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    v1.0.31
    OpenPayerPolicy UpdatesGenetic & Molecular TestingBCBS Tennessee CYP450 Coverage Update | OpenPayer
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    CurrentBlue Cross Blue Shield - TennesseePolicy N/A

    Cytochrome P450 Genotyping

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    This policy governs coverage of cytochrome P450 genotyping used to determine drug-metabolizer status or guide medication selection and dosing. Coverage is provided for specified genes and clinical situations when the medical appropriateness criteria are met; other listed uses are considered investigational.

    Policy Summary
    PayerBlue Cross Blue Shield - Tennessee
    PolicyCytochrome P450 Genotyping
    Policy CodePolicy N/A
    Change TypeNo material change
    Effective Date12/31/2026
    Next Review DateN/A
    Key ActionEnsure the clinical record supports the applicable diagnosis or treatment context, medication, testing purpose, and expected impact on medication selection, dosing, or management.
    SourceLink
    POLICY UPDATE CHANGES

    No material clinical or coverage changes in this revision.

    4CYP genes in medical appropriateness criteria
    8Investigational drug-use categories
    3Tacrolimus/transplant conditions for CYP3A5 coverage
    12/31/2026Effective date

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    Coverage Criteria

    Medical appropriateness for CYP2D6, CYP2C9, CYP2B6, or CYP3A5

    CYP2D6, CYP2C9, CYP2B6, or CYP3A5 genotyping is medically appropriate when ANY ONE of the following gene-specific criteria is met.

    Any qualifying gene-specific indication

    • CYP2D6 indications

      • Tamoxifen therapy: Results are expected to influence endocrine treatment selection, dosing, or management; the individual has estrogen receptor-positive breast cancer for which tamoxifen is planned or currently prescribed; and testing is ordered to identify CYP2D6 metabolizer status before or during tamoxifen therapy.
    • CYP2C9 indication: The individual 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.
    • CYP2B6 indication: The individual has HIV infection; efavirenz-containing antiretroviral therapy is planned, initiated, or being evaluated because of toxicity concerns; and test results are expected to influence medication selection or dosing.
    • CYP3A5 indication: Organ transplantation is planned or anticipated; tacrolimus therapy is expected; and results will be used to guide tacrolimus dosing and immunosuppressive management.

    Medically necessary genotyping

    Covered when the applicable medical appropriateness criteria are met.

    Medically necessary CYP450 genotyping: CYP2D6 and CYP2C9 genotyping to determine drug metabolizer status, and CYP3A5 genotyping to aid drug or dose choice to increase efficacy or avoid toxicity in transplants, are medically necessary when the medical appropriateness criteria are met.

    Investigational drug-selection and dosing uses

    The following uses are considered investigational.

    Investigational drug-selection or dosing uses: CYP450 genotyping used for selection or dosing of clopidogrel; selective norepinephrine reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors; selective serotonin reuptake inhibitors; tricyclic antidepressants; codeine; antipsychotic drugs; beta blockers; or for dosing and management of anti-tuberculosis medications is investigational.

    CYP2C19 testing for Helicobacter pylori

    The following use is considered investigational.

    CYP2C19 for Helicobacter pylori: CYP2C19 genotyping is used to determine drug metabolizer status in the treatment of Helicobacter pylori.

    This use is investigational.

    Multiple-CYP450 mutation panels

    The following testing approach is considered investigational.

    Multiple-CYP450 mutation panels: A genetic testing panel that includes multiple CYP450 mutations is investigational, except for CYP3A5 as described in the policy.

    Coverage is provided when the applicable medical appropriateness criteria are met. Medically necessary uses include CYP2D6, CYP2C9, CYP2B6, and CYP3A5 genotyping for specified clinical situations involving drug selection, dosing, or management. CYP3A5 testing may support tacrolimus dosing and immunosuppressive management when transplantation is planned or anticipated. Uses identified as investigational—including specified drug-selection or dosing applications, CYP2C19 genotyping for Helicobacter pylori treatment, and multiple-CYP450 mutation panels except for the specified CYP3A5 use—are not covered as medically necessary.

    Covered Gene-Specific Indications

    Gene-specific covered indications

    The following gene-specific indications are covered when the applicable medical appropriateness criteria are met.

    Covered gene-specific indications

    • CYP2D6 genotyping for specified eliglustat, tetrabenazine, or tamoxifen treatment decisions.
    • CYP2C9 genotyping for relapsing multiple sclerosis when siponimod is being considered.
    • CYP2B6 genotyping for qualifying efavirenz-containing HIV therapy.
    • CYP3A5 genotyping for tacrolimus dosing and immunosuppressive management when organ transplantation is planned or anticipated.

