-576. https://doi.org/10.1038/s41386-019-0554-x
12. Brown, J. T., Bishop, J. R., Sangkuhl, K., Nurmi, E. L., Mueller, D. J., Dinh, J. C., Gaedigk, A., Klein, T. E., Caudle, K. E., McCracken, J. T., de Leon, J., & Leeder, J. S. (2019). Clinical Pharmacogenetics Implementation Consortium Guideline for Cytochrome P450 (CYP)2D6 Genotype and Atomoxetine Therapy. Clin Pharmacol Ther, 106(1), 94-102. https://doi.org/10.1002/cpt.1409
13. Castro-Rojas, C. A., Esparza-Mota, A. R., Hernandez-Cabrera, F., Romero-Diaz, V. J., Gonzalez-Guerrero, J. F., Maldonado-Garza, H., Garcia-Gonzalez, I. S., Buenaventura-Cisneros, S., Sanchez-Lopez, J. Y., Ortiz-Lopez, R., Camacho-Morales, A., Barboza-Quintana, O., & Rojas-Martinez, A. (2017). Thymidylate synthase gene variants as predictors of clinical response and toxicity to fluoropyrimidine-based chemotherapy for colorectal cancer. Drug Metab Pers Ther, 32(4), 209-218. https://doi.org/10.1515/dmpt-2017-0028
14. Caudle, K. E., Rettie, A. E., Whirl-Carrillo, M., Smith, L. H., Mintzer, S., Lee, M. T., Klein, T. E., & Callaghan, J. T. (2014). Clinical pharmacogenetics implementation consortium guidelines for CYP2C9 and HLA-B genotypes and phenytoin dosing. Clin Pharmacol Ther, 96(5), 542-548. https://doi.org/10.1038/clpt.2014.159
15. Caudle, K. E., Sangkuhl, K., Whirl-Carrillo, M., Swen, J. J., Haidar, C. E., Klein, T. E., Gammal, R. S., Relling, M. V., Scott, S. A., Hertz, D. L., Guchelaar, H. J., & Gaedigk, A. (2020). Standardizing CYP2D6 Genotype to Phenotype Translation: Consensus Recommendations from the Clinical Pharmacogenetics Implementation Consortium and Dutch Pharmacogenetics Working Group. Clin Transl Sci, 13(1), 116-124. https://doi.org/10.1111/cts.12692
16. Chang, K. L., Weitzel, K., & Schmidt, S. (2015). Pharmacogenetics: Using Genetic Information to Guide Drug Therapy. Am Fam Physician, 92(7), 588-594. https://www.aafp.org/afp/2015/1001/p588.html
17. Clancy, J. P., Johnson, S. G., Yee, S. W., McDonagh, E. M., Caudle, K. E., Klein, T. E., Cannavo, M., & Giacomini, K. M. (2014). Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for ivacaftor therapy in the context of CFTR genotype. Clin Pharmacol Ther, 95(6), 592-597. https://doi.org/10.1038/clpt.2014.54
18. CPIC. (2019). What is CPIC?https://cpicpgx.org/
19. CPIC. (2021, 06/15/2021). Genes-Drugs. Retrieved 1/20/2021 from https://cpicpgx.org/genes-drugs/
20. Crews, K. R., Monte, A. A., Huddart, R., Caudle, K. E., Kharasch, E. D., Gaedigk, A., Dunnenberger, H. M., Leeder, J. S., Callaghan, J. T., Samer, C. F., Klein, T. E., Haidar, C. E., Van Driest, S. L., Ruano, G., Sangkuhl, K., Cavallari, L. H., Müller, D. J., Prows, C. A., Nagy, M., Somogyi, A. A., & Skaar, T. C. (2021). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for CYP2D6, OPRM1, and COMT genotype and select opioid therapy. Clinical Pharmacology & Therapeutics, n/a(n/a). https://doi.org/https://doi.org/10.1002/cpt.2149
21. Desta, Z., Gammal, R. S., Gong, L., Whirl-Carrillo, M., Gaur, A. H., Sukasem, C., Hockings, J., Myers, A., Swart, M., Tyndale, R. F., Masimirembwa, C., Iwuchukwu, O. F., Chirwa, S., Lennox, J., Gaedigk, A., Klein, T. E., & Haas, D. W. (2019). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2B6 and Efavirenz-Containing Antiretroviral Therapy. Clin Pharmacol Ther, 106(4), 726-733. https://doi.org/10.1002/cpt.1477
22. EMA. (2020). Test before fluorouracil, capecitabine, tegafur or flucytosine therapy. Reactions Weekly, 1804(1), 6-6. https://doi.org/10.1007/s40278-020-78435-3
23. FDA. HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2011/009218s107lbl.pdf
24. FDA. (2005). 510(k) SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY ASSAY ONLY TEMPLATE. https://www.accessdata.fda.gov/cdrh_docs/reviews/K043576.pdf
25. FDA. (2008). HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.lundbeck.com/upload/us/files/pdf/Products/Xenazine_PI_US_EN.pdf
