Medical Policy: 02.04.48 

Original Effective Date: October 2013 

Reviewed: July 2017 

Revised: July 2017 

 

Benefit Application:

Benefit determinations are based on the applicable contract language in effect at the time the services were rendered. Exclusions, limitations or exceptions may apply. Benefits may vary based on contract, and individual member benefits must be verified. Wellmark determines medical necessity only if the benefit exists and no contract exclusions are applicable. This medical policy may not apply to FEP. Benefits are determined by the Federal Employee Program.

 

This Medical Policy document describes the status of medical technology at the time the document was developed. Since that time, new technology may have emerged or new medical literature may have been published. This Medical Policy will be reviewed regularly and be updated as scientific and medical literature becomes available.

 

Description:

Metabolism is the term for how the body processes substances. Just as the body processes (metabolizes) foods, it is also metabolizes medications. One gene in particular,  cytochrome P450 (also called CYP450), is known to be in involved in processing a large number of drugs. Certain genetic variants (mutations), affect how well or poorly a drug is metabolized.  It has been proposed that genetic testing for CYP450 gene mutations/variants may be helpful in determining how a person would metabolize a drug and assist in selecting and dosing drugs that are impacted by these genetic mutations/variants.

 

Drug efficacy and toxicity vary substantially across individuals.  Because drugs and doses are typically adjusted to meet individual requirements as needed by using trial and error, clinical consequences may include a prolonged time to optimal therapy and serious adverse events. 

 

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 signal transduction pathways also may have major effects on the activity of those molecules and also on the efficacy and 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 single 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.

 

The cytochrome P450 (CYP450) family is a major subset of drug-metabolizing enzymes; several CYP450 enzymes are involved in the metabolism of a significant proportion of currently administered drugs. Genotyping for cytochrome P450 has been proposed for possible use in medical management of drug therapies including but not limited to antidepressants, anti-epileptics, antipsychotics, barbituates, clopidogrel (plavix), opioid analgesics, proton pump inhibitors and tamoxifen.

 

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.  Individuals with a lack of function activity in these enzymes (CYP2C19, CYP2D6, CYP2C9, etc.) can be classified according to how fast they metabolize medications:

  • Poor metabolizers (PMs): lack active enzyme gene alleles, they will process a certain drug more slowly than normal because of the missing enzyme(s), the medication can build up in their system which can increase the likelihood that it will cause side effects. The individual might still be able to benefit from the medication, but at lower dosages.
  • Intermediate metabolizers (IMs): have one active and one inactive enzyme gene allele, these individuals have a reduced enzyme function in processing drugs, they may not process some medications as well as a normal metabolizer would. This can increase risk of side effects and drug interactions.
  • Normal metabolizers (extensive metabolizers Ems): these individuals have 2 copies (alleles) of the most common (wild type) DNA sequence of a particular CYP450 enzyme gene resulting in an active molecule and are termed extensive metabolizers. Medications are processed normally, these individuals are more likely to benefit from treatment and have fewer side effects than people who don’t process the same medication(s) as well.
  • Ultra-rapid metabolizers (UMs): individuals with more than 2 alleles of an active enzyme gene, which cause the medications to leave the body too quickly and often before they have had a chance to work properly. These individuals will likely need a higher than usual dose of medications.

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 among different non-genetic factors also influence CYP450-specific metabolizing functions. Therefore, 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.

 

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. However, testing and interpretation are time-consuming and inconvenient; as a result, phenotyping is seldom performed.

 

To definitively show that pharmacogenetic testing has value in clinical practice, it is not enough to demonstrate that drug response varies by genotype. There must be an alternative treatment strategy, and proof that testing for the genotype and subsequently tailoring the treatment strategy based on genetic information are more clinically effective or cost effective (or both) than merely treating everyone in the usual manner.  Use of the test to identify gene variants and affected populations must be more efficient than current practice in preventing serious adverse effects. After taking into account known non-genetic factors that cause variation in response, the remaining variability in patient response can often be managed with appropriate monitoring, or can be reversed by withdrawal of the drug by changing drugs or dosage. Adverse effects of available drugs are generally preventable. However, there are a few circumstances (see below) where genotyping may direct early selection of the most effective drug or dose, and/or avoid drugs or doses likely to cause toxicity. 

 

 

Selection and/or Dosing of Clopidogrel (Plavix)

Clopidogrel (plavix) is an orally administered antiplatelet drug that is used to prevent blood clots that could lead to heart attacks or strokes in individuals with established atherosclerotic disease. The degree of platelet inhibition seen following use of clopidogrel (plavix) varies from patient to patient in a normal or bell-shaped distribution. The variability in non-response is such that, when laboratory measurements of platelet aggregation are performed, 4 to 30% of patients treated with clopidogrel (plavix) do not have an adequate anti-platelet response.

