Cytochrome P450 Genotype-Guided Treatment Strategy

POLICY NUMBER

A.2.04.38

DESCRIPTION

The cytochrome P450 (CYP450) family is involved in the metabolism of many currently administered drugs, and genetic variants in cytochrome P450 are associated with altered metabolism of many drugs. Testing for cytochrome P450 variants may assist in selecting and dosing drugs affected by these genetic variants.

Drug Efficacy and Toxicity

Drug efficacy and toxicity vary substantially across individuals. Because drugs and doses are typically adjusted, if needed, by trial-and-error, clinical consequences may include a prolonged time to optimal therapy. In some cases, serious adverse events may result.

Multiple factors may influence the variability of drug effects, including age, liver function, concomitant diseases, nutrition, smoking, and drug-drug interactions. Inherited (germline) DNA sequence variation in genes coding for drug-metabolizing enzymes, drug receptors, drug transporters, and molecules involved in signal transduction pathways also may have major effects on the activity of those molecules and thus on the efficacy or toxicity of a drug.

Pharmacogenomics studies how an individual's genetic inheritance affects the body's response to drugs. It may be possible to predict therapeutic failures or severe adverse drug reactions in individual patients by testing for important DNA variants (genotyping) in genes related to the metabolic pathway (pharmacokinetics) or signal transduction pathway (pharmacodynamics) of the drug. Potentially, test results could be used to optimize drug choice and/or dose for more effective therapy, avoid serious adverse effects, and decrease medical costs.

Cytochrome P450 System

The cytochrome P450 (CYP450) family is a major subset of all drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. CYP2D6 metabolizes approximately 25% of all clinically used medications (eg, dextromethorphan, β-blockers, antiarrhythmics, antidepressants, and morphine derivatives), including most prescribed drugs. CYP2C19 metabolizes several important types of drugs, including proton pump inhibitors, diazepam, propranolol, imipramine, and amitriptyline.

Some CYP450 enzyme genes are highly polymorphic, resulting in some enzyme variants that have variable metabolic capacities among individuals, and some with little to no impact on activity. Thus, CYP450 enzymes constitute an important group of drug-gene interactions influencing the variability of the effect of some CYP450-metabolized drugs.

Individuals with 2 copies (alleles) of the most common (wild-type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule are termed extensive metabolizers (normal). Poor metabolizerslack active enzyme gene alleles, and intermediate metabolizers, who have 1 active and 1 inactive enzyme gene allele, may experience to a lesser degree some of the consequences of poor metabolizers. Ultrarapid metabolizers are individuals with more than 2 alleles of an active enzyme gene. There is pronounced ethnic variability in the population distribution of metabolizer types for a given CYP enzyme.

Ultrarapid metabolizers administered an active drug may not reach therapeutic concentrations at usual recommended doses of active drugs, while poor metabolizers may suffer more adverse events at usual doses due to reduced metabolism and increased concentrations. Conversely, for administered prodrugs that must be converted by CYP450 enzymes into active metabolites, ultrarapid metabolizers may suffer adverse events, and poor metabolizers may not respond.

Many drugs are metabolized to varying degrees by more than one enzyme, either within or outside of the CYP450 superfamily. Also, the interaction between different metabolizing genes, the interaction between genes and environment, and interactions among different non-genetic factors also influence CYP450-specific metabolizing functions. Thus, identification of a variant in a single gene in the metabolic pathway may be insufficient in all but a small proportion of drugs to explain inter-individual differences in metabolism and consequent efficacy or toxicity.

Determining Genetic Variability in Drug Response

Genetically determined variability in drug response has been traditionally addressed using a trial-and-error approach to prescribing and dosing, along with therapeutic drug monitoring for drugs with a very narrow therapeutic range and/or potential serious adverse events outside that range. However, therapeutic drug monitoring is not available for all drugs of interest, and a cautious trial-and-error approach can lengthen the time to achieving an effective dose.

CYP450 enzyme phenotyping (identifying metabolizer status) can be accomplished by administering a test enzyme substrate to a patient and monitoring parent substrate and metabolite concentrations over time (e.g., in urine). However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.

The clinical utility of CYP450 genotyping (i.e., the likelihood that genotyping will significantly improve drug choice, dosing, and patient outcomes) may be favored when the drug under consideration has a narrow therapeutic dose range, when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in patients with gene sequence variants. Under these circumstances, genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. For example, warfarin, some neuroleptics and tricyclic antidepressants have narrow therapeutic windows and can cause serious adverse events when concentrations exceed certain limits, resulting in cautious dosing protocols. The potential severity of the disease condition may call for immediate and sufficient therapy; genotyping might speed the process of achieving a therapeutic dose and avoiding significant adverse events.