26. FDA. (2014). HIGHLIGHTS OF PRESCRIBING INFORMATION. https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/205494s003lbl.pdf
27. FDA. (2016). SUPPLEMENT APPROVAL. https://www.accessdata.fda.gov/drugsatfda_docs/appletter/2016/020839Orig1s062,s064ltr.pdf
28. FDA. (2018). Pharmacogenomics: Overview of the Genomics and Targeted Therapy Group. https://www.fda.gov/Drugs/ScienceResearch/ucm572617.htm
29. FDA. (2021a). Nucleic Acid Based Tests. Retrieved 1/20/2021 from https://www.fda.gov/MedicalDevices/ProductsandMedicalProcedures/InVitroDiagnostics/ucm330711.htm
30. FDA. (2021b, 11/08/2021). Table of Pharmacogenetic Associations. https://www.fda.gov/medical-devices/precision-medicine/table-pharmacogenetic-associations
31. FDA. (2021c). Table of Pharmacogenomic Biomarkers in Drug Labeling. https://www.fda.gov/drugs/science-and-research-drugs/table-pharmacogenomic-biomarkers-drug-labeling
32. Franklin, G. M. (2014). Opioids for chronic noncancer pain: a position paper of the American Academy of Neurology. Neurology, 83(14), 1277-1284. https://doi.org/10.1212/wnl.0000000000000839
33. Gammal, R. S., Court, M. H., Haidar, C. E., Iwuchukwu, O. F., Gaur, A. H., Alvarellos, M., Guillemette, C., Lennox, J. L., Whirl-Carrillo, M., Brummel, S. S., Ratain, M. J., Klein, T. E., Schackman, B. R., Caudle, K. E., & Haas, D. W. (2016). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther, 99(4), 363-369. https://doi.org/10.1002/cpt.269
34. Goetz, M. P., Sangkuhl, K., Guchelaar, H. J., Schwab, M., Province, M., Whirl-Carrillo, M., Symmans, W. F., McLeod, H. L., Ratain, M. J., Zembutsu, H., Gaedigk, A., van Schaik, R. H., Ingle, J. N., Caudle, K. E., & Klein, T. E. (2018). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther, 103(5), 770-777. https://doi.org/10.1002/cpt.1007
35. Gonsalves, S. G., Dirksen, R. T., Sangkuhl, K., Pulk, R., Alvarellos, M., Vo, T., Hikino, K., Roden, D., Klein, T. E., Poler, S. M., Patel, S., Caudle, K. E., Gordon, R., Brandom, B., & Biesecker, L. G. (2019). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for the Use of Potent Volatile Anesthetic Agents and Succinylcholine in the Context of RYR1 or CACNA1S Genotypes. Clin Pharmacol Ther, 105(6), 1338-1344. https://doi.org/10.1002/cpt.1319
36. Greden, J. F., Parikh, S. V., Rothschild, A. J., Thase, M. E., Dunlop, B. W., DeBattista, C., Conway, C. R., Forester, B. P., Mondimore, F. M., Shelton, R. C., Macaluso, M., Li, J., Brown, K., Gilbert, A., Burns, L., Jablonski, M. R., & Dechairo, B. (2019). Impact of pharmacogenomics on clinical outcomes in major depressive disorder in the GUIDED trial: A large, patient- and rater-blinded, randomized, controlled study. Journal of Psychiatric Research. https://doi.org/https://doi.org/10.1016/j.jpsychires.2019.01.003
37. GTR. (2017). OneOme RightMed pharmacogenomic test. https://www.ncbi.nlm.nih.gov/gtr/tests/552110.3/performance-characteristics/
38. Hershfield, M. S., Callaghan, J. T., Tassaneeyakul, W., Mushiroda, T., Thorn, C. F., Klein, T. E., & Lee, M. T. (2013). Clinical Pharmacogenetics Implementation Consortium guidelines for human leukocyte antigen-B genotype and allopurinol dosing. Clin Pharmacol Ther, 93(2), 153-158. https://doi.org/10.1038/clpt.2012.209
39. Hicks, J. K., Bishop, J. R., Sangkuhl, K., Muller, D. J., Ji, Y., Leckband, S. G., Leeder, J. S., Graham, R. L., Chiulli, D. L., A, L. L., Skaar, T. C., Scott, S. A., Stingl, J. C., Klein, T. E., Caudle, K. E., & Gaedigk, A. (2015). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther, 98(2), 127-134. https://doi.org/10.1002/cpt.147
40. Hicks, J. K., Sangkuhl, K., Swen, J. J., Ellingrod, V. L., Muller, D. J., Shimoda, K., Bishop, J. R., Kharasch, E. D., Skaar, T. C., Gaedigk, A., Dunnenberger, H. M., Klein, T. E., Caudle, K. E., & Stingl, J. C. (2017). Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther, 102(1), 37-44. https://doi.org/10.1002/cpt.597
