ModifiedBlue Cross Blue Shield of VermontPolicy 2.04.VT38

Cytochrome P450 Genotype-Guided Treatment Strategy Corporate Medical Policy

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This policy governs coverage of cytochrome P450 genotyping used to determine drug metabolizer status and guide medication selection or dosing. It identifies limited medically necessary indications, requires prior approval for specified genetic testing codes, and considers other CYP450-guided treatment uses investigational.

Policy Summary

PayerBlue Cross Blue Shield of Vermont

PolicyCytochrome P450 Genotype-Guided Treatment Strategy Corporate Medical Policy

Policy CodePolicy 2.04.VT38

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 1, 2026

Next Review DateJul 1, 2027

Key ActionSubmit complete authorization information in accordance with the policy guidelines; missing information may delay the decision.

SourceLink

POLICY UPDATE CHANGES

The policy added CYP2C9 genotyping as a medically necessary indication for individuals with relapsing forms of multiple sclerosis being considered for siponimod.

The coding table changed selected molecular testing codes to require prior approval and removed code 81418 from the investigational category effective October 1, 2026.

Codes 0029U and 0031U were deleted from the coding table effective July 1, 2026.

The policy consolidated investigational CYP450 indications into a single bulleted section.

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ModifiedBlue Cross Blue Shield of VermontPolicy 2.04.VT38

Cytochrome P450 Genotype-Guided Treatment Strategy Corporate Medical Policy

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Sign up for bcbsvermont Policy 2.04.VT38 alerts

Get alerted when Policy 2.04.VT38 changes without checking for updates manually.

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Policy Summary

PayerBlue Cross Blue Shield of Vermont

PolicyCytochrome P450 Genotype-Guided Treatment Strategy Corporate Medical Policy

Policy CodePolicy 2.04.VT38

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 1, 2026

Next Review DateJul 1, 2027

Key ActionSubmit complete authorization information in accordance with the policy guidelines; missing information may delay the decision.

SourceLink

POLICY UPDATE CHANGES

The policy added CYP2C9 genotyping as a medically necessary indication for individuals with relapsing forms of multiple sclerosis being considered for siponimod.

The coding table changed selected molecular testing codes to require prior approval and removed code 81418 from the investigational category effective October 1, 2026.

Codes 0029U and 0031U were deleted from the coding table effective July 1, 2026.

The policy consolidated investigational CYP450 indications into a single bulleted section.

2Medically necessary CYP450 genotyping indications

3CYP genes with testing codes requiring prior approval

11Investigational drug or treatment-use categories

>50 mg/dayTetrabenazine dose threshold

19Visible procedure and tracking codes

17Visible codes requiring prior approval

Coverage Criteria

Medically Necessary CYP2D6 Genotyping

CYP2D6 genotyping to determine drug metabolizer status may be considered medically necessary when an individual meets at least one of the following criteria:

ONE of the following

Has Gaucher disease and is being considered for treatment with eliglustat.
Has Huntington disease and is being considered for treatment with tetrabenazine at a dosage greater than 50 mg per day.

Medically Necessary CYP2C9 Genotyping

CYP2C9 genotyping to determine drug metabolizer status may be considered medically necessary when the following criterion is met:

Has a relapsing form of multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, or active secondary progressive disease, and is being considered for treatment with siponimod.

Investigational CYP450 Genotyping

CYP450 genotyping to aid in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational for any of the following uses, and for all other indications:

ANY of the following

Selection or dosage of codeine.
Dosing of efavirenz and other antiretroviral therapies for HIV infection.
Dosing of immunosuppressants for organ transplantation.
Selection or dosing of beta-blockers, such as metoprolol.
Dosing and management of antitubercular medications.
Dosing and management of warfarin.
Management of treatment with tamoxifen for women at high risk for or with breast cancer.

Multivariant CYP450 genetic testing panels that include multiple CYP450 variants are considered investigational and are not covered, regardless of the drug or clinical indication for which testing is requested.

Medically Necessary Indications

CYP2D6 Genotyping — Covered Indications

CYP2D6 genotyping may be considered medically necessary to determine drug metabolizer status when one of the following indications applies.

Qualifying CYP2D6 indication

Gaucher disease and eliglustat: The individual has Gaucher disease and is being considered for treatment with eliglustat.
Huntington disease and tetrabenazine: The individual has Huntington disease and is being considered for treatment with tetrabenazine at a dosage greater than 50 mg per day.>50 mg per day

CYP2C9 Genotyping — Covered Indication

CYP2C9 genotyping may be considered medically necessary to determine drug metabolizer status when all of the following are met.

