Sunflower Health Plan Concert Genetic Testing: Pharmacogenetics (PDF) Form

Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 CONCERT GENETIC TESTING: PHARMACOGENETICS See Important Reminder at the end of this policy for important regulatory and legal information. OVERVIEW Pharmacogenetic tests are germline genetic tests that are developed to aid in assessing an individual's response to a drug treatment or to predict the risk of toxicity from a specific drug treatment. Testing may be performed prior to initiation of treatment to identify if an individual has genetic variants that could either affect response to a particular drug and/or increase the risk of adverse drug reactions. Testing may also be performed during treatment to assess an individual who has had an adverse drug reaction or to assess response to treatment. Test methodology includes genotyping and single nucleotide variant testing. POLICY REFERENCE TABLE Below are a list of higher volume tests and the associated laboratories for each coverage criteria section. This list is not all inclusive. Coding Implications This clinical policy references Current Procedural Terminology (CPT®). CPT® is a registered trademark of the American Medical Association. All CPT codes and descriptions are copyrighted 2022, American Medical Association. All rights reserved. CPT codes and CPT descriptions are from the current manuals and those included herein are not intended to be all-inclusive and are included for informational purposes only. Codes referenced in this clinical policy are for informational purposes only. Inclusion or exclusion of any codes does not guarantee coverage. Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement of covered services. 1 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 Coverage Criteria Sections Pharmacogenetic Panel Tests Example Tests (Labs) Common CPT Codes Common ICD Codes Ref GeneSight Psychotropic (Myriad Genetics) Professional PGXTM (formerly GeneceptTM Assay) (Genomind) PGxOne (Admera Health) 0345U 81418 Genomind Professional PGX Express CORE Cytochrome P450 Genotyping Panel (ARUP Laboratories) 0175U 81418 OneOme RightMed Pharmacogenomic Test {OneOme) 0347U, 0348U, 0349U, 0350U Focused Pharmacogenomics Panel (Mayo Clinic Laboratories) 0029U Warfarin Response Genotype (Mayo Medical Laboratories) 0030U F01 through F69, F80 through F99, Z81.8, Z86.59 24, 25, 26, 27, 28 I20.0, I21.01 through I22.9, I24.1, I25.110, I63.50 through I63.549 , I66.01 though I66.9, I73 B20, C00.0 through C96.9, D00.0 through D49.9, E75.22, F01 through F99, G10, G71.14, G89.0 through G89.4, I20.0, I21.01 through I22.9, I24.1, I25.110, I26.01 through I26.99, I48.0, I60.00 through I66.99, I73, I82.210 through I82.91, K50.00 through K50.019 K51.00 through K51.319, R52, R79.9, T46.6X1A through T46.6X6S, Z13.71 through Z13.79, Z80.3, Z81.8, Z82.49, Z85.3, Z86.000, Z86.59, Z86.71 through Z86.79 I20.0, I21.01 through I22.9, I24.1, I25.110, I63.50 through I63.549 , I66.01 through I66.9, I73 I21.0 through I22.9, I26.01 through I26.99, I48.0, I60.00 through I66.99, I82.210 through I82.91, 2 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 Psych HealthPGx Panel, (RPRD Diagnostics) PersonalisedRX Serotonin Receptor Genotype (HTR2A and HTR2C), Mayo Medical Laboratories 0173U 0380U 0033U Pharmacogenetic Single Gene Tests CYP2C9 Variant Analysis Cytochrome P450 2C9 Genotype (Quest Diagnostics) 81227 CYP2C19 Variant Analysis CYP2C19 Single Gene Test (Blueprint Genetics) 81225 CYP2D6 Variant Analysis CYP2D6 (ARUP Laboratories) CYP2D6 Common Variants and Copy Number (Mayo Clinic Laboratories) CYP2D6 Full Gene Sequencing (Mayo Clinic Laboratories) CYP2D6-2D7 Hybrid Gene Targeted Sequence Analysis (Mayo Clinic Laboratories) CYP2D7-2D6 Hybrid Gene Targeted Sequence Analysis (Mayo Clinic Laboratories) CYP2D6 CYP2D6 Nonduplicated Gene Analysis (Mayo Clinic Laboratories) 81226 0070U 0071U 0072U 0073U 0074U Z86.71 through Z86.79 F01 through F69, F80 through F99, Z81.8, Z86.59 G35, I21.0 through I22.9, I26.01 through I26.99, I48.0, I60.00 through I66.99, I82.210 through I82.91, Z86.71 through Z86.79 I21.0 through I22.9, I24.9, I26.01 through I26.99, I48.0, I60.00 thorugh I66.99, I82.210 through I82.91, Z86.71 through Z86.79 3, 4, 5, 19, 20 1, 2, 6, 18, 23 1, 2, 7, 8, 9, 22 C50.011 through C50.929, C I24.1, I25.110, I63.50 throug I66.01 through I66.9, I73, Z 3 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 CYP2D6 5’ gene duplication/multiplication targeted sequence analysis (Mayo Clinic Laboratories) CYP2D6 3’ gene duplication/multiplication targeted sequence analysis (Mayo Clinic Laboratories) CYP4F2 Single Gene Test (Blueprint Genetics) 0075U 0076U 81479 CYP4F2 Variant Analysis 81232 81381 81374, 81381 G40 DPYD Variant Analysis HLA-B*15:02 Variant Analysis HLA-B*15:02 and HLA-A*31:01 Variant Analysis DPD 5-Fluorouracil Toxicity (LabCorp) HLA-B*15:02, Carbamazepine Sensitivity (LabCorp) Carbamazepine Hypersensitivity Pharmacogenomics (Mayo Medical Laboratories) HLA-B*57:01 Variant Analysis HLA-B*57:01 Typing (Quest Diagnostics) HLA-B*58:01 Variant Analysis HLA-B*58:01 Typing (Quest Diagnostics) TPMT