41. Holmes, D. R., Jr., Dehmer, G. J., Kaul, S., Leifer, D., O'Gara, P. T., & Stein, C. M. (2010). ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol, 56(4), 321-341. https://doi.org/10.1016/j.jacc.2010.05.013
42. ISPG. (2019). A Statement from the International Society of Psychiatric Genetics. https://ispg.net/genetic-testing-statement/
43. Johnson, J. A., Caudle, K. E., Gong, L., Whirl-Carrillo, M., Stein, C. M., Scott, S. A., Lee, M. T., Gage, B. F., Kimmel, S. E., Perera, M. A., Anderson, J. L., Pirmohamed, M., Klein, T. E., Limdi, N. A., Cavallari, L. H., & Wadelius, M. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther, 102(3), 397-404. https://doi.org/10.1002/cpt.668
44. Kapur, B. M., Lala, P. K., & Shaw, J. L. (2014). Pharmacogenetics of chronic pain management. Clin Biochem, 47(13-14), 1169-1187. https://doi.org/10.1016/j.clinbiochem.2014.05.065
45. Karnes, J. H., Rettie, A. E., Somogyi, A. A., Huddart, R., Fohner, A. E., Formea, C. M., Ta Michael Lee, M., Llerena, A., Whirl-Carrillo, M., Klein, T. E., Phillips, E. J., Mintzer, S., Gaedigk, A., Caudle, K. E., & Callaghan, J. T. (2021). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clinical Pharmacology & Therapeutics, 109(2), 302-309. https://doi.org/https://doi.org/10.1002/cpt.2008
46. Kekic, A., Seetharam, M., Singh, P., Kunze, K., Golafshar, M. A., Azevedo, C., Welp, S., Bofferding, A., Koep, T., Ross, J., Nelson, E., Grilli, C., & Samadder, J. (2020). Integrating pharmacogenomics panel testing for supportive care medications in patients with solid tumors. Journal of Clinical Oncology, 38(15_suppl), e24114-e24114. https://doi.org/10.1200/JCO.2020.38.15_suppl.e24114
47. Kelly, L. E., Rieder, M., van den Anker, J., Malkin, B., Ross, C., Neely, M. N., Carleton, B., Hayden, M. R., Madadi, P., & Koren, G. (2012). More codeine fatalities after tonsillectomy in North American children. Pediatrics, 129(5), e1343-1347. https://doi.org/10.1542/peds.2011-2538
48. Krishnamurthi, S., & Kamath, S. (2022, 01/24/2022). Chemotherapy-associated diarrhea, constipation, and intestinal perforation: pathogenesis, risk factors, and clinical presentation. https://www.uptodate.com/contents/chemotherapy-associated-diarrhea-constipation-and-intestinal-perforation-pathogenesis-risk-factors-and-clinical-presentation
49. Lee, C. R., Luzum, J. A., Sangkuhl, K., Gammal, R. S., Sabatine, M. S., Stein, C. M., Kisor, D. F., Limdi, N. A., Lee, Y. M., Scott, S. A., Hulot, J. S., Roden, D. M., Gaedigk, A., Caudle, K. E., Klein, T. E., Johnson, J. A., & Shuldiner, A. R. (2022). Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2526
50. Lima, J. J., Thomas, C. D., Barbarino, J., Desta, Z., Van Driest, S. L., El Rouby, N., Johnson, J. A., Cavallari, L. H., Shakhnovich, V., Thacker, D. L., Scott, S. A., Schwab, M., Uppugunduri, C. R. S., Formea, C. M., Franciosi, J. P., Sangkuhl, K., Gaedigk, A., Klein, T. E., Gammal, R. S., & Furuta, T. (2020). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C19 and Proton Pump Inhibitor Dosing. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.2015
51. Lunenburg, C., van der Wouden, C. H., Nijenhuis, M., Crommentuijn-van Rhenen, M. H., de Boer-Veger, N. J., Buunk, A. M., Houwink, E. J. F., Mulder, H., Rongen, G. A., van Schaik, R. H. N., van der Weide, J., Wilffert, B., Deneer, V. H. M., Swen, J. J., & Guchelaar, H. J. (2019). Dutch Pharmacogenetics Working Group (DPWG) guideline for the gene-drug interaction of DPYD and fluoropyrimidines. Eur J Hum Genet. https://doi.org/10.1038/s41431-019-0540-0
52. Martin, M. A., Hoffman, J. M., Freimuth, R. R., Klein, T. E., Dong, B. J., Pirmohamed, M., Hicks, J. K., Wilkinson, M. R., Haas, D. W., & Kroetz, D. L. (2014). Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Clin Pharmacol Ther, 95(5), 499-500. https://doi.org/10.1038/clpt.2014.38
