Concert Genetic Testing: Toxicology and Pharmacogenetics (Version B)
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Defines medical necessity and coverage criteria for pharmacogenetic and toxicology-related genetic tests and single-gene variant analyses for members of Arizona Complete Health (Centene-affiliated plans). Affects ordering providers and laboratories seeking reimbursement for listed tests.
Added NAT2 Variant Analysis and related content (including replacing HLA-B*58.01 with NAT2 and CPT code adjustment).
Added CPT codes 0423U, 0434U, 0437U, 0438U to the policy coding reference table and criteria for pharmacogenetic panel tests.
Pharmacogenetic panel tests must have proven clinical validity demonstrated through independent evaluation from a recognized third‑party source (e.g., MolDX, ECRI, Hayes, Optum Genomics or FDA).
Pharmacogenetic panel testing criteria replaced prior statement that panels were not medically necessary and aligned with LCD guidelines for certain psychiatric indications.
Multiple single-gene variant criteria and references were updated (e.g., removal of SLCO1B1 from non-covered list; additions of FDA or NCCN references; added HLA A*02:01 criteria).
Throughout policy: replaced 'coverage criteria' with 'criteria.'
Coverage Criteria for Pharmacogenetic and Toxicology Genetic Tests
BCHE variant analysis
BCHE variant analysis to determine drug metabolizer status is considered medically necessary when:
ANY of the following
- Member is being considered for, or is currently undergoing treatment with mivacurium (e.g., Mivacron)
- Member is being considered for, or is currently undergoing treatment with succinylcholine (e.g., Anectine, Suxamethonium)
CYP2C9 variant analysis
CYP2C9 variant analysis to determine drug metabolizer status is considered medically necessary when:
ANY of the following
- Member is being considered for, or is currently undergoing treatment with siponimod (e.g., Mayzent)
- Member is being considered for, or is currently undergoing treatment with celecoxib (e.g., Celebrex, Elyxyb)
- Member is being considered for, or is currently undergoing treatment with dronabinol (e.g., Marinol, Syndros)
- Member is being considered for, or is currently undergoing treatment with erdafitinib (e.g., Balversa)
- Member is being considered for, or is currently undergoing treatment with flurbiprofen (e.g., Ansaid)
- Member is being considered for, or is currently undergoing treatment with fosphenytoin (e.g., Cerebyx, Sesquient)
- Member is being considered for, or is currently undergoing treatment with meloxicam (e.g., Anjeso, Mobic, Vivlodex, Qmiiz ODT)
- Member is being considered for, or is currently undergoing treatment with nateglinide (e.g., Starlix)
- Member is being considered for, or is currently undergoing treatment with phenytoin (e.g., Dilantin, Phenytek)
- Member is being considered for, or is currently undergoing treatment with piroxicam (e.g., Feldene)
- Member is being considered for, or is currently undergoing treatment with warfarin (e.g., Coumadin, Jantoven)
BCHE
BCHE variant analysis to determine drug metabolizer status:
CYP2C9
CYP2C9 variant analysis to determine drug metabolizer status:
CYP2C19 variant analysis
CYP2C19 variant analysis to determine drug metabolizer status is considered medically necessary when:
ANY of the following
- Member is being considered for, or is currently undergoing treatment with clopidogrel (e.g., Plavix)
- Member is being considered for, or is currently undergoing treatment with abrocitinib (e.g., Cibinqo)
- Member is being considered for, or is currently undergoing treatment with belzutifan (e.g., Welireg)
- Member is being considered for, or is currently undergoing treatment with brivaracetam (e.g., Briviact, Brivajoy)
- Member is being considered for, or is currently undergoing treatment with citalopram (e.g., Celexa)
- Member is being considered for, or is currently undergoing treatment with clobazam (e.g., Onfi)
- Member is being considered for, or is currently undergoing treatment with flibanserin (e.g., Addyi)
- Member is being considered for, or is currently undergoing treatment with pantoprazole (e.g., Protonix)
CYP2D6 variant analysis
CYP2D6 variant analysis to determine drug metabolizer status is considered medically necessary when:
ANY of the following
- Member is being considered for, or is currently undergoing treatment with eliglustat (e.g., Cerdelga)
- ...tetrabenazine (e.g., Xenazine)
- ...amphetamine (e.g., Adzenys, Dyanavel, Evekeo)
- ...aripiprazole (e.g., Abilify, Abilify Maintena) or aripiprazole lauroxil (e.g., Aristada)
- ...atomoxetine (e.g., Strattera)
- ...brexpiprazole (e.g., Rexulti)
- ...clozapine (e.g., Versacloz, FazaClo, Clozaril)
- ...deutetrabenazine (e.g., Austedo)
- ...gefitinib (e.g., Iressa)
- ...iloperidone (e.g., Fanapt)
