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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.
Various 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 (polymorphisms) 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 efficacy or toxicity of a drug.
Pharmacogenomics is the study of 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 polymorphisms (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. See Pharmacogenomic and Metabolite Markers for Patients with Inflammatory Bowel Disease Treated with Azathioprine (6-MP) medical policy.
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 many of the 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 enzyme variants constitute one important group of drug-gene interactions influencing the variability of 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 (EMs; normal). Poor metabolizers lack active enzyme gene alleles, and intermediate metabolizers (IMs), who have one active and one inactive enzyme gene allele, may experience to a lesser degree some of the consequences of poor metabolizers. Ultrarapid metabolizers are individuals with more than two 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 effects 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. In addition, interaction between different metabolizing genes, interaction of genes and environment, and interactions between 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 (TDM) for drugs with a very narrow therapeutic range and/or potential serious adverse effects outside that range. However, TDM 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 consequent patient outcomes) is favored when the drug under consideration has a narrow therapeutic dose range (window), 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. Yet 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 avoid significant adverse events.
Diagnostic genotyping tests for some CYP450 enzymes are now available. Some tests are offered as in-house laboratory services, which do not require FDA approval but which must meet Clinical Laboratory Improvement Act (CLIA) quality standards for high complexity testing.
Several testing kits for CYP450 genotyping have been cleared for marketing by FDA (FDA product code: NTI). These include:
Several manufacturers market panels of diagnostic genotyping tests for CYP450 genes, such as the YouScript Panel (Genelex Corp., Seattle, WA), which includes CYP2D6, CYP2C19, CYP2C9, VKORC1, CYP3A4 and CYP3A5. Other panel tests include both CYP450 genes and other non-CYP450 genes involved in drug metabolism, such as the GeneSight Psychotropic panel (Assurex Health, Mason, OH); these tests are beyond the scope of this 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, may be considered medically necessary.
CYP450 genotyping for the purpose of aiding in the choice of drug or dose to increase efficacy and/or avoid toxicity for all other drugs is considered investigational. This includes, but is not limited to, CYP450 genotyping for the following applications:
The use of genetic testing panels that include multiple CYP450 mutations is considered investigational.
POLICY EXCEPTIONSFederal 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.
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 Nervous/Mental Conditions, 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 Medically Necessary, “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.
The coverage guidelines outlined in the Medical Policy Manual should not be used in lieu of the Member's specific benefit plan language.
POLICY HISTORY3/31/2005: 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 "and other 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.
SOURCE(S)Blue Cross Blue Shield association policy #2.04.38
CODE REFERENCEThis 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.