and NUDT15 Variant Analysis Thiopurine S- Methyltransferase (TPMT) Genotype (Quest Diagnostics) TPMT and NUDT15 (ARUP Laboratories) Thiopurine Methyltransferase (TPMT) and Nudix Hydrolase (NUDT15) Genotyping (Mayo Clinic Laboratories) NT (NUDT15 and TPMT) genotyping panel (RPRD Diagnostics) 81381 81381 81335 81335, 81306 0034U 0169U I21.0 through I22.9, I26.01 through I26.99, I48.0, I60.00 through I66.99, I82.210 through I82.91, Z86.71 through Z86.79 C00.0 through C96.9, D00.0 through D49.9 G40 4 10, 11 12, 19 12 13 B20, Z21 M10, N20 through N22 14 15, 16 C91.0, K50.00 through K50.90 K51.00 through K51.319, M35.9, M05 through M06.9, C85.90 4 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 UGT1A1 Variant Analysis VKORC1 Variant Analysis Other Single Gene Variant Analysis UGT1A1 Irinotecan Toxicity (LabCorp) 81350 B20, C18, C19, C20, E80.4 21 VKORC1 Single Gene Test (Blueprint Genetics) 81355 Catechol-O- Methyltransferase (COMT) Genotype (Mayo Clinic Laboratories) COMT single gene test (Blueprint Genetics) Cytochrome P450 1A2 Genotype (Mayo Clinic Laboratories) CYP1A2 single gene test (Blueprint Genetics) Cardio IQ KIF6 Genotype (Quest Diagnostics) Opioid Receptor, mu OPRM1 Genotype, 1 Variant (ARUP Laboratories) 0032U 81479 0031U 81479 81479 81479 SLCO1B1, 1 Variant (ARUP Laboratories) 81328 TYMS Single Gene (Sequencing & Deletion/Duplication) (Fulgent Genetics) 81479 I21.0 through I22.9, I26.01 through I26.99, I48.0, I60.00 through I66.99, I82.210 through I82.91, Z86.71 through Z86.79 F01 through F69, F80 through F99, G20, Z81.8, Z86.59 4 22 F01 through F69, F80 through F99, Z81.8, Z86.59 E78.0 through E78.9, R79.9, Z82.49 G89.0 through G89.4 E78.00 through E78.5, G71.14, R79.9, T46.6X1A through T46.6X6S, Z82.49 C00.0 through C96.9, D00.0 through D49.9 17 10 OTHER RELATED POLICIES This policy document provides coverage for tests that determine the dosage of or the selection of a specific drug based on pharmacogenetic testing. For other related testing, please refer to: 5 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 ● ● ● ● ● Oncology: Molecular Analysis of Solid Tumors and Hematologic Malignancies for coverage criteria related to DNA testing of a solid tumor or a blood cancer. Genetic Testing: Hematologic Conditions (non-cancerous) for coverage criteria related to diagnostic testing for non-cancerous genetic blood disorders. Genetic Testing: Multisystem Inherited Disorders, Intellectual Disability, and Developmental Delay for coverage criteria related to diagnostic testing for cystic fibrosis, and related therapies. Genetic Testing: Metabolic, Endocrine, and Mitochondrial Disorders for coverage criteria related to MTHFR testing. Genetic Testing: General Approach to Genetic Testing for coverage criteria related to pharmacogenetic testing that are not specifically discussed in this or other specific policies. CRITERIA It is the policy of health plans affiliated with Centene Corporation® that the specific genetic testing noted below is medically necessary when meeting the related criteria: PHARMACOGENETIC PANEL TESTS I. The use of pharmacogenetic testing panels (81418, 0029U, 0030U, 0033U, 0173U, 0345U, 0347U, 0348U, 0349U, 0350U, 0380U) is considered investigational* for all indications. *See HLA-B*15:02 and HLA-A*31:01 Variant Analysis and TPMT and NUDT15 Variant Analysis below for coverage criteria. These tests involve analysis of more than one gene, but are not considered experimental/investigational as a panel (“panel” defined as a genetic testing analyzing more than one gene) back to top PHARMACOGENETIC SINGLE GENE TESTS CYP2C9 Variant Analysis I. CYP2C9 variant analysis (81227) to determine drug metabolizer status is considered medically necessary when: 6 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 A. The member/enrollee is being considered for treatment with siponimod* (Mayzent®). II. CYP2C9 variant analysis (81227) to determine drug metabolizer status is considered investigational for all other indications, including: A. For the purpose of managing the administration and dosing of warfarin. *Commonly prescribed for individuals diagnosed with multiple sclerosis back to top CYP2C19 Variant Analysis I. CYP2C19 variant analysis (81225) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is being considered for or is currently undergoing treatment with clopidogrel (Plavix), AND B. The member/enrollee meets all of the following: 1. Will be undergoing percutaneous coronary intervention (PCI), AND 2. Has acute coronary syndromes (ACS), AND 3. Is at high risk for poor outcomes (e.g., urgent PCI for an ACS event, elective PCI for unprotected left main disease or last patent coronary artery). II. CYP2C19 variant analysis (81225) to determine drug metabolizer status is considered investigational for all other indications. back to top CYP2D6 Variant Analysis I. CYP2D6 variant analysis (81226, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee has Gaucher disease and is being considered for treatment with eliglustat (CerdelgaTM), OR 7 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 B. The member/enrollee has Huntington disease and