Coding and Prior-Approval Status

Requires Prior ApprovalCPT

81225

CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) gene analysis, common variants (e.g., *2, *3, *4, *8, *17)

Requires Prior ApprovalCPT

81226

CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) gene analysis, common variants (e.g., *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)

Requires Prior ApprovalCPT

81227

CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) gene analysis, common variants (e.g., *2, *3, *5, *6)

Requires Prior ApprovalCPT

81418

CYP450-related molecular testing code moved from investigational to requiring prior approval effective 10/01/2026

Investigational or prior-approval coding updatesCPT

G9143	Added as investigational
0013U	Changed from investigational to requiring prior approval
0032U	Changed from investigational to requiring prior approval
0033U	Changed from investigational to requiring prior approval
0173U	Changed from investigational to requiring prior approval
0175U	Changed from investigational to requiring prior approval
0392U	Added to the coding table as investigational

Deleted CodesCPT

0029U	Deleted from coding table effective 07/01/2026
0031U	Deleted from coding table effective 07/01/2026

Requires Prior ApprovalCPT

81226	CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) gene analysis, common variants (e.g., 2, 3, 4, 8, *17)
81227	CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) gene analysis, common variants (e.g., 2, 3, 4, 5, 6, 9, 10, 17, 19, 29, 35, 41, 1XN, 2XN, *4XN)
81230	CYP3A4 (cytochrome P450 family 3 subfamily A member 4) gene analysis, common variants (e.g., 2, 22)
81231	CYP3A5 (cytochrome P450 family 3 subfamily A member 5) gene analysis, common variants (e.g., 2, 3, 4, 5, 6, 7)
81355	VKORC1 (vitamin K epoxide reductase complex, subunit 1) gene analysis, common variant(s) (e.g., -1639G>A, c.173+1000C>T)
81402	Molecular pathology procedure level 3; panels that include the CYP gene cytochrome P450 family
81404	Molecular pathology procedure level 5; panels that include the CYP gene cytochrome P450 family
81405	Molecular pathology procedure level 6; panels that include the CYP gene cytochrome P450 family
81418	Drug metabolism genomic sequence panel, testing at least 6 genes, including CYP2C19, CYP2D6, and CYP2D6 duplications
81479	Unlisted molecular pathology procedure

1–10 of 17

1/2

No Prior ApprovalCPTCovered

81291

MTHFR (5,10-methylenetetrahydrofolate reductase) gene analysis, common variants (e.g., 677T, 1298C)

InvestigationalHCPCSExperimental

0175U	Psychiatry (e.g., depression, anxiety) genomic analysis panel, variant analysis of 15 genes
G9143	Warfarin responsiveness testing by genetic technique using any method, any number of specimen(s)

Tetrabenazine dose

Threshold>50 mg per day

MedicationTetrabenazine

Applicable useHuntington disease treatment consideration

Drug metabolism genomic sequence panel

Minimum panel sizeAt least 6 genes

Required gene content

Authorization and Provider Requirements

Prior Authorization

Prior Approval for Specified CYP450 Testing

Prior approval is required for specified CYP450 gene analyses identified in the coding table, including common-variant testing for CYP2C19, CYP2D6, and CYP2C9.

CYP2C19 analysis — CPT 81225
CYP2D6 analysis, including listed common variants and duplications/multiplications — CPT 81226
CYP2C9 analysis — CPT 81227

Prior Authorization

Prior Approval for Pharmacogenomic Testing

Prior approval is required for additional pharmacogenomic genes, CYP-containing molecular panels, and drug-metabolism testing categories listed in the coding table.

CYP3A4 — CPT 81230; CYP3A5 — CPT 81231
VKORC1 warfarin-metabolism analysis — CPT 81355
Molecular pathology levels 3, 5, and 6 for panels including CYP genes — CPT 81402, 81404, and 81405

Clinical Background

The cytochrome P450 (CYP450) family metabolizes many commonly administered drugs. Genetic variation can alter drug metabolism, and genotyping may help determine an individual’s metabolizer status to support medication selection or dosing. Coverage is limited to specific clinical situations involving eliglustat, tetrabenazine, or siponimod.

Investigational and Noncovered Uses

CYP450 genotyping is considered investigational for all indications other than the limited medically necessary uses specified in the policy. This includes testing used to guide selection or dosing of codeine, antiretroviral therapies, organ-transplant immunosuppressants, beta-blockers, antitubercular medications, warfarin, tamoxifen, mental-health medications, or clopidogrel, as well as panels containing multiple CYP450 variants.

Policy Summary

PayerBlue Cross Blue Shield of Vermont

PolicyCytochrome P450 Genotype-Guided Treatment Strategy Corporate Medical Policy

Policy CodePolicy 2.04.VT38

Change TypeModified

Effective DateJan 1, 2027

Last ReviewSep 1, 2026

Next Review DateJul 1, 2027

Key ActionSubmit complete authorization information in accordance with the policy guidelines; missing information may delay the decision.