53. Mayo. (2019). Focused Pharmacogenomics Panel, Varies. https://www.mayocliniclabs.com/test-catalog/Clinical+and+Interpretive/65566
54. Moriyama, B., Obeng, A. O., Barbarino, J., Penzak, S. R., Henning, S. A., Scott, S. A., Agundez, J., Wingard, J. R., McLeod, H. L., Klein, T. E., Cross, S. J., Caudle, K. E., & Walsh, T. J. (2017). Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy. Clin Pharmacol Ther, 102(1), 45-51. https://doi.org/10.1002/cpt.583
55. Muir, A. J., Gong, L., Johnson, S. G., Lee, M. T., Williams, M. S., Klein, T. E., Caudle, K. E., & Nelson, D. R. (2014). Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for IFNL3 (IL28B) genotype and PEG interferon-alpha-based regimens. Clin Pharmacol Ther, 95(2), 141-146. https://doi.org/10.1038/clpt.2013.203
56. Myriad. (2016). What is the difference between traditional “single-gene” testing and the GeneSight® test’s proprietary CPGx® approach?https://s3.amazonaws.com/myriad-web/Managed+Care/CPGx-approach.pdf
57. Myriad. (2019). GeneSight. https://s3.amazonaws.com/myriad-web/Managed+Care/GeneSight-ExecutiveSummary.pdf
58. OneOme. (2021). The RightMed® Test. https://oneome.com/rightmed-test/#genes-covered
59. Phillips, E. J., Sukasem, C., Whirl-Carrillo, M., Muller, D. J., Dunnenberger, H. M., Chantratita, W., Goldspiel, B., Chen, Y. T., Carleton, B. C., George, A. L., Jr., Mushiroda, T., Klein, T., Gammal, R. S., & Pirmohamed, M. (2018). Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther, 103(4), 574-581. https://doi.org/10.1002/cpt.1004
60. Plumpton, C. O., Pirmohamed, M., & Hughes, D. A. (2019). Cost-Effectiveness of Panel Tests for Multiple Pharmacogenes Associated With Adverse Drug Reactions: An Evaluation Framework. Clin Pharmacol Ther, 105(6), 1429-1438. https://doi.org/10.1002/cpt.1312
61. Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Gaedigk, A., Hachad, H., Ji, Y., Kalman, L. V., Ly, R. C., Moyer, A. M., Scott, S. A., van Schaik, R. H. N., Whirl-Carrillo, M., & Weck, K. E. (2021). Recommendations for Clinical CYP2D6 Genotyping Allele Selection: A Joint Consensus Recommendation of the Association for Molecular Pathology, College of American Pathologists, Dutch Pharmacogenetics Working Group of the Royal Dutch Pharmacists Association, and the European Society for Pharmacogenomics and Personalized Therapy. J Mol Diagn, 23(9), 1047-1064. https://doi.org/10.1016/j.jmoldx.2021.05.013
62. Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Hachad, H., Ji, Y., Kalman, L. V., Ly, R. C., Moyer, A. M., Scott, S. A., Whirl-Carrillo, M., & Weck, K. E. (2020). Recommendations for Clinical Warfarin Genotyping Allele Selection: A Report of the Association for Molecular Pathology and the College of American Pathologists. J Mol Diagn, 22(7), 847-859. https://doi.org/10.1016/j.jmoldx.2020.04.204
63. Pratt, V. M., Cavallari, L. H., Del Tredici, A. L., Hachad, H., Ji, Y., Moyer, A. M., Scott, S. A., Whirl-Carrillo, M., & Weck, K. E. (2019). Recommendations for Clinical <em>CYP2C9</em> Genotyping Allele Selection: A Joint Recommendation of the Association for Molecular Pathology and College of American Pathologists. The Journal of Molecular Diagnostics, 21(5), 746-755. https://doi.org/10.1016/j.jmoldx.2019.04.003
64. Pratt, V. M., Del Tredici, A. L., Hachad, H., Ji, Y., Kalman, L. V., Scott, S. A., & Weck, K. E. (2018). Recommendations for Clinical CYP2C19 Genotyping Allele Selection: A Report of the Association for Molecular Pathology. The Journal of Molecular Diagnostics, 20(3), 269-276. https://doi.org/https://doi.org/10.1016/j.jmoldx.2018.01.011
65. Ramsey, L. B., Johnson, S. G., Caudle, K. E., Haidar, C. E., Voora, D., Wilke, R. A., Maxwell, W. D., McLeod, H. L., Krauss, R. M., Roden, D. M., Feng, Q., Cooper-DeHoff, R. M., Gong, L., Klein, T. E., Wadelius, M., & Niemi, M. (2014). The clinical pharmacogenetics implementation consortium guideline for SLCO1B1 and simvastatin-induced myopathy: 2014 update. Clin Pharmacol Ther, 96(4), 423-428. https://doi.org/10.1038/clpt.2014.125