Clinical laboratories may develop and validate tests in-house and market them as a laboratory service; laboratory-developed tests (LDTs) must meet the general regulatory standards of the Clinical Laboratory Improvement Amendments (CLIA). Diagnostic genotyping tests for certain CYP450 enzymes are available under the auspices of the CLIA. Laboratories that offer LDTs must be licensed by the CLIA for high-complexity testing. To date, the U.S. Food and Drug Administration (FDA) has chosen not to require any regulatory review of this test.

Several testing kits for CYP450 genotyping cleared for marketing by the FDA (FDA product code: NTI) are summarized below.

Selected Testing Kits for CYP450 Genotyping Cleared for Marketing by the Food and Drug Administration

Several manufacturers market diagnostic genotyping panel tests for CYP450 genes, such as the YouScript Panel (Aranscia), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4 and CYP3A5. Other panel tests include both CYP450 and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Myriad Genetics). These tests are beyond the scope of this policy.

Food and Drug Administration Labeling on CYP450 Genotyping

The FDA maintains online compendia of pharmacogenetic associations under 3 categories: 1. pharmacogenetic associations for which the data support therapeutic management recommendations; 2. pharmacogenetic associations for which the data indicate a potential impact on safety or response and 3. pharmacogenetic associations for which the data demonstrate a potential impact on pharmacokinetic properties only.

The FDA has included pharmacogenomics information in the physician prescribing information (drug labels) of multiple drugs. In most cases, this information is general and lacks specific directives for clinical decision making. In the following examples, the FDA has given clear and specific directives on either use of a specific dose (eg, eliglustat, tetrabenazine) or when a drug may not be used at all (eg, codeine).

EliglustatThe FDA has approved eliglustat for treatment of adults with Gaucher disease type 1 who are CYP2D6 extensive metabolizers, intermediate metabolizers, or poor metabolizers as detected by an FDA-cleared test. Further, the label acknowledges the limitation of use among ultrarapid metabolizers because they may not achieve adequate concentrations and a specific dosage was not recommended for patients with indeterminate CYP2D6 metabolizer status. Further, the label states that the dosing strategy should be 84 mg orally, twice daily for CYP2D6 extensive metabolizers or intermediate metabolizers and 84 mg orally, once daily for CYP2D6 poor metabolizers. The FDA has included a boxed warning to warn about the reduced effectiveness in poor metabolizers and to advise healthcare professionals to consider alternative dosing or to use of other medications in patients identified as potential poor metabolizers.

TetrabenazineThe FDA has approved tetrabenazine for the treatment of chorea associated with Huntington disease. According to the label, patients requiring doses above 50 mg/d should be genotyped for the drug-metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer or extensive metabolizer. For patients categorized as poor metabolizers using an FDA-approved test, the maximum daily dose should not exceed 50 mg, with a maximum single dose of 25 mg.

CodeineThe FDA does not recommend genotyping before prescribing codeine. The FDA has contraindicated codeine for treating pain or cough in children under 12 years of age and codeine is not recommended for use in adolescents ages 12 to 18 years who are obese or have conditions such as obstructive sleep apnea or severe lung disease. There is an additional warning to mothers not to breastfeed when taking codeine.

SiponimodThe FDA has approved siponimod for the treatment of relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease in adults. The recommended maintenance dosage is 2 mg. The recommended maintenance dosage in patients with a CYP2C9*1/*3 or *2/*3 genotype is 1 mg. Siponimod is contraindicated in patients with a CYP2C9*3/*3 genotype.

Related medical policies -

• Pharmacogenomic and Metabolite Markers for Patients Treated with Thiopurines

• Genotype-Guided Tamoxifen Treatment

• Genetic Testing for Diagnosis and Management of Mental Health Conditions

• Genotype-Guided Warfarin Dosing

POLICY

CYP450 genotyping for the purpose of aiding in the choice of clopidogrel versus alternative anti-platelet agents, or in decisions on the optimal dosing for clopidogrel, is considered investigational.

CYP2D6 genotyping to determine drug metabolizer status may be considered medically necessary for individuals:

• With Gaucher disease being considered for treatment with eliglustat; OR

• With Huntington disease being considered for treatment with tetrabenazine in a dosage greater than 50 mg per day.

CYP2C9 genotyping to determine drug metabolizer status may be considered medically necessary for individuals:

• With relapsing forms of multiple sclerosis, to include clinically isolated syndrome, relapsing-remitting disease, and active secondary progressive disease, being considered for treatment with siponimod.

CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for the following drugs is considered investigational, aside from determinations in the separate related policies noted above:

• selection or dosage of codeine;

• dosing of efavirenz and other antiretroviral therapies for HIV (human immunodeficiency virus) infection;

• dosing of immunosuppressant for organ transplantation;

• selection or dosing of beta blockers (e.g., metoprolol);

• dosing and management of antitubercular medications.

The use of genetic testing panels that include multiple CYP450 variants is considered investigational.

POLICY EXCEPTIONS

Federal Employee Program (FEP) may dictate that all FDA-approved devices, drugs or biologics may not be considered investigational and thus these devices may be assessed only on the basis of their medical necessity.

POLICY GUIDELINES

The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.

This policy does not address the use of genetic panel tests for genes other than CYP450-related genes (eg, the Genecept Assay), which are discussed in the  Genetic Testing for Diagnosis and Management of Mental Health Conditions  medical policy.

The Food and Drug Administration maintains a database of pharmacogenomic biomarkers in drug labeling. See Policy Description for details.

Medically Necessary is defined as those services, treatments, procedures, equipment, drugs, devices, items or supplies furnished by a covered Provider that are required to identify or treat a Member's illness, injury or Mental Health Disorders, and which Company determines are covered under this Benefit Plan based on the criteria as follows in A through D:

A.  consistent with the symptoms or diagnosis and treatment of the Member's condition, illness, or injury; and

B.  appropriate with regard to standards of good medical practice; and

C.  not solely for the convenience of the Member, his or her Provider; and

D.  the most appropriate supply or level of care which can safely be provided to Member. When applied to the care of an Inpatient, it further means that services for the Member's medical symptoms or conditions require that the services cannot be safely provided to the Member as an Outpatient.

For the definition of medical necessity, “standards of good medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. BCBSMS makes no payment for services, treatments, procedures, equipment, drugs, devices, items or supplies which are not documented to be Medically Necessary. The fact that a Physician or other Provider has prescribed, ordered, recommended, or approved a service or supply does not in itself, make it Medically Necessary.

Investigative is defined as the use of any treatment procedure, facility, equipment, drug, device, or supply not yet recognized as a generally accepted standard of good medical practice for the treatment of the condition being treated and; therefore, is not considered medically necessary. For the definition of Investigative, “generally accepted standards of medical practice” means standards that are based on credible scientific evidence published in peer-reviewed medical literature generally recognized by the relevant medical community, and physician specialty society recommendations, and the views of medical practitioners practicing in relevant clinical areas and any other relevant factors. In order for equipment, devices, drugs or supplies [i.e, technologies], to be considered not investigative, the technology must have final approval from the appropriate governmental bodies, and scientific evidence must permit conclusions concerning the effect of the technology on health outcomes, and the technology must improve the net health outcome, and the technology must be as beneficial as any established alternative and the improvement must be attainable outside the testing/investigational setting.

POLICY HISTORY

3/31/2005: Approved by Medical Policy Advisory Committee (MPAC)

5/11/2005: Code Reference section completed

10/11/2006: Policy reviewed, no changes

9/18/2007: Policy reviewed, no changes

06/23/2010: Policy description unchanged. Policy statement revised to state that CYP450 phenotyping may be considered medically necessary in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) for specified reasons. Other uses remain investigational; specific indications added to the investigational policy statement. FEP verbiage added to the policy exceptions section. Deleted outdated references from the Sources section. CPT code 87999 moved from non-covered to covered. 

06/22/2011: The first policy statement was corrected by changing “phenotyping” to “genotyping.”

01/09/2013: Policy statements clarified; intent unchanged. Previously stated the following: "CYP450 genotyping for CYP2C19 *2 and *3 alleles may be considered medically necessary in patients with cardiovascular disease undergoing treatment with clopidogrel (Plavix) in order to identify those who are poor metabolizers of the drug (patients with CYP2C19*2/2,*3/3, and *2/3 genotypes) and who are therefore likely to exhibit poor response to the drug. Aside from the use with clopidogrel treatment noted above and the separate policies noted above, genotyping to determine specific cytochrome p450 (CYP450) genetic polymorphisms for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity is considered investigational." Added CPT code 81225 to the Code Reference section and deleted unlisted CPT code 87999. Added ICD-9 codes 410.00 – 410.92, 411.0, 411.1, 434.10-434.91, and 443.9 to the Code Reference section.