- ...lofexidine (e.g., Lucemyra)
- ...meclizine (e.g., Antivert, Bonine, Dramamine, Verticalm, Zentrip)
- ...metoclopramide (e.g., Reglan, Metozolv)
- ...oliceridine (e.g., Olinvyk)
- ...pimozide (e.g., Orap)
- ...pitolisant (e.g., Wakix)
- ...propafenone (e.g., Rythmol)
- ...thioridazine (e.g., Mellaril)
- ...tramadol (e.g., ConZip, Ultram)
- ...valbenazine (e.g., Ingrezza)
- ...venlafaxine (e.g., Effexor)
- ...vortioxetine (e.g., Trintellix, Brintellix)
- ...codeine
CYP3A5 variant analysis
CYP3A5 variant analysis to determine drug metabolizer status is considered medically necessary when:
CYP4F2 variant analysis
CYP4F2 variant analysis to determine drug metabolizer status is considered medically necessary when:
DPYD variant analysis
DPYD variant analysis to determine drug metabolizer status is considered medically necessary when the member meets the indication(s) listed in the policy:
HLA-A*02:01 variant analysis
HLA-A*02:01 variant analysis is considered medically necessary when ALL of the following are met:
ALL of the following
- Member is age 18 years or older
- Member has a diagnosis of metastatic uveal melanoma OR unresectable uveal melanoma
HLA-B*15:02 variant analysis
HLA-B*15:02 variant analysis to determine drug metabolizer status is considered medically necessary when:
ANY of the following
- Member is being considered for, or is currently undergoing treatment with fluorouracil (e.g., Carac, Efudex, Tolak, Fluoroplex) OR capecitabine (e.g., Xeloda)
- Member is being considered for, or is currently undergoing treatment with carbamazepine-containing therapy OR phenytoin OR fosphenytoin
HLA-B*57:01 variant analysis
HLA-B*57:01 variant analysis to determine drug metabolizer status is considered medically necessary when:
NAT2 variant analysis
NAT2 variant analysis to determine drug metabolizer status is considered medically necessary when:
TPMT & NUDT15 variant analysis
TPMT and NUDT15 variant analysis to determine drug metabolizer status is considered medically necessary when:
UGT1A1 variant analysis
UGT1A1 variant analysis to determine drug metabolizer status is considered medically necessary when:
UGT2B17 variant analysis
UGT2B17 variant analysis to determine drug metabolizer status is considered medically necessary when:
VKORC1 variant analysis
VKORC1 variant analysis to determine drug metabolizer status is considered medically necessary when:
Warfarin multigene panel
Warfarin sensitivity multigene panel (small targeted panel) is considered medically necessary when ALL of the following are met:
ALL of the following
- Member is being considered for, or is undergoing treatment with warfarin
- Member has not reached a therapeutic dose
ONE OF
- Indication: prophylaxis/treatment of venous thrombosis or pulmonary embolism
- Indication: prophylaxis/treatment of thromboembolic complications associated with atrial fibrillation and/or cardiac valve replacement
- Indication: history of prior myocardial infarction
Other genes not supported
Other single-gene pharmacogenetic variant analyses listed below are NOT supported by current evidence for determining drug metabolizer status:
Pharmacogenetic testing coverage criteria
Overall pharmacogenetic testing coverage stance and specific criteria:
ALL of the following
- Warfarin multigene panels: medical necessity requires member is being considered for or undergoing warfarin therapy AND has not reached therapeutic dose
- Panels: must have proven clinical validity demonstrated through independent evaluation from a recognized third-party source (e.g., MolDx, ECRI, Hayes, Optum Genomics, or FDA)
- Panels may be medically necessary when diagnosis and treatment context meet LCD-based criteria (e.g., major depressive disorder or generalized anxiety disorder for specific validated panels)
Other single-gene pharmacogenetic tests
Stance on other single-gene pharmacogenetic tests:
FDA-based gene-drug interaction recommendations
FDA Table-based pharmacogenetic recommendations and management actions referenced in this policy (examples):
ANY of the following
- HLA-B*15:02: Avoid carbamazepine in HLA-B*15:02-positive patients unless benefits outweigh risks; consider avoiding fosphenytoin and phenytoin alternatives; genotyping is not a substitute for clinical vigilance
- HLA-B*57:01: Do not use abacavir in patients positive for HLA-B*57:01
- TPMT and NUDT15: For intermediate or poor metabolizers, alter dosing of azathioprine/mercaptopurine/thioguanine and consider alternatives in poor metabolizers; refer to FDA labeling for specifics
- UGT1A1: Reduce starting dose of belinostat in *28/*28 poor metabolizers; for irinotecan monitor closely and consider dose reduction for intermediate or poor metabolizers
- UGT2B17 (with CYP2C19): Poor metabolizers may have higher systemic concentrations for belzutifan; monitor for anemia/hypoxia