is being considered for treatment with tetrabenazine (Xenazine®) in a dosage greater than 50 mg per day, OR C. The member/enrollee is being considered for treatment with codeine. II. CYP2D6 variant analysis (81226, 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, 0076U) to determine drug metabolizer status is considered investigational for all other indications, including: A. For the purpose of managing treatment with tamoxifen for women at high risk for or with breast cancer, AND B. For the purpose of managing the administration and dosing of tramadol. back to top CYP4F2 Variant Analysis I. CYP4F2 variant analysis (81479) to determine drug metabolizer status is considered investigational for all other indications, including: A. For the purpose of managing the administration and dosing of warfarin. back to top DPYD Variant Analysis I. DPYD variant analysis (81232) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee being considered for treatment with any 5-FU containing therapy* (e.g., Fluorouracil®, Xeloda®). II. DPYD variant analysis (81232) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for individuals diagnosed with colorectal, breast, and aerodigestive tract tumors back to top 8 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 HLA-B*15:02 Variant Analysis I. HLA-B*15:02 variant analysis (81381) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is being considered for treatment with any carbamazepine containing therapy* (e.g., Tegretol®, Carbatrol®), OR B. The member/enrollee is being considered for treatment with phenytoin** (e.g., Dilantin®, Phenytek®). II. HLA-B*15:02 variant analysis (81381) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for individuals with epilepsy, trigeminal neuralgia, or bipolar disorder **Commonly prescribed for treatment of neonatal seizures back to top HLA-B*15:02 and HLA-A*31:01 Variant Analysis I. HLA-B*15:02 and HLA-A*31:01 variant analysis (81381) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is being considered for treatment with any carbamazepine containing therapy* (e.g., Tegretol®, Carbatrol®). II. HLA-B*15:02 and HLA-A*31:01 variant analysis (81381) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for individuals with epilepsy, trigeminal neuralgia, or bipolar disorder back to top HLA-B*57:01 Variant Analysis I. HLA-B*57:01 variant analysis (81381) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is being considered for treatment with abacavir* (Ziagen®). 9 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 II. HLA-B*57:01 variant analysis (81381) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for individuals with HIV back to top HLA-B*58:01 Variant Analysis I. HLA-B*58:01 variant analysis (81381) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is being considered for treatment with any allopurinol* (e.g. Aloprim® and Zyloprim®) containing therapy. II. HLA-B*58:01 variant analysis (81381) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for individuals with hyperuricemia, gout, or kidney stones back to top TPMT and NUDT15 Variant Analysis I. TMPT and NUDT15 variant analysis (81306, 81335, 0034U, 0169U) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is beginning therapy with azathioprine* (e.g. Imuran and Azasan), mercaptopurine* (e.g. Purinethol® and Purixan®), or thioguanine* (e.g. Tabloid®), OR B. The member/enrollee is on thiopurine therapy and has had abnormal complete blood count results that do not respond to dose reduction. II. TPMT and NUDT15 variant analysis (81306, 81335, 0034U, 0169U) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for patients with autoimmune disorders (e.g. inflammatory bowel disease, Crohn’s disease, rheumatoid arthritis) and for treatment of hematologic malignancies (e.g., leukemia and lymphoma) back to top 10 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 UGT1A1 Variant Analysis I. UGT1A1 variant analysis (81350) to determine drug metabolizer status is considered medically necessary when: A. The member/enrollee is beginning irinotecan therapy (e.g., Onivyde®, Camptosar®) for elevated serum bilirubin or Gilbert syndrome, or for cancer treatment (e.g.,colon cancer), OR B. The member/enrollee is beginning therapy with atazanavir* (e.g. Reyataz®). II. UGT1A1 variant analysis (81350) to determine drug metabolizer status is considered investigational for all other indications. *Commonly prescribed for patients with HIV back to top VKORC1 Variant Analysis I. II. VKORC1 variant analysis (81355) for the purpose of managing the administration and dosing of warfarin is considered investigational. VKORC1 variant analysis (81355) to determine drug metabolizer status is considered investigational for all other indications, including: A. For the purpose of managing the administration and dosing of warfarin. Other Single Gene Variant Analysis I. Variant analysis of all other genes for drug metabolizer status is considered investigational, including but not limited to: A. COMT (0032U, 81479) B. CYP1A2 (0031U, 81479) C. KIF6 (81479) D. OPRM1 (81479) back to top 11 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 E. SLCO1B1 (81328) F. TYMS (81479, 81346) back to top BACKGROUND AND RATIONALE Pharmacogenetic Panel Testing There are no professional society guidelines that address the clinical utility of large pharmacogenetic testing panels for the general population or for a specific population. The US Food and Drug Administration (FDA) also does not address the usage of pharmacogenetic panels. There are several recent studies that investigated the usefulness of pharmacogenetic panels [for example, Greden et al (2019), Perlis et al (2020), Shan et al (2019), Tiwari et al (2022), Oslin (2022)]. However, these studies had different study designs and often conflicting results regarding clinical utility, making it difficult to determine whether there is clinical utility for a given patient with a given indication for a given panel. However, there are several single gene pharmacogenetic tests where the Clinical Pharmacogenetics Implementation Consortium (CPIC) and the FDA describe the clinical utility of the test results for a given gene/drug/testing indication. These are described below. CYP2C9 Variant Analysis US Food and Drug Administration (FDA) The FDA approved siponimod (Mayzent) in March 2019 for the treatment of relapsing forms of multiple sclerosis in adults. This approval was based on a double-blind, randomized, phase 3 study and the CYP2C9 genotype has an impact on the metabolism of siponimod. As part of the FDA approval, CYP2C9 genotype determination should be assessed prior to administration. Dosing regimen is dependent on genotype CYP2C9, specifically *1/*3 or *2/*3 genotype while the presence of CYP2C9*3/*3 is contraindicated. Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2017) updated guidelines for pharmacogenetics-guided warfarin dosing what states that "Although there is substantial 12 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 evidence associating CYP2C9 and VKORC1 variants with warfarin dosing, randomized clinical trials have demonstrated inconsistent results in terms of clinical outcomes." (p. 10) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2014; updated 2020) published a guideline on phenytoin prescribing based on HLA-B*1502 and CYP2C9 genotype which recommends against prescribing phenytoin in individuals who are HLA-B*1502 carriers (strong recommendation) and recommends considering adjusting starting dose in individuals who are HLA-B*1502 non-carriers who have CYP2C9 poor metabolizer genotype (strong recommendation) or CYP2C9 intermediate metabolizer genotype (moderate recommendation). (p. 15) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2020) published a therapeutic recommendations for NSAIDs based on CYP2C9 genotype stating that, “The quality of evidence linking genotype to NSAID therapeutic response and adverse events was graded as weak in most cases.” (p. 5) American College of Medical Genetics and Genomics (ACMG) The American College of Medical Genetics (2008) policy statement on pharmacogenetic testing concluded: "There is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients." (p. 139) CYP2C19 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (Lee et al, 2020) updated guideline on antiplatelet therapy dosage recommends the following: “As the FDA boxed warning does not require genetic testing to initiate clopidogrel therapy, if a patient’s genotype is not known, the decision to perform CYP2C19 testing is at the discretion of the treating clinician. Although clinical guidelines from the American College of Cardiology Foundation/American Heart Association and European Society of Cardiology recommend against routine CYP2C19 testing, these groups have noted that use of CYP2C19 testing to guide selection of prasugrel or ticagrelor in CYP2C19 IMs and PMs may be considered in select patients undergoing PCI and with ACS at high risk for poor outcomes (e.g., urgent PCI for an ACS event, elective PCI for unprotected left main disease or last patent coronary artery). Recent meta- analyses have demonstrated that CYP2C19 genotype- guided therapy could identify patients undergoing PCI who benefit most from alternative antiplatelet therapy.” (p. 5) 13 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 The Clinical Pharmacogenetics Implementation Consortium (2016) updated guideline on Voriconazole dosage based on CYP2C19 genotypes stating that, “Clinical studies have not consistently demonstrated an association between CYP2C19 genotype and adverse reactions. However, as individual patients who are poor metabolizers may have elevated levels leading to toxicity, the use of another antifungal agent is recommended.” (p. 5 and 6) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2015) conducted a systematic literature review on the influence of CYP2D6 and CYP2C19 genotyping on selective serotonin reuptake inhibitor (SSRI) therapy and provided dosing recommendations for SSRIs based on phenotypes that classified patients as ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. However, CPIC noted that patients on an effective and stable dose of SSRIs would not benefit from dose modifications based on CYP2D6 and CYP2C19 genotype