SourceLink

On This Page

Dosing and management of medication for treatment of mental health conditions.

Selection of clopidogrel versus alternative antiplatelet agents, or decisions regarding the optimal dosing of clopidogrel.

Use of genetic testing panels that include multiple CYP450 variants.

All other indications.

Relapsing multiple sclerosis and siponimod: The individual has relapsing multiple sclerosis, including clinically isolated syndrome, relapsing-remitting disease, or active secondary progressive disease, and is being considered for treatment with siponimod.

Required duplication analysisCYP2D6 duplications

Drug metabolism genomic sequence panel

CYP2C19 testingRequired

CYP2D6 testingRequired

CYP2D6 duplication analysisRequired

Drug-metabolism genomic sequence panel testing at least six genes, including CYP2C19, CYP2D6, and CYP2D6 duplications — CPT 81418

Unlisted molecular pathology procedure — CPT 81479

Warfarin drug-response targeted sequence analysis, including CYP2C9 and CYP4F2 — PLA code 0030U

MTHFR analysis (CPT 81291) is listed as not requiring prior approval.

Prior Authorization

Prior Approval for Targeted and Psychiatry Panels

Prior approval is required for targeted sequence, duplication or copy-number, and psychiatry genomic panel services listed in the coding table.

CYP2D6 targeted sequence analysis for a nonduplicated gene — 0074U
CYP2D6 5' gene duplication or multiplication analysis — 0075U
CYP2D6 3' gene duplication or multiplication analysis — 0076U
Copy-number sequence analysis — 0156U
Psychiatry genomic analysis panel with variant analysis of 14 genes — 0173U
Psychiatry genomic analysis panel with variant analysis of 15 genes — 0175U

Unsupported block type: documentationи

Note

Eligible Provider

Testing must be ordered or provided by a qualified healthcare professional practicing within the scope of the professional’s license(s).

Eligible providers: qualified healthcare professionals.
The professional must hold and practice under applicable licensure.

Denial Risk

Listed Investigational Uses

CYP450 genotyping is considered investigational when used to guide drug selection or dosing for the following listed drugs or treatment situations.

Selection or dosage of codeine
Dosing of efavirenz or other antiretroviral therapies for HIV infection
Dosing of immunosuppressants for organ transplantation
Selection or dosing of beta-blockers, such as metoprolol
Dosing or management of antitubercular medications
Dosing or management of warfarin
Management of tamoxifen treatment for women at high risk for or with breast cancer
Dosing or management of medications for mental health conditions
Selection of clopidogrel versus alternative antiplatelet agents or optimization of clopidogrel dosing
Genetic testing panels containing multiple CYP450 variants

Denial Risk

All Other Indications

CYP450 genotyping is considered investigational for all indications outside the limited medically necessary indications established by the policy.

Do not assume coverage for CYP450 testing solely because the test may inform drug choice, dose, efficacy, or toxicity.
The member contract and applicable benefit language control when they conflict with the medical policy.

Documentation Required

Incomplete Authorization Request

An incomplete authorization request may delay the coverage decision while missing information is obtained. Submit a complete request in accordance with the policy guidelines before testing is performed.

Review the request for missing clinical, testing, and authorization information.
Allow for decision delays when required information has not been submitted.

Denial Risk

Investigational Services May Be Denied

Services identified as investigational in the coding table may be denied. This includes investigational drug-metabolism and pharmacogenomic services, even when submitted by an eligible provider.

Drug-metabolism genomic sequence panel testing with at least six genes, including CYP2C19, CYP2D6, and CYP2D6 duplications — CPT 81418
Drug-metabolism gene-drug interaction testing involving variant analysis of multiple genes, including CYP2D6 deletion/duplication analysis, is listed as investigational.
Warfarin responsiveness testing by genetic technique — G9143 — is listed as investigational.

Documentation Required

Provider Actions Before Testing

Before ordering CYP450 or related pharmacogenomic testing, use a qualified, appropriately licensed healthcare professional, confirm the test and indication, obtain prior approval when required, and submit complete supporting information under the policy guidelines.

Confirm that the ordering or performing professional practices within the scope of the applicable license.
Identify whether the requested CYP450 analysis, panel, targeted sequence, duplication/copy-number service, or drug-metabolism test requires prior approval.
Document the clinical indication and submit all information required for authorization.
Verify member-specific benefits, exclusions, and contract requirements before providing the service.
Recognize that testing listed as investigational may be denied, including testing for listed investigational uses or all other indications outside the policy’s medically necessary scope.