- VKORC1/CYP2C9/CYP4F2: Genetic variants can alter warfarin dose requirements; select initial dose considering genetic and clinical factors and monitor/adjust by INR
Pharmacogenetic coverage criteria (revised)
Revised pharmacogenetic coverage criteria and notable changes (summary):
ALL of the following
- Pharmacogenetic panel tests were changed from 'not medically necessary' to may be medically necessary for specified psychiatric indications (major depressive disorder, generalized anxiety disorder) when LCD-based and additional criteria are met
- Panels must demonstrate clinical validity via independent third-party evaluation (e.g., MolDx, ECRI, Hayes, Optum Genomics, or FDA)
- Added multiple validated panel test names to the list of medically necessary tests and updated coding references
- SLCO1B1 removed from non-covered gene list; other single-gene criteria updated and coding changes applied (e.g., NAT2 added, CPT code adjustments)
Administrative coverage notes
Administrative coverage notes and applicability:
Coding and Billing Guidance
| 0423U | CPT code added to policy coding reference table (pharmacogenetic panel) |
| 0434U | CPT code added to policy coding reference table (pharmacogenetic panel) |
| 0437U | CPT code added to policy coding reference table (pharmacogenetic panel) |
| 0438U | CPT code added to policy coding reference table (pharmacogenetic panel) |
Provider Responsibilities and Operational Requirements
Coding guidance and claim submission
Providers should reference the most up-to-date sources of professional coding guidance prior to the submission of claims for reimbursement. CPT codes and descriptions in this policy are for informational purposes only; inclusion or exclusion of any codes does not guarantee coverage. Added CPT codes 0423U, 0434U, 0437U, and 0438U to the policy coding reference table for pharmacogenetic panel tests. Verify coding, billing, and modifier requirements with current AMA/CPT publications and payer-specific billing guidance before claim submission.
Warfarin panel prior authorization context
Multigene (warfarin) panels may imply prior authorization requirements when used to guide warfarin therapy. Coverage for warfarin sensitivity multigene panels is limited to situations where the member/enrollee is being considered for or is undergoing warfarin therapy and additional clinical criteria are met (e.g., has not reached a therapeutic dose; undergoing prophylaxis/treatment for venous thrombosis, pulmonary embolism, thromboembolic complications of atrial fibrillation or cardiac valve replacement; or history of myocardial infarction). Providers should verify prior authorization requirements with the payer before ordering testing.
- Prior authorization may be required when member/enrollee is being considered for or is undergoing warfarin therapy
- Clinical prerequisites: not at therapeutic dose OR specific thrombotic indications as listed in clinical criteria
Single-gene test indication requirements
Single-gene pharmacogenetic tests are authorized only when the member/enrollee is being considered for or is currently undergoing treatment with the specific drug/indication listed in each gene-specific criterion (for example, CYP2C19 testing when the member is being considered for clopidogrel). Panels are not a substitute for single-gene testing unless the panel meets the policy's panel-specific criteria.
- Single-gene analyses: ordered when member/enrollee is being considered for or is currently undergoing treatment with the listed drug/indication
- Panels must meet panel-specific medical necessity criteria to be used instead of single-gene testing
Use of this policy in coverage decisions
This clinical policy is intended as a guide to medical necessity to assist coverage decisions and benefit administration. It does not replace provider clinical judgment. Providers remain responsible for treatment decisions and should document clinical rationale, test selection, and how results will be used in patient management.
- Policy guides coverage decisions and administering benefits
- Providers must document clinical rationale and remain responsible for treatment decisions
State and Medicare precedence
State Medicaid provisions and Medicare National Coverage Determinations (NCDs) and Local Coverage Determinations (LCDs) take precedence where they conflict with this clinical policy. For Medicaid members, follow applicable state Medicaid coverage rules. For Medicare members, review all applicable NCDs, LCDs, and Medicare Coverage Articles prior to applying this policy.
- State Medicaid coverage provisions override this policy when conflicts exist
- Review applicable Medicare NCDs/LCDs and Coverage Articles for Medicare members
Definitions and Terminology
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