results. Additionally, CPIC asserted that genetic testing is only one factor among several clinical factors that should be considered when determining a therapeutic approach. (p. 131 and 132) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2016) also conducted a systematic literature review of the influence of CYP2D6 and CYP2C19 genotype on the dosing of tricyclic antidepressants and provided dosing recommendations for tricyclic antidepressants based on patient classifications of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. (p. 14 through 16) American College of Cardiology Foundation and American Heart Association The American College of Cardiology Foundation/American Heart Association ACS guidelines (2012) noted that genetic testing for CYP2C19 loss-of-function alleles may be considered on a case-by-case basis, especially for patients who experience recurrent ACS events despite ongoing therapy with clopidogrel. In addition, the committee recommended that genotyping might be considered if results of testing may alter management, which they suggest until better clinical evidence exists to provide a more scientifically derived recommendation. (p. 653) CYP2D6 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2018) published a guideline for tamoxifen prescribing based on CYP2D6 genotype/metabolic phenotype. The guideline acknowledged that there was moderate evidence that CYP2D6 poor metabolizers have a higher risk of breast cancer recurrence or worse event-free survival. However, the evidence was considered weak regarding an association between CYP2D6 metabolizer groups and clinical outcome. (p. 6 and 7) 14 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2014; updated 2021) published a guideline for codeine therapy based on CYP2D6 genotype/metabolic phenotype. The guideline states that “the association of CYP2D6 metabolizer phenotype with formation of morphine from codeine is well defined” (p. 6) and recommends using alternative analgesics to codeine in patients who are CYP2D6 poor or ultrarapid metabolizers. (p. 16) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2015) conducted a systematic literature review on the influence of CYP2D6 and CYP2C19 genotyping on selective serotonin reuptake inhibitor (SSRI) therapy and provided dosing recommendations for SSRIs based on phenotypes that classified patients as ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. However, CPIC noted that patients on an effective and stable dose of SSRIs would not benefit from dose modifications based on CYP2D6 and CYP2C19 genotype results. Additionally, CPIC asserted that genetic testing is only one factor among several clinical factors that should be considered when determining a therapeutic approach. (p. 131) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2016) also conducted a systematic literature review of the influence of CYP2D6 and CYP2C19 genotype on the dosing of tricyclic antidepressants and provided dosing recommendations for tricyclic antidepressants based on patient classifications of ultrarapid metabolizers, extensive metabolizers, intermediate metabolizers, and poor metabolizers. (p. 14 through 16) National Comprehensive Cancer Network (NCCN) NCCN breast cancer guidelines (4.2022) recommend against CYP2D6 genotype testing for women being considered for tamoxifen treatment. (p. DCIS-2 and p. BINV-K) American Society of Clinical Oncology (ASCO) The guidelines from the American Society of Clinical Oncology (2016) on the use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer stated that "The clinician should not use CYP2D6 polymorphisms to guide adjuvant endocrine therapy selection and at this point, data do not support the use of CYP2D6 testing to select patients who may or may not benefit from tamoxifen therapy." (p. 1145) CYP4F2 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) 15 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 The Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines (2017) on warfarin dosing states that if the CYP4F2*3 allele is detected, clinicians can consider altering warfarin doses but this recommendation is considered optional. (p. 9) DPYD Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (2017) updated guideline on DYPD and Fluoropyrimidine dosing noted that genetic testing for DPYD may include “resequencing of the complete coding regions” or may be confined to analysis of particular risk variants which may affect 5-fluorouracil toxicity. The guideline further noted that, while other genes (TYMS, MTHFR) may be tested for variants, the clinical utility of such tests is yet unproven. The guideline further stated that in patients who have undergone genetic testing and who are known carriers of a DPYD risk variant, it is recommended to adjust the dosage of 5-fluorouracil-based treatments, or exclude them, depending on the patient’s level of DPYD activity. (p. 4) National Comprehensive Cancer Network NCCN colon cancer guidelines (2.2022) do not recommend use of area under the curve guidance for 5-fluorouracil (5-FU) dosing. NCCN recognizes that pretreatment DPYD testing has the potential to identify the 