CAM 218

Pharmacogenetic Testing

Category:Laboratory   Last Reviewed:January 2020
Department(s):Medical Affairs   Next Review:April 2020
Original Date:April 2019    

Description
Pharmacogenetics is defined as the study of variability in drug response due to heredity (Nebert, 1999). 

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 are essential to produce 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.  Approximately 58 CYP genes are in humans (Bains, 2013; Tantisira & Weiss, 2019). 

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 (Relling et al., 2011). 

Dihydropyrimidine dehydrogenase (DPYD) gene encodes for dihydropyrimidine dehydrogenase (DPD), 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 (Amstutz et al., 2018).

Human Leukocyte antigens (HLAs) are genes that encode a variety of cell surface proteins, such as antigen-presenting molecules and other proteins. HLAs are also known as major histocompatibility complex (MHC) (Viatte, 2017).

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 and Medicaid (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.
    • Atomoxetine
    • Codeine
    • Desipramine
    • Fluvoxamine
    • Nortriptyline
    • Ondansetron
    • Paroxetine
    • Tamoxifen
    • Tramadol
    • Tropisetron 
  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.
    • Amitriptyline
    • Clomipramine
    • Doxepin
    • Imipramine
    • 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.
    • Citalopram         
    • Escitalopram
    • Clopidogrel
    • Sertraline        
    • Voriconazole
  4. Testing for the CYP2C9, CYP4F2, VKORC1, and rs12777823 genotype once per lifetime is considered MEDICALLY NECESSARY for individuals being considered for Warfarin therapy. 
  5. 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.
    • Azathioprine
    • Mercaptopurine
    • Thioguanine 
  6. Testing for the DPYD genotype once per lifetime (please see policy guideline)* is considered MEDICLLY 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.
    • Capecitabine
    • Fluorouracil 
  7. 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:
    • HLA-B*57:01 before treatment with Abacavir
    • HLA-B*58:01 before treatment with Allopurinol
    • HLA-B*15:02 for treatment with Oxcarbazepine
    • HLA-B*15:02 and HLA-A*31:01 for treatment with Carbamazepine 
  8. 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.
    • Phenytoin 
  9. Testing for the G6PD genotypic 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.
    • Pegloticase
    • Primaquine
    • Rasburicase
    • Tafenoquine
  10. Testing for the following genotypes once per lifetime (please see policy guidelines)* 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.
    • CFTR for treatment with Ivacaftor
    • CYP2B6 for treatment with Efavirenz
    • CYP2C9 for treatment with Siponimod
    • CYP3A5 for treatment with Tacrolimus
    • IFNL3 treatment with Peginterferon alfa-2a, Peginterferon alfa-2b or Ribavirin 
    • UGT1A1 for treatment with Atazanavir or  Irinotecan
  11. 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.
  12. 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.
  1. The following pharmacogenetic testing is investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY:
    • Genotyping for any medication therapy more than once per lifetime (please see policy guideline).*
    • Testing for the specific genotype for individuals on medications not listed as meeting coverage criteria for testing.
    • Testing for all other genotypes, including, but not limited to, use of other medication therapy not listed as meeting coverage criteria.
    • Genotyping the general population.
    • 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 investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY:
    • 5HT2C (serotonin receptor)
    • 5HT2A (serotonin receptor)
    • SLC6A4 (serotonin transporter)
    • DRD1 (dopamine receptor)
    • DRD2 (dopamine receptor)
    • DRD4 (dopamine receptor) 
    • DAT1 or SLC6A3 (dopamine transporter)
    • DBH (dopamine beta-hydroxylase)
    • COMT (catechol-O-methyl-transferase)
    • MTHFR (methylenetetrahydrofolate reductase)
    • γ-Aminobutyric acid (GABA) A receptor
    • OPRM1 (µ-opioid receptor)
    • OPRK1 (κ-opioid receptor)
    • TYMS
    • UGT2B15 (uridine diphosphate glycosyltransferase 2 family, member 15)
    • Cytochrome P450 genes:  CYP3A4, CYP1A2

Policy Guideline
Genotyping once per lifetime

Any gene should be tested once per lifetime regardless the indication (except 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 investigational and/or unproven and is therefore considered NOT MEDICALLY NECESSARY

Rationale 
Genetic variations play a role in an individual’s response to medications. Drug metabolism and responses are affected by many factors including age, sex, interactions with other drugs, and disease states with genetic variations offering only a partial explanation of an individual's response (Tantisira & Weiss, 2019). However, 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, Lala, & Shaw, 2014; Ting & Schug, 2016). Genetic variation can influence pharmacodynamics factors through variations affecting drug target receptors and downstream signal transduction, or pharmacokinetic factors, affecting drug metabolism and/or elimination (Tantisira & Weiss, 2019).

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. They may serve to “activate” an inactive form of a drug, and they may serve a role in the inactivation and/or clearance of 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, 2019)..