    Not Covered Uses

    The following uses are not covered as medically necessary because they are considered investigational: CYP450 genotyping for selection or dosing of clopidogrel; selective norepinephrine reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors; selective serotonin reuptake inhibitors; tricyclic antidepressants; codeine; antipsychotic drugs; beta blockers; or anti-tuberculosis medications. CYP2C19 genotyping to determine drug-metabolizer status in the treatment of Helicobacter pylori is also investigational. Genetic testing panels containing multiple CYP450 mutations are investigational, except for CYP3A5 testing as described in the policy.

    Provider Documentation and Denial Risks

    Documentation Required

    Support the applicable clinical criteria

    Document the relevant diagnosis or treatment context, planned or current medication, purpose of testing, and how results are expected to influence medication selection, dosing, or management when required by the applicable criterion.

    • For tamoxifen: estrogen receptor-positive breast cancer; tamoxifen planned or currently prescribed; testing to identify CYP2D6 metabolizer status before or during therapy; and results expected to influence endocrine treatment selection, dosing, or management.
    • For efavirenz-containing HIV therapy: HIV infection; therapy planned, initiated, or being evaluated because of toxicity concerns; and results expected to influence medication selection or dosing.
    • For tacrolimus: organ transplantation planned or anticipated; tacrolimus therapy expected; and results to guide tacrolimus dosing and immunosuppressive management.
    Denial Risk

    Investigational indication or panel

    Coverage may be denied when testing is used for an investigational indication, including drug selection or dosing for clopidogrel, antidepressants, codeine, antipsychotic drugs, beta blockers, or anti-tuberculosis medications; CYP2C19 testing for Helicobacter pylori treatment; or a multiple-CYP450 mutation panel other than the specified CYP3A5 use.

    • Investigational drug-selection or dosing uses include selective norepinephrine reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, SSRIs, and tricyclic antidepressants.
    • Multiple-CYP450 mutation panels are investigational except for CYP3A5 as described in the policy.
    Denial Risk

    Medical appropriateness criteria not met

    Coverage may be denied when the applicable gene-specific medical appropriateness criteria are not met. The policy requires at least one qualifying indication for CYP2D6, CYP2C9, CYP2B6, or CYP3A5 genotyping.

    • Qualifying indications include specified eliglustat or tetrabenazine treatment decisions, qualifying tamoxifen therapy, relapsing multiple sclerosis when siponimod is being considered, qualifying efavirenz-containing HIV therapy, or tacrolimus dosing and immunosuppressive management when transplantation is planned or anticipated.

    Clinical Background

    Cytochrome P450 (CYP450) enzymes metabolize a substantial proportion of commonly used medications. Inherited variation in these enzymes can affect an individual's ability to metabolize specific drugs, potentially influencing medication selection, dosing, efficacy, and toxicity. CYP450 genotyping evaluates inherited variations in CYP450 enzyme genes to help determine drug-metabolizer status. The policy recognizes clinically relevant use in selected treatment situations, including tacrolimus metabolism and transplant immunosuppressive management, while considering many other proposed uses investigational because clinical outcome benefits remain uncertain.

    Definitions

    Cytochrome P450 (CYP450) family
    DefinitionThe cytochrome P450 (CYP450) family is a major subset of all drug-metabolizing enzymes.
    Drug metabolismSeveral CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs.
    Example enzymeCYP2D6 metabolizes approximately 25% of all clinically used medications.
    CYP450 genotyping
    DefinitionCYP450 genotyping is testing for variations in CYP450 enzyme genes that can affect an individual's capability to metabolize specific drugs.
    Clinical purposeGenotyping has been proposed to direct early selection of the most effective drug or dose, avoid significant adverse events, and speed the process of achieving a therapeutic dose.
    Test availabilityDiagnostic genotyping tests for certain CYP450 enzymes are available, including FDA-cleared testing kits.
    Policy Summary
    PayerBlue Cross Blue Shield - Tennessee
    PolicyCytochrome P450 Genotyping
    Policy CodePolicy N/A
    Change TypeNo material change
    Effective Date12/31/2026
    Next Review DateN/A
    Key ActionEnsure the clinical record supports the applicable diagnosis or treatment context, medication, testing purpose, and expected impact on medication selection, dosing, or management.
    SourceLink
    On This Page
    Coverage CriteriaCovered Gene-Specific IndicationsNot Covered UsesProvider Documentation and Denial RisksClinical BackgroundDefinitions