66. Relling, M. V., Gardner, E. E., Sandborn, W. J., Schmiegelow, K., Pui, C. H., Yee, S. W., Stein, C. M., Carrillo, M., Evans, W. E., & Klein, T. E. (2011). Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther, 89(3), 387-391. https://doi.org/10.1038/clpt.2010.320
67. Relling, M. V., McDonagh, E. M., Chang, T., Caudle, K. E., McLeod, H. L., Haidar, C. E., Klein, T., & Luzzatto, L. (2014). Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for rasburicase therapy in the context of G6PD deficiency genotype. Clin Pharmacol Ther, 96(2), 169-174. https://doi.org/10.1038/clpt.2014.97
68. Relling, M. V., Schwab, M., Whirl-Carrillo, M., Suarez-Kurtz, G., Pui, C. H., Stein, C. M., Moyer, A. M., Evans, W. E., Klein, T. E., Antillon-Klussmann, F. G., Caudle, K. E., Kato, M., Yeoh, A. E. J., Schmiegelow, K., & Yang, J. J. (2018). Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline for thiopurine dosing based on TPMT and NUDT15 genotypes: 2018 update. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.1304
69. Roscizewski, L., Henneman, A., & Snyder, T. (2021). Effect of pharmacogenomic testing on pharmacotherapy decision making in patients with symptoms of depression in an interprofessional primary care clinic. J Am Pharm Assoc (2003). https://doi.org/10.1016/j.japh.2021.10.033
70. Saito, Y., Stamp, L. K., Caudle, K. E., Hershfield, M. S., McDonagh, E. M., Callaghan, J. T., Tassaneeyakul, W., Mushiroda, T., Kamatani, N., Goldspiel, B. R., Phillips, E. J., Klein, T. E., & Lee, M. T. (2016). Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther, 99(1), 36-37. https://doi.org/10.1002/cpt.161
71. Sema4. (2019). Comprehensive Pharmacogenetic Genotyping Panel. https://sema4.com/products/test-catalog/comprehensive-pharmacogenetic-genotyping-panel/#
72. Stevenson, J. M., Alexander, G. C., Palamuttam, N., & Mehta, H. B. (2021). Projected Utility of Pharmacogenomic Testing Among Individuals Hospitalized With COVID-19: A Retrospective Multicenter Study in the United States. Clin Transl Sci, 14(1), 153-162. https://doi.org/10.1111/cts.12919
73. Suchowersky, O. (2021, 12/02/2021). Huntington disease: Management. https://www.uptodate.com/contents/huntington-disease-management
74. Tantisira, K., & Weiss, S. (2020, 01/09/2019). Overview of pharmacogenomics. https://www.uptodate.com/contents/overview-of-pharmacogenomics?search=Cytochrome%20P450&source=search_result&selectedTitle=1~150&usage_type=default&display_rank=1
75. Tantry, U., Hennekens, C., Zehnder, J., & Gurbel, P. (2021, 11/09/2021). Clopidogrel resistance and clopidogrel treatment failure. Wolters Kluwer. https://www.uptodate.com/contents/clopidogrel-resistance-and-clopidogrel-treatment-failure
76. Theken, K. N., Lee, C. R., Gong, L., Caudle, K. E., Formea, C. M., Gaedigk, A., Klein, T. E., Agúndez, J. A. G., & Grosser, T. (2020). Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin Pharmacol Ther, 108(2), 191-200. https://doi.org/10.1002/cpt.1830
77. Ting, S., & Schug, S. (2016). The pharmacogenomics of pain management: prospects for personalized medicine. J Pain Res, 9, 49-56. https://doi.org/10.2147/jpr.s55595
78. Tuteja, S., Glick, H., Matthai, W., Nachamkin, I., Nathan, A., Monono, K., Carcuffe, C., Maslowski, K., Chang, G., Kobayashi, T., Anwaruddin, S., Hirshfeld, J., Jr., Wilensky, R. L., Herrmann, H. C., Kolansky, D. M., Rader, D. J., & Giri, J. (2020). Prospective CYP2C19 Genotyping to Guide Antiplatelet Therapy Following Percutaneous Coronary Intervention: A Pragmatic Randomized Clinical Trial. Circ Genom Precis Med. https://doi.org/10.1161/circgen.119.002640