Due to the variations in enzyme activity conferred by allelic differences, some CYP 450 alleles are associated with 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 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 active drug, potentially causing unwanted side effects.  Due to these differences in enzyme activity, some alleles are associated with higher risk of adverse outcomes depending on the drug prescribed (Tantisira & Weiss, 2019).

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 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, 2019)

CYP2C19
Clopidogrel (brand name, Plavix), which is used to inhibit platelet aggregation, 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, Hennekens, Zehnder, & Gurbel, 2018). 

CYP2D6
Tetrabenazine (brand name Xenazine) is used in the treatment of chorea associated with Huntington’s 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, 2018).

Tamoxifen, a drug commonly used for 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 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, 2019)

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 lower risk of myelosuppression. Therefore, genotyping for TPMT is critical before starting therapy with thiopurine drugs (Relling et al., 2011).

DPYD
Dihydropyrimidine dehydrogenase (DPYD) gene encodes for the rate-limiting enzyme dihydropyrimidine dehydrogenase, which is involved in catabolism of fluoropyrimidines drugs used in 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 in Europeans HapB3 with c.1129–5923C>G DPYD variant 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 c.557A>G (rs115232898, p.Y186C) is relatively common (3–5% carrier frequency). Other DPYD decreased function variants are rare. Therefore, most genetic tests available focus on identification of most common variants with well-established risk: (c.190511G>A, c.1679T>G, c.2846A>T, c.1129– 5923C>G) (Amstutz et al., 2018).

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, 2017).

Due to the increase in pharmacogenetic genotyping, proprietary gene panels are 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, pharmacodynamic activity of the compound and its metabolites, any FDA information on that drug, and other validated research on the relevant alleles and integrates this information 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 for evaluating every metabolic pathway of a drug 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).

A study evaluating GeneSight Psychotropic’s clinical utility was performed by Greden et al. 1167 patients with major depressive disorder and who had previously had inadequate response to an antidepressant were assigned to a traditional treatment arm (TAU) and an arm informed by the pharmacogenetic test results. 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). 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).

Tanner et al evaluated the impact of combinatorial pharmacogenomics on the treatment of major depressive disorder (MDD). 1871 patients with MDD were evaluated and 8 genes (CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A4, HTR2A, and SLC6A4) were genotyped in these patients. These genotyping results were combined with a pharmacological profile of 33 medications in the GeneSight panel, and these 33 medications were divided into 3 categories, green, yellow, and red. Green was “use as directed”, yellow was “‘use with caution”, and red was “use with increased caution and more frequent monitoring”. Medications were considered “congruent” if they were classified as green or yellow and “incongruent” if they were classified as red. Patients were evaluated on symptom improvement (percent decrease in Beck's Depression Inventory [BDI]), response (≥50% decrease in BDI), and remission (BDI≤10) at follow-up according to provider type and whether medications were genetically congruent (little/no gene-drug interactions). Overall, the cohort taking congruent medications saw a 31% relative improvement over those taking incongruent medications (Tanner et al., 2018).

Benitez et al 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 $5505, 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, Cool, & Scotti, 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”. 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). 

Guidelines 
Clinical Pharmacogenetics Implementation Consortium (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, 2018). 

In their 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 noncarrier

 

 

 

Extensive Metabolizer (EM)

Initiate therapy with recommended maintenance dosed

 

Strong 

(Caudle et al., 2014) 

 

Intermediate Metabolizer (IM)

Consider 25% reduction of recommended starting maintenance dose. Subsequent maintenance doses should be adjusted according to therapeutic drug monitoring and response. 

Moderate 

 

 

Poor Metabolizer (PM) 

Consider 50% reduction of recommended starting maintenance dose. Subsequent maintenance doses should be adjusted according to therapeutic drug monitoring and response. 

 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)

Amitriptyline and Nortripyline

Other TCAs:

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

UM

Avoid codeine use due to potential for toxicity.

Strong

(Crews et al., 2014)

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

UM

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% reductiond of recommended starting dose and titrate to response or use an alternative drug not metabolized by CYP2D6.

Optional

Ondansetron and Tropisetron

UM

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

UM

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

CYP2C19 Genotype 

Drug

Phenotype

Summary of CPIC Therapeutic Recommendations

Level of Recommendations

Reference

Amitriptyline and Nortripyline 

Other TCAs:

clomipramine, doxepin, imipramine, and trimipramine

UM

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

UM

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

Sertaline

UM

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

UM, EM

Clopidogrel: label-recommended dosage and administration.

Strong

(Scott et al., 2013)

IM

Alternative antiplatelet therapy (if no contraindication), e.g., prasugrel, ticagrelor.

Moderate

PM

Alternative antiplatelet therapy (if no contraindication), e.g., prasugrel, ticagrelor.

Strong

Voriconazole

UM

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)

Rapid Metabolizer (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

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

Phenotype

CYP2D6

CYP2D6

CYP2D6

CYP2D6

CYP2C19

UM

NM

IM

PM

UM

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

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.

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.

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.

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.

