Pharmacogenetic Testing Policy Number: AHS – M2021 – Pharmacogenetic Prior Policy Name and Number, as applicable: Testing • M2021 – Cytochrome P450 Initial Presentation Date: 06/16/2021 Revision Date: N/A I. Policy 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 (DPD), encoded by the gene DPYD, is a rate-limiting enzyme responsible for fluoropyrimidine catabolism. The fluoropyrimidines (5-fluorouracil and capecitabine) are drugs used in the treatment of solid tumors, such as colorectal, breast, and aerodigestive tract tumors (Amstutz et al., 2018). A variety of cell surface proteins, such as antigen-presenting molecules and other proteins, are encoded by the human leukocyte antigen genes (HLAs). HLAs are also known as major histocompatibility complex (MHC) (Viatte, 2017). II. Related Policies Policy Number Policy Title AHS-G2100 In Vitro Chemoresistance and Chemosensitivity Assays M2021 Pharmacogenetic Testing Page 1 of 58 AHS-G2115 Metabolite Markers of Thiopurines Testing AHS-M2030 Testing for Targeted Therapy of Non-Small-Cell Lung Cancer AHS-M2067 Therapeutic Drug Monitoring for 5-Fluorouracil AHS-M2082 Genetic Testing for Lipoprotein A Variant(s) as a Decision Aid for Aspirin Treatment and/or CVD Risk Assessment AHS-M2109 Molecular Panel Testing of Cancers for Diagnosis, Prognosis, and Identification of Targeted Therapy III. Indications and/or Limitations of Coverage 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 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. a. Amphetamine b. Aripiprazole c. Aripiprazole Lauroxil d. Atomoxetine e. Brexpiprazole f. Carvedilol g. Cevimeline h. Clozapine i. Codeine j. Desipramine k. Deutetrabenazine l. Eligustat M2021 Pharmacogenetic Testing Page 2 of 58 m. Fluvoxamine n. Gefitinib o. Iloperidone p. Lofexidine q. Meclizine r. Metoclopramide s. Nortriptyline t. Ondansetron u. Paroxetine v. Perphenazine w. Pimozide x. Propafenone y. Tamoxifen z. Tetrabenazine aa. Thioridazine bb. Tolterodine cc. Tramadol dd. Tropisetron ee. Valbenazine ff. Venlafaxine gg. Vortioxetine 2. Testing for the CYP2D6 and CYP2C19 genotype once per lifetime (please see policy guideline)* IS 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. a. Amitriptyline b. Clomipramine c. Doxepin d. Imipramine e. Trimipramine 3. Testing for the CYP2C19 genotype once per lifetime (please see policy guideline)* IS MEDICALLY NECESSARY for individuals being considered for therapy with any of the M2021 Pharmacogenetic Testing Page 3 of 58 medications listed below, or who are in their course of therapy with these medications, to aid in therapy selection and/or dosing. a. Brivaracetam b. Citalopram c. Clobazam d. Clopidogrel e. Escitalopram f. Flibanserin g. Pantoprazole (in pediatric individuals) h. Sertraline i. Voriconazole 4. Testing for the CYP2C9 genotype once per lifetime (please see policy guideline)* IS 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. a. Celecoxib b. Dronabinol c. Erdafitinib d. Flurbiprofen e. Piroxicam f. Siponimod 5. Testing for the CYP2C9, CYP4F2, VKORC1, and rs12777823 genotype once per lifetime IS MEDICALLY NECESSARY for individuals being considered for Warfarin therapy. 6. Testing for the TPMT and NUDT15 genotype once per lifetime (please see policy guideline)* IS 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. a. Azathioprine M2021 Pharmacogenetic Testing Page 4 of 58 b. Mercaptopurine c. Thioguanine 7. Testing for the DPYD genotype once per lifetime (please see policy guideline)* IS 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. a. Capecitabine b. Fluorouracil 8. Testing for the following Human Leukocyte Antigens (HLAs) genotypes once per lifetime IS 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: a. HLA-B*57:01 before treatment with Abacavir b. HLA-B*58:01 before treatment with Allopurinol c. HLA-B*15:02 for treatment with Oxcarbazepine d. HLA-B*15:02 and HLA-A*31:01 for treatment with Carbamazepine 9. Testing for the CYP2C9 and HLA-B*15:02 genotype once per lifetime IS 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. a. Phenytoin 10. Testing for the G6PD genotype once per lifetime (please see policy guideline)* IS 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. a. Pegloticase b. Primaquine c. Rasburicase d. Tafenoquine M2021 Pharmacogenetic Testing Page 5 of 58 11. Testing for the following genotypes once per lifetime (please see policy guideline)* IS 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. a. BCHE for treatment with mivacurium or succinylcholine b. CFTR for treatment with Ivacaftor, Elexacaftor and Tezacaftor, Ivacaftor and Lumacaftor, or Ivacaftor and Tezacaftor c. CYP2B6 for treatment with Efavirenz d. CYP3A5 for treatment with Tacrolimus e. IFNL3 treatment with Peginterferon alfa-2a, Peginterferon alfa-2b or Ribavirin f. NAT2 for treatment with Amifampridine or Amifampridine Phosphate g. UGT1A1 for treatment with Atazanavir, Belinostat, Irinotecan, Nilotinib, or Pazopanib 12. Testing for the RYR1 and CACNA1S genotype once per lifetime (please see policy guideline)* IS MEDICALLY NECESSARY for individuals being considered for the use of depolarizing muscle relaxants, such as succinylcholine, or halogenated volatile anesthetics. 13. Genetic testing for the presence of variants in the SLCO1B1 gene for the purpose of identifying patients at risk of statin-induced myopathy IS NOT MEDICALLY NECESSARY. The following does not meet coverage criteria due to a lack of available published scientific literature confirming that the test(s) is/are required and beneficial for the diagnosis and treatment of a patient’s illness. 14. The following pharmacogenetic testing IS INVESTIGATIONAL: a. Genotyping for any medication therapy more than once per lifetime (please see policy guideline). * b. Testing for the specific genotype for individuals on medications not listed as meeting coverage criteria for testing. c. Testing for all other genotypes including, but not limited to, use of other medication therapy not listed as meeting coverage criteria. d. Genotyping the general population. e. Pharmacogenetic panel testing for individuals not being considered for any of the above conditions. M2021 Pharmacogenetic Testing Page 6 of 58 15. All other single nucleotide polymorphism (SNP) testing, either as individual SNPs or as a panel of SNPs, IS INVESTIGATIONAL for all indications. The list of SNPs includes, but is not limited to, the following: a. 5HT2C (serotonin receptor) b. 5HT2A (serotonin receptor) c. SLC6A4 (serotonin transporter) d. DRD1 (dopamine receptor) e. DRD2 (dopamine receptor) f. DRD4 (dopamine receptor) g. DAT1 or SLC6A3 (dopamine transporter) h. DBH (dopamine beta-hydroxylase) i. COMT (catechol-O-methyl-transferase) j. MTHFR (methylenetetrahydrofolate reductase) k. γ-Aminobutyric acid (GABA) A receptor l. OPRM1 (µ-opioid receptor)