79. van der Wouden, C. H., van Rhenen, M. H., Jama, W. O. M., Ingelman-Sundberg, M., Lauschke, V. M., Konta, L., Schwab, M., Swen, J. J., & Guchelaar, H. J. (2019). Development of the PGx-Passport: A Panel of Actionable Germline Genetic Variants for Pre-Emptive Pharmacogenetic Testing. Clin Pharmacol Ther, 106(4), 866-873. https://doi.org/10.1002/cpt.1489
80. Viatte, S. (2021, 07/30/2021). Human leukocyte antigens (HLA): A roadmap. https://www.uptodate.com/contents/human-leukocyte-antigens-hla-a-roadmap

Coding Section 

Code	Number	Description
CPT	81220	CFTR (cystic fibrosis transmembrane conductance regulator) (e.g., cystic fibrosis) gene analysis; common variants
	81225	CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *8, *17)
	81226	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)
	81227	CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3, *5, *6)
	81230	CYP3A4 (cytochrome P450 family 3 subfamily A member 4) (e.g., drug metabolism) gene analysis, common variant(s) (e.g., *2, *22)
	81231	CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (e.g., drug metabolism) gene analysis, common variants (e.g., *2, *3, *4, *5 *6, *7)
	81232	DPYD (dihydropyrimidine dehydrogenase) (e.g., 5-fluorouracil/5-FU and capecitabine drug metabolism), gene analysis, common variant(s) (e.g., *2A, *4, *5, *6)
	81247	G6PD (glucose-6-phosphate dehydrogenase) (e.g., hemolytic anemia, jaundice), gene analysis; common variant(s) (e.g., A, A-)
	81283	IFNL3 (interferon, lambda 3) (e.g., drug response), gene analysis, rs12979860 variant
	81291	MTHFR (5,10-methylenetetrahydrofolate reductase) (e.g., hereditary hypercoagulability) gene analysis, common variants (e.g., 677T, 1298C)
	81306	NUDT15 (nudix hydrolase 15) (e.g., drug metabolism) gene analysis, common variant(s) (e.g., *2, *3, *4, *5, *6)
	81328	SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (e.g., adverse drug reaction), gene analysis, common variant(s) (e.g., *5)
	81335	TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism), gene analysis, common variants (e.g., *2, *3)
	81346	TYMS (thymidylate synthetase) (e.g., 5-fluorouracil/5-FU drug metabolism), gene analysis, common variant(s) (e.g., tandem repeat variant)
	81350	UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (e.g., irinotecan metabolism), gene analysis, common variants (e.g., *28, *36, *37)
	81355	VKORC1 (vitamin K epoxide reductase complex, subunit 1) (e.g., warfarin metabolism), gene analysis, common variant(s) (e.g., -1639G>A, c.173+1000C>T)
	81381	HLA Class I typing, high resolution (i.e., alleles or allele groups); one allele or allele group (e.g., B*57:01P), each
	81405	Molecular pathology procedure, Level 6 (e.g., analysis of 6 – 10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11 – 25 exons, regionally targeted cytogenomic array analysis)  Gene: GABRG2 (gamma-aminobutyric acid [GABA] A receptor, gamma 2) (e.g., generalized epilepsy with febrile seizures), full gene sequence
	81418	Drug metabolism (e.g., pharmacogenomics) genomic sequence analysis panel, must include testing of at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplication/deletion analysis
	81479	Unlisted molecular pathology procedure  Genes: 5HT2C 5HT2A COMT CYP1A2 CYP2B6 CYP4F2 DAT1  DBH  DRD1  DRD2  DRD4  OPRM1 OPRK1 SLC6A3 SLC6A4  UGT2B15 Rs12777823 RYR1 CACNA1S BCHE NAT2
	0029U	Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (i.e., CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823)
	0030U	Drug metabolism (warfarin drug response), targeted sequence analysis (i.e., CYP2C9, CYP4F2, VKORC1, rs12777823)
	0031U	CYP1A2 (cytochrome P450 family 1, subfamily A, member 2) (e.g., drug metabolism) gene analysis, common variants (i.e., *1F, *1K, *6, *7)
	0032U	COMT (catechol-O-methyltransferase) (e.g., drug metabolism) gene analysis, c.472G>A (rs4680) variant
	0033U	HTR2A (5-hydroxytryptamine receptor 2A), HTR2C (5-hydroxytryptamine receptor 2C) (e.g., citalopam metabolism) gene analysis, common variants (i.e., HTR2A rs7997012 [c.614-2211T>C], HTR2C rs3813929 [c.759C>T] and rs1414334 [c.551-3008C>G])