04/04/2014: Investigational policy statement revised to remove “dose of atomoxetine HCl (approved for treatment of attention-deficit/hyperactivity disorder)” and to add “selection and dosing of selective norepinephrine reuptake inhibitors, selection and dosing of tricyclic antidepressants, and dosing and management of antituberculosis medications."

02/02/2015: Policy reviewed; description updated regarding devices. First investigational statement revised for clarity: 1) changed "deciding whether to prescribe codeine for nursing mothers" to "selection or dosage of codeine" and 2) added "andother antiretroviral therapies for HIV (human immunodeficiency virus)infection" to dosing of efavirenz. It previously stated: dose of efavirenz (common component of highly active antiretroviral therapy for HIV infection). Added the following investigational statement: The use of genetic testing panels that include multiple CYP450 mutations is considered investigational.

08/26/2015: Medical policy revised to add ICD-10 codes.

06/09/2016: Policy number added. Policy Guidelines updated to add medically necessary and investigative definitions.

02/23/2018: Policy Guidelines updated to add genetics nomenclature update and genetic counseling information. Code Reference section updated to add CPT codes 81230, 81231, and 0033U as investigational.

08/15/2018: Policy title changed from "Cytochrome P450 Genotyping" to "Cytochrome P450 Genotype-Guided Treatment Strategy." Policy description updated regarding laboratory testing, devices, and FDA labeling on CYP450 genotyping. Policy statement regarding CYP450 genotyping for aiding in the choice of clopidogrel changed from medically necessary to investigational. Added medically necessary statement for CYP2D6 genotyping for patients being considered for eliglustat or tetrabenazine therapy. Third policy statement updated to add "serotonin-norepinephrine reuptake inhibitors" to the investigational criteria. Policy Guidelines updated regarding genetic counseling. Code Reference section updated to add CPT code 81226 as covered. Added ICD-10 diagnosis codes E75.22 and G10. Removed ICD-9 diagnosis codes and the following ICD-10 diagnoses: I21.01 – I21.4, I22.0 – I22.9, I24.1, I20.0, I63.40 – I63.59, I63.8, I63.9, I66.01 – I66.9, and I73.9. CPT code 81225 moved from covered to investigational.

10/01/2018: Code Reference section updated to add new CPT codes 0070U, 0071U, 0072U, 0073U, 0074U, 0075U, and 0076U.

08/12/2019: Policy description updated to add related medical policies. Second investigational statement updated to remove criteria regarding pharmacologic treatments used to treat mental health disorders as they are addressed in the Genetic Testing for Diagnosis and Management of Mental Health Conditions medical policy; intent unchanged. Policy Guidelines updated regarding genetic panel tests.

07/13/2020: Policy description updated. Policy statements unchanged. Policy Guidelines updated to remove genetics nomenclature and genetic counseling information.

08/26/2021: Policy reviewed. Policy statements unchanged. Policy Guidelines updated to change "Nervous/Mental Conditions" to "Mental Health Disorders" and "Medically Necessary" to "medical necessity."

12/19/2022: Code Reference section updated to add new CPT code 81418, effective 01/01/2023.

01/17/2023: Policy description updated regarding devices, FDA labeling on CYP450 genotyping, and siponimod. Added statement that CYP2C9 genotyping to determine drug metabolizer status may be considered medically necessary for individuals meeting the specified criteria. Investigational statement updated to change "antituberculosis" to "antitubercular." Policy Guidelines updated. Code Reference section updated to change "Covered Codes" to "Medically Necessary Codes." Added CPT code 81227 and ICD-10 diagnosis code G35 as medically necessary. Added CPT codes 0029U and 0031U as investigational.

03/31/2023: Code Reference section updated to add new CPT code 0380U as investigational, effective 04/01/2023.

08/02/2023: Policy description updated regarding devices. Policy statements unchanged.

12/21/2023: Code Reference section updated to add new 2024 CPT codes 0434U and 0438U, effective 01/01/2024.

07/22/2024: Policy reviewed; no changes.

12/31/2024: Code Reference section updated to make note of deleted CPT code 0380U.

08/21/2025: Policy description updated regarding panel tests. Policy statements unchanged.

10/01/2025: Code Reference section updated to add new ICD-10 diagnosis codes G35.A, G35.B0, G35.B1, G35.B2, G35.C0, G35.C1, G35.C2, and G35.D.

SOURCE(S)

Blue Cross Blue Shield association policy #2.04.38

CODE REFERENCE

This may not be a comprehensive list of procedure codes applicable to this policy.

The code(s) listed below are ONLY medically necessary if the procedure is performed according to the "Policy" section of this document.

Medically Necessary Codes

Investigational Codes

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