1-2% of individuals with truncating alleles that may have an increased risk of severe toxicity, but does not currently recommend universal pretreatment genotyping of DPYD variants in patients with colon cancers. (p. MS-41 and MS-42) HLA-B*15:02 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline on HLA-B genotyping and carbamazepine dosing (2017), which reaffirmed the original recommendation (2013) and stated the following: “If a patient is carbamazepine-naive…and HLA-B*15:02 positive, carbamazepine…should be avoided.” (p. 7) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2020) published a guideline on phenytoin prescribing based on HLA-B*1502 and CYP2C9 genotype which states: “If a patient is phenytoin-naive and HLA-B*15:02 positive, the patient is at an increased risk of SJS/TEN [Stevens-Johnson syndrome and toxic epidermal necrolysis] and the recommendation is to consider using an anticonvulsant other than phenytoin unless the benefits of treating the underlying disease clearly outweigh the risks.” (p. 6) 16 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 HLA-B*15:02 and HLA-A*31:01 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline on HLA-B genotyping and carbamazepine dosing (2017), which reaffirmed the original recommendation (2013) and stated the following: “For patients who are HLA-A*31:01 negative, carbamazepine may be prescribed per standard guidelines)...If a carbamazepine-naïve patient also received testing for HLA- B*15:02 and is positive for this allele, carbamazepine should be avoided regardless of the HLA-A*31:01 genotype result. If a patient is carbamazepine-naïve and HLA-A*31:01 positive, and if alternative agents are available, carbamazepine should be avoided due to the greater risk of SJS/TEN [Stevens-Johnson syndrome/toxic epidermal necrolysis], DRESS [drug reaction with eosinophilia and systemic symptoms], and MPE [maculopapular exanthema]. Other aromatic anticonvulsants, including oxcarbazepine, have very limited evidence, if any, linking SJS/TEN, DRESS, and/or MPE with the HLA-A*31:01 allele, and thus no recommendation can be made with respect to choosing another aromatic anticonvulsant as an alternative agent.” (p. 7) HLA-B*57:01 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) updated the guideline on HLA-B genotyping and abacavir dosing (2014) and reaffirmed the CPIC 2012 guidelines which recommend that “...HLA-B*5701 screening should be performed in all abacavir-naive individuals before initiation of abacavir-containing therapy.” (p. 736) HLA-B*58:01 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (2016) revalidated the original 2013 recommendation that stated, “...given the high specificity for allopurinol-induced SCAR, allopurinol should not be prescribed to patients who have tested positive for HLA-B*58:01.” (p. 156) 17 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 TPMT and NUDT15 Variant Analysis National Comprehensive Cancer Network (NCCN) NCCN guidelines on acute lymphoblastic leukemia (1.2022) recommend consideration of TPMT gene polymorphisms in patients receiving 6-MP (mercaptopurine), especially in patients who develop severe neutropenia after starting 6-MP. NCCN recommends consideration of TPMT and NUDT15 genotyping for all patients starting 6-MP. (p. ALL-D 2A, p. ALL-D 9A) Finally they state that quantification of 6-MP metabolites can be very useful in determining whether the lack of myelosuppression is due to non-compliance or hypermetabolism. (p. MS-14) Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2018) published a guideline on thiopurine dosing based on TPMT and NUDT15 genotypes, with recommendations for starting doses of thiopurines based on an individual’s status as a normal, intermediate, or poor metabolizer. (p. 14) UGT1A1 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics and Pharmacogenomics Implementation Consortium (CPIC) (2015) guidelines for UGT1A1 genotypes and atazanavir prescribing recommended that poor metabolizers consider an alternative agent particularly where jaundice would be of concern to the patient. “A UGT1A1 genotype is most helpful if available before atazanavir is prescribed” and that “individuals who are homozygous for UGT1A1*28 or UGT1A1*6 are very likely to have Gilbert syndrome. Knowing an individual’s UGT1A1 genotype prior to prescribing may have implications for selection and dosing for drugs known to be UGT1A1 substrates or inhibitors, such as irinotecan and nilotinib.” (p. 367) VKORC1 Variant Analysis Clinical Pharmacogenetics Implementation Consortium (CPIC) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2017) updated guidelines for pharmacogenetics-guided warfarin dosing what states that "Although there is substantial evidence associating CYP2C9 and VKORC1 variants with warfarin dosing, randomized clinical trials have demonstrated inconsistent results in terms of clinical outcomes." (p. 10) 18 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 Other Single Gene Variant Analysis Clinical Pharmacogenomics Implementation Consortium (CPIC) The Clinical Pharmacogenetics and Pharmacogenomics Implementation Consortium (CPIC) (2014) updated guidelines for SLCO1B genotypes and simvastatin-induced myopathy and recommended prescribing a lower dose or considering an alternative statin and considering routine creatinine kinase surveillance in patients with SLCO1B genotypes consistent with intermediate or low statin metabolism. (p. 426) The Clinical Pharmacogenetics Implementation Consortium (CPIC) (2021) published a guideline for codeine therapy based on OPRM1 and COMT genotype/metabolic phenotype. The guideline states that "OPRM1 variants inconsistently have been shown to alter postoperative dose requirements for some opioids. There is evidence for a small increase in postoperative morphine dose requirements (~ 10%) in some clinical studies in patients carrying at least one copy of the OPRM1 rs1799971 G allele, although the alteration in morphine dose is so modest as to not be clinically actionable. There is also insufficient evidence at this time to conclude altered analgesic response to other opioids in relation to rs1799971, or other OPRM1 variants. For the most highly studied COMT variant, rs4680, there is no evidence to support an association of this variant with opioid adverse events, and there is mixed evidence for an association between COMT rs4680 genotype and analgesia or opioid dose requirements. For all other COMT variants, there is mixed evidence for an association between COMT genotype and analgesia, opioid dose requirements, or adverse events." (p. 8) The Clinical Pharmacogenetics Implementation Consortium (2017) updated guideline on DYPD and Fluoropyrimidine dosing noted that genetic testing for DPYD may include “resequencing of the complete coding regions” or may be confined to analysis of particular risk variants which may affect 5-fluorouracil toxicity. The guideline further noted that, while other genes (TYMS, MTHFR) may be tested for variants, the clinical utility of such tests is yet unproven. (p. 4) Reviews, Revisions, and Approvals Policy developed back to top Revision Date 03/23 Approval Date 03/23 19 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 REFERENCES 1. Hicks JK, Bishop JR, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and CYP2C19 Genotypes and Dosing of Selective Serotonin Reuptake Inhibitors. Clin Pharmacol Ther. 2015;98(2):127-134. doi:10.1002/cpt.147 2. Hicks JK, Sangkuhl K, Swen JJ, et al. Clinical pharmacogenetics implementation consortium guideline (CPIC) for CYP2D6 and CYP2C19 genotypes and dosing of tricyclic antidepressants: 2016 update. Clin Pharmacol Ther. 2017;102(1):37-44. doi:10.1002/cpt.597 3. Flockhart DA, O'Kane D, Williams MS, et al. Pharmacogenetic testing of CYP2C9 and 4. VKORC1 alleles for warfarin. Genet Med. 2008;10(2):139-150. doi:10.1097/GIM.0b013e318163c35f Johnson JA, Caudle KE, Gong L, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Pharmacogenetics-Guided Warfarin Dosing: 2017 Update. Clin Pharmacol Ther. 2017;102(3):397-404. doi:10.1002/cpt.668 5. Center for Drug Evaluation and Research Labeling: Mayzent™ (Siponimod). U.S. Food & 6. Drug Administration website. Available at: https://www.accessdata.fda.gov/drugsatfda_docs/nda/2019/209884Orig1s000Lbl.pdf Jneid H, Anderson JL, Wright RS, et al. 2012 ACCF/AHA focused update of the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction (updating the 2007 guideline and replacing the 2011 focused update): a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol. 2012;60(7):645-681. doi:10.1016/j.jacc.2012.06.004 7. Goetz MP, Sangkuhl K, Guchelaar HJ, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2D6 and Tamoxifen Therapy. Clin Pharmacol Ther. 2018;103(5):770-777. doi:10.1002/cpt.1007 8. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2022. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf 9. Harris LN, Ismaila N, McShane LM, et al. Use of Biomarkers to Guide Decisions on Adjuvant Systemic Therapy for Women With Early-Stage Invasive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline. J Clin Oncol. 2016;34(10):1134- 1150. doi:10.1200/JCO.2015.65.2289 10. Amstutz U, Henricks LM, Offer SM, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther. 2018;103(2):210-216. doi:10.1002/cpt.911 20 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 11. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Colon Cancer. Version 2.2022. http://www.nccn.org/professionals/physician_gls/pdf/colon.pdf 12. Phillips EJ, Sukasem C, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for HLA Genotype and Use of Carbamazepine and Oxcarbazepine: 2017 Update. Clin Pharmacol Ther. 2018;103(4):574-581. doi:10.1002/cpt.1004 13. Martin MA, Hoffman JM, Freimuth RR, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for HLA-B Genotype and Abacavir Dosing: 2014 update. Clin Pharmacol Ther. 2014;95(5):499-500. doi:10.1038/clpt.2014.38 14. Saito Y, Stamp LK, Caudle KE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines for human leukocyte antigen B (HLA-B) genotype and allopurinol dosing: 2015 update. Clin Pharmacol Ther. 2016;99(1):36-37. doi:10.1002/cpt.161 15. Relling MV, Schwab M, Whirl-Carrillo M, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for Thiopurine Dosing Based on TPMT and NUDT15 Genotypes: 2018 Update. Clin Pharmacol Ther. 2019;105(5):1095-1105. doi:10.1002/cpt.1304 16. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Acute Lymphoblastic Leukemia. Version 1.2022. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf 17. Ramsey LB, Johnson SG, Caudle KE, et al. The Clinical Pharmacogenetics Implementation Consortium Guideline for SLCO1B1 and Simvastatin-Induced Myopathy: 2014 update. Clin Pharmacol Ther. 2014;96(4):423-428. doi:10.1038/clpt.2014.125 18. Moriyama B, Obeng AO, Barbarino J, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guidelines for CYP2C19 and Voriconazole Therapy [published correction appears in Clin Pharmacol Ther. 2018 Feb;103(2):349]. Clin Pharmacol Ther. 2017;102(1):45-51. doi:10.1002/cpt.583 19. Karnes JH, Rettie AE, Somogyi AA, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for CYP2C9 and HLA-B Genotypes and Phenytoin Dosing: 2020 Update. Clin Pharmacol Ther. 2021;109(2):302-309. doi:10.1002/cpt.2008 20. Theken, K.N., Lee, C.R., Gong, L., Caudle, K.E., Formea, C.M., Gaedigk, A., Klein, T.E., Agúndez, J.A. and Grosser, T. (2020), Clinical Pharmacogenetics Implementation Consortium Guideline (CPIC) for CYP2C9 and Nonsteroidal Anti-Inflammatory Drugs. Clin. Pharmacol. Ther., 108: 191-200. doi:10.1002/cpt.1830 21. Gammal RS, Court MH, Haidar CE, et al. Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for UGT1A1 and Atazanavir Prescribing. Clin Pharmacol Ther. 2016;99(4):363-369. doi:10.1002/cpt.269 22. Crews KR, Monte AA, Huddart R, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2D6, OPRM1, and COMT Genotypes and Select Opioid Therapy [published online ahead of print, 2021 Jan 2]. Clin Pharmacol Ther. 2021;10.1002/cpt.2149. doi:10.1002/cpt.2149 23. Lee CR, Luzum JA, Sangkuhl K, et al. Clinical Pharmacogenetics Implementation Consortium Guideline for CYP2C19 Genotype and Clopidogrel Therapy: 2022 Update 21 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 [published online ahead of print, 2022 Jan 16]. Clin Pharmacol Ther. 2022;10.1002/cpt.2526. doi:10.1002/cpt.2526. 24. Greden JF, Parikh SV, Rothschild AJ, et al. Impact of pharmacogenomics clinical outcomes major depressive disorder in the GUIDED trial: a large, patient- and rater-blinded, randomized, controlled study. J Psychiatr Res. 2019;111:59-67. doi:10.1016/j.jpsychires.2019.01.003 25. Perlis RH, Dowd D,Fava M, Lencz T, Krause DS. Randomized,controlled, participant- and rater-blind trial of pharmacogenomic test-guided treatment versus treatment as usual for major depressive disorder. Depress Anxiety. 2020;37(9): 834-841. doi:10.1002/da.23029 26. Shan X, Zhao W, Qiu Y,et al. Preliminary clinical investigation of combinatorial pharmacogenomic testing for the optimized treatment of depression: a randomized single- blind study. Front Neurosci. 2019;13:960. doi:10.3389/fnins.2019.00960 27. Tiwari AK, Zai CC, Altar CA, et al. Clinical utility of combinatorial pharmacogenomic testing in depression: a Canadian patient- and rater-blinded, randomized, controlled trial. Transl Psychiatry. 2022;12(1):101. doi:10.1038/s41398-022-01847-8 28. Oslin DW, Lynch KG, Shih MC, et al. Effect of Pharmacogenomic Testing for Drug-Gene Interactions on Medication Selection and Remission of Symptoms in Major Depressive Disorder: The PRIME Care Randomized Clinical Trial. JAMA. 2022;328(2):151-161. doi:10.1001/jama.2022.9805 back to top Important Reminder This clinical policy has been developed by appropriately experienced and licensed health care professionals based on a review and consideration of currently available generally accepted standards of medical practice; peer-reviewed medical literature; government agency/program approval status; evidence-based guidelines and positions of leading national health professional organizations; views of physicians practicing in relevant clinical areas affected by this clinical policy; and other available clinical information. The Health Plan makes no representations and accepts no liability with respect to the content of any external information used or relied upon in developing this clinical policy. 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Coverage decisions and the administration of benefits are subject to all terms, conditions, exclusions and limitations of the coverage documents (e.g., evidence of coverage, certificate of coverage, policy, 22 Concert Genetic Testing: Pharmacogenetics V2.2023 Date of Last Revision: 3/1/2023 contract of insurance, etc.), as well as to state and federal requirements and applicable Health Plan-level administrative policies and procedures. This clinical policy is effective as of the date determined by the Health Plan. The date of posting may not be the effective date of this clinical policy. This clinical policy may be subject to applicable legal and regulatory requirements relating to provider notification. If there is a discrepancy between the effective date of this clinical policy and any applicable legal or regulatory requirement, the requirements of law and regulation shall govern. 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