	0034U	TPMT (thiopurine S-methyltransferase), NUDT15 (nudix hydroxylase 15)(e.g., thiopurine metabolism) gene analysis, common variants (i.e., TPMT *2, *3A, *3B, *3C, *4, *5, *6, *8, *12; NUDT15 *3, *4, *5)
	0070U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, common and select rare variants (i.e., *2, *3, *4, *4N, *5, *6, *7, *8, *9, *10, *11, *12, *13, *14A, *14B, *15, *17, *29, *35, *36, *41, *57, *61, *63, *68, *83, *xN)
	0071U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, full gene sequence (List separately in addition to code for primary procedure)
	0072U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., CYP2D6-2D7 hybrid gene) (List separately in addition to code for primary procedure)
	0073U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., CYP2D7-2D6 hybrid gene) (List separately in addition to code for primary procedure)
	0074U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., non-duplicated gene when duplication/multiplication is trans) (List separately in addition to code for primary procedure)
	0075U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., 5’ gene duplication/multiplication) (List separately in addition to code for primary procedure)
	0076U	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (e.g., drug metabolism) gene analysis, targeted sequence analysis (i.e., 3’ gene duplication/ multiplication) (List separately in addition to code for primary procedure)
	0169U	NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism) gene analysis, common variants Proprietary test: NT (NUDT15 and TPMT) genotyping panel Lab/Manufacturer: RPRD Diagnostics
	0286U	CEP72 (centrosomal protein, 72-KDa), NUDT15 (nudix hydrolase 15) and TPMT (thiopurine S-methyltransferase) (e.g., drug metabolism) gene analysis, common variants Proprietary test: CNT (CEP72, TPMT and NUDT15) genotyping panel Lab/Manufacturer: RPRD Diagnostics
	0345U	Psychiatry (e.g., depression, anxiety, attention deficit hyperactivity disorder [ADHD]), genomic analysis panel, variant analysis of 15 genes, including deletion/duplication analysis of CYP2D6 Protietary test: GeneSight® Psychotropic Lab/Manufacturer: Assurex Health, Inc
	0347U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 16 gene report, with variant analysis and reported phenotypes Protietary test: RightMed® PGx16 Test Lab/Manufacturer: OneOme®
	0348U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 25 gene report, with variant analysis and reported phenotypes Protietary test: RightMed® Comprehensive Test Exclude F2 and F5 Lab/Manufacturer: OneOme®
	0349U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis, including reported phenotypes and impacted gene-drug interactions Protietary test: RightMed® Comprehensive Test Lab/Manufacturer: OneOme®
	0350U	Drug metabolism or processing (multiple conditions), whole blood or buccal specimen, DNA analysis, 27 gene report, with variant analysis and reported phenotypes Protietary test: RightMed® Gene Report Lab/Manufacturer: OneOme®
	0380U (effective 04/01/2023)	Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis, 20 gene variants and CYP2D6 deletion or duplication analysis with reported genotype and phenotype
	0392U (effective 07/01/2023)	Drug metabolism (depression, anxiety, attention deficit hyperactivity disorder [ADHD]), gene-drug interactions, variant analysis of 16 genes, including deletion/duplication analysis of CYP2D6, reported as impact of gene-drug interaction for each drug
	G9143	Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)
ICD-10 CM Codes	B50.0	Plasmodium falciparum malaria with cerebral complications
	B50.8	Other severe and complicated Plasmodium falciparum malaria
	B50.9	Plasmodium falciparum malaria, unspecified
	B51.0	Plasmodium vivax malaria with rupture of spleen
	B51.8	Plasmodium vivax malaria with other complications