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

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.

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.

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.

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.

Strong

 

Drug

NUDT15 Phenotype

Summary of CPIC Therapeutic Recommendations

Level of Recommendations

Reference

Mercaptopurine

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.

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)

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 naıve, 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-naıve 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-naıve, 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

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 allopurinolc

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 muscle relaxants succinylcholine are relatively contraindicated in persons with MHS. They should not be used, except in extraordinary circumstances where the benefits outweigh the risks. In general, alternative anesthetics are widely available and effective in patients with MHS.

Strong

(Gonsalves et al., 2018)

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

American College of Medical Genetics and Genomics (ACMG, 2007) 
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)/ American Heart Association (AHA) Joint Guidelines (2010) 
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). 

2014 American Academy of Neurology 
The American Academy of Neurology 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). 

2017 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) 

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Coding Section 

Code 

Number

Description

CPT

81220

CFTR (cystic fibrosis transmembrane conductance regulator) (eg, 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) (eg, drug metabolism) gene analysis, common variant(s) (eg, *2, *22)

 

81231

CYP3A5 (cytochrome P450 family 3 subfamily A member 5) (eg, drug metabolism) gene analysis, common variants (eg, *2, *3, *4, *5 *6, *7)

 

81232

DPYD (dihydropyrimidine dehydrogenase) (eg, 5-fluorouracil/5-FU and capecitabine drug metabolism), gene analysis, common variant(s) (eg, *2A, *4, *5, *6)

 

81247

G6PD (glucose-6-phosphate dehydrogenase) (eg, hemolytic anemia, jaundice), gene analysis; common variant(s) (eg, A, A-)

 

81283

IFNL3 (interferon, lambda 3) (eg, drug response), gene analysis, rs12979860 variant

 

81291

MTHFR (5,10-methylenetetrahydrofolate reductase) (eg, hereditary hypercoagulability) gene analysis, common variants (eg, 677T, 1298C)

 

81306

NUDT15 (nudix hydrolase 15) (eg, drug metabolism) gene analysis, common variant(s) (eg, *2, *3, *4, *5, *6)

 

81328

SLCO1B1 (solute carrier organic anion transporter family, member 1B1) (eg, adverse drug reaction), gene analysis, common variant(s) (eg, *5)

 

81335

TPMT (thiopurine S-methyltransferase) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3)

 

81346 

TYMS (thymidylate synthetase) (eg, 5-fluorouracil/5-FU drug metabolism), gene analysis, common variant(s) (eg, tandem repeat variant) 

 

81350

UGT1A1 (UDP glucuronosyltransferase 1 family, polypeptide A1) (eg, irinotecan metabolism), gene analysis, common variants (eg, *28, *36, *37)

 

81355

VKORC1 (vitamin K epoxide reductase complex, subunit 1) (eg, warfarin metabolism), gene analysis, common variant(s) (eg, -1639G>A, c.173+1000C>T)

 

81381

HLA Class I typing, high resolution (ie, alleles or allele groups); one allele or allele group (eg, B*57:01P), each

 

81405

Molecular pathology procedure, Level 6 (eg, 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) (eg, generalized epilepsy with febrile seizures), full gene sequence

 

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

 

0029U

Drug metabolism (adverse drug reactions and drug response), targeted sequence analysis (ie, CYP1A2, CYP2C19, CYP2C9, CYP2D6, CYP3A4, CYP3A5, CYP4F2, SLCO1B1, VKORC1 and rs12777823)

 

0030U

Drug metabolism (warfarin drug response), targeted sequence analysis (ie, CYP2C9, CYP4F2, VKORC1, rs12777823)

 

0031U

CYP1A2 (cytochrome P450 family 1, subfamily A, member 2) (eg, drug metabolism) gene analysis, common variants (ie, *1F, *1K, *6, *7)

 

0032U

COMT (catechol-O-methyltransferase) (eg, drug metabolism) gene analysis, c.472G>A (rs4680) variant

 

0033U

HTR2A (5-hydroxytryptamine receptor 2A), HTR2C (5-hydroxytryptamine receptor 2C) (eg, citalopam metabolism) gene analysis, common variants (ie, 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)(eg, thiopurine metabolism) gene analysis, common variants (ie, TPMT *2, *3A, *3B, *3C, *4, *5, *6, *8, *12; NUDT15 *3, *4, *5)

 

0070U

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, common and select rare variants (ie, *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) (eg, 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) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D6-2D7 hybrid gene) (List separately in addition to code for primary procedure)

 

0073U

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, CYP2D7-2D6 hybrid gene) (List separately in addition to code for primary procedure)

 

0074U

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 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) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 5’ gene duplication/multiplication) (List separately in addition to code for primary procedure)

 

0076U

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg, drug metabolism) gene analysis, targeted sequence analysis (ie, 3’ gene duplication/ multiplication) (List separately in addition to code for primary procedure)

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 and Blue Shield Association technology assessment program (TEC) and other non-affiliated 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     

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


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