	B51.9	Plasmodium vivax malaria without complication
	D75.A (EFFECTIVE 10/01/2019)	Glucose-6-phosphate dehydrogenase (G6PD) deficiency without anemia
	F30.10	Manic episode
	F31.0	Bipolar disorder
	F32.0	Major depressive disorder
	F33.0	Major depressive disorder, recurrent
	F34.0	Cyclothymic, Dysthymic, and Other specified persistent mood disorders
	F39	Unspecified mood [affective] disorder
	F90.0 – F90.9	Attention-deficit hyperactivity disorder
	G35	Multiple sclerosis
	I23.6	Thrombosis of atrium, auricular appendage, and ventricle as current complications following acute myocardial infarction
	I26 Codes	Pulmonary embolism
	I26.93 (EFFECTIVE 10/01/2019)	Single subsegmental pulmonary embolism without acute cor pulmonale
	I26.94 (EFFECTIVE 10/01/2019)	Multiple subsegmental pulmonary emboli without acute cor pulmonale
	I27.82	Chronic pulmonary embolism
	I48 Codes	Atrial fibrillation and flutter
	I48.11 (EFFECTIVE 10/01/2019)	Longstanding persistent atrial fibrillation
	I48.19 (EFFECTIVE 10/01/2019)	Other persistent atrial fibrillation
	I48.20 (EFFECTIVE 10/01/2019)	Chronic atrial fibrillation, unspecified
	I48.21 (EFFECTIVE 10/01/2019)	Permanent atrial fibrillation
	I49 Codes	Other cardiac arrhythmias
	I51.3	Intracardiac thrombosis, not elsewhere classified
	I63.30 – I63.49	Cerebral infarction due to thrombosis of cerebral arteries
	163.6	Cerebral infarction due to cerebral venous thrombosis, nonpyogenic
	I67.6	Nonpyogenic thrombosis of intracranial venous system
	I74 Codes	Arterial embolism and thrombosis
	I81	Portal vein thrombosis
	I82.451 – I82.469 (EFFECTIVE 10/01/2019)	Acute embolism and thrombosis of peroneal and calf muscular veins
	I82.551 – I82.569 (EFFECTIVE 10/01/2019)	Chronic embolism and thrombosis of peroneal and calf muscular veins
	N48.81	Thrombosis of superficial vein of penis
	T45.515A	Adverse effect of anticoagulants
	T45.516A	Underdosing of anticoagulants
	T82.867A	Thrombosis due to cardiac prosthetic devices, implants and grafts
	Z13.79	Encounter for other screening for genetic and chromosomal anomalies
	Z51.81	Encounter for therapeutic drug level monitoring
	Z95.2	Presence of prosthetic heart valve
	M1A.00X0 – M1A9XX1	Idiopathic chronic gout, Chronic gout
	M05 Codes	Rheumatoid arthritis with rheumatoid factor
	M06 Codes	Other rheumatoid arthritis
	Z94.4	Liver transplant status

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive. 

This medical policy was developed through consideration of peer-reviewed medical literature generally recognized by the relevant medical community, U.S. FDA approval status, nationally accepted standards of medical practice and accepted standards of medical practice in this community, Blue Cross Blue Shield Association technology assessment program (TEC) and other nonaffiliated technology evaluation centers, reference to federal regulations, other plan medical policies, and accredited national guidelines.

"Current Procedural Terminology © American Medical Association. All Rights Reserved" 

History From 2018 Forward     

06/14/2023	Added code 0392U effective 07/01/2023
05/31/2023	Moving review date to July. No other changes.
03/08/2023	Adding code ‘0380U’, effective date 04/01/2023
01/24/2023	Interim review, no change to policy intent. Adding CPT 81418, 0346U, 0347U, 0348U, 0349U and 0350U.
04/26/2022	Annual review, updating policy to include Oliceridine, Pitolisant and Sacituzumab. Also updating rationale, references and coding. Adding table of terminology.
04/20/2021	Annual review, adding additional medications with testing criteria, also updating description, rationale and references.
04/20/2020	Annual review, expanding list of medications allowed for testing.
01/02/2020	Interim review updating policy with additional medical necessity criteria for testing. Also updating coding.
09/24/2019	Updated coding. No other changes made.
04/04/2019	New Policy