 

Guidelines from the American Heart Association and the American College of Cardiology recommend the use of dual antiplatelet therapy with aspirin and a P2Y12 inhibitor, such as clopidogrel (plavix), prasugrel or ticagrelor, for the prevention of atherothrombotic events after acute myocardial infarction (MI). However, a substantial number of subsequent ischemic events still occur, which may be at least partly due to interindividual variability in the response to clopidogrel (plavix). Clopidogrel (plavix) is a prodrug which is converted by several CYP450 enzymes, CYP2C19 in particular, to an active metabolite. For this reason, genetic polymorphisms that inhibit the CYP2C19 enzyme are associated with impaired pharmacodynamics response in healthy individuals.  Previous studies have shown that persistent high platelet reactivity, despite clopidogrel (plavix) treatment at standard dosing, is associated with CYP2C19 variants that code for inactive enzymes, higher loading and/or maintenance doses decrease reactivity even in initial non-responders, presumed to be CYP2C19 PMs. Higher platelet reactivity has been associated with a higher rate of subsequent thrombotic events. However, the intrinsic variability of platelet monitoring is a known limitation of all tests measuring platelet aggregation, making it difficult to use these tests for treatment modulation.

 

In 2009, FDA expanded the pharmacogenetics section of the clopidogrel (plavix) label to include information on the metabolic impact of polymorphic CYP450 enzymes. However, no dosing or drug selection recommendations were made.  In March 2010, based on the available data at the time, the U.S. Food and Drug Administration issued a safety communication indicating it was adding a boxed warning to the label of clopidogrel (plavix) about diminished effectiveness in poor metabolizers. The boxed warning states that the effectiveness of clopidogrel (plavix) is dependent on its activation to an active metabolite by the cytochrome p450 (CYP450) system, principally CYP2C19. The labeling states that clopidogrel (plavix) at recommended doses forms less of that metabolite and has smaller effect on platelet function in patients who are CYP2C19 poor metabolizers.  Citing cohort studies and retrospective analyses of clinical trials, the labeling states that poor metabolizers with acute coronary syndrome or undergoing percutaneous coronary intervention (PCI) treated with clopidogrel (plavix) at recommended doses exhibit higher cardiovascular event rates than do patients with normal CYP2C19 function. The labeling states that tests are available to identify a patient’s CYP2C19 genotype, and that these tests can be used as an aid in determining therapeutic strategy. The labeling states that clinicians should consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

 

A clinical alert in 2010 issued by the American College of Cardiology Foundation (ACCF) and the American Heart Assocation (AHA) regarding clopidogrel (plavix) boxed warning by the FDA, stated that the boxed warning leaves the issue of whether to perform CYP2C19 testing up to the individual physician. In summary, they indicate that clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel (palvix) metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel (plavix) has been associated with adverse patient outcomes in registry experiences and clinical trials. The evidence base is insufficient to recommend either genetic or platelet function testing at the present time. There is no information that routine testing improves outcome in large subgroups of patients. However, clinical judgement is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic testing to determine if a patient is predisposed to poor clopidogrel (plavix) metabolism (poor metabolizers) may be considered before starting clopidogrel (plavix) therapy in patients believed to be at moderate or high risk for poor outcomes. This might include individuals undergoing elective high risk percutaneous coronary intervention (PCI) e.g. treatment of extensive and/or very complex disease. Moreover, if a person is identified as a potentially poor metabolizer (PM), other treatments should be considered i.e. alternative dosing of clopidogrel (plavix) or use of other available agents such as prasugrel (effient), if not contraindicated for the individual.   

 

In 2012 ACCF/AHA Focused Updated of the Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction, Class IIb recommendation suggests that a selective, limited approach to platelet genotype assessment of platelet function testing is more prudent course until better clinical evidence exists for us to provide a more scientific derived recommendation, in patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI).

 

The evidence for testing for CYP2C19 metabolizer status by CYP2C19 genotyping in patients with need for antiplatelet therapy who are undergoing or being considered for clopidogrel (plavix) therapy includes randomized controlled clinical trials (RCTs), observational studies, systemic reviews and meta-analyses. Systemic reviews of observational studies report that genetic variants may be associated with modest increase in the rate of stent thrombosis and clinical end points. CYP2C19 genotype testing has been associated with increased risk of thrombosis in patients with coronary disease or cardiac interventions being considered as candidates for clopidogrel (plavix) treatment. This observation is most pronounced for stent thrombosis in patients undergoing percutaneous coronary intervention (PCI). The evidence addressing whether the use of CYP2C19 genotype directed therapy improves outcomes are limited. However, a number of publications have evaluated outcomes in patients treated with clopidogrel (plavix) according to their CYP2C19 genetic status. These studies showed that patients with genetic variants (poor metabolizers) exhibit higher cardiovascular event rates (worse outcomes) than those patients without genetic variants. This data raises the possibility that the efficacy of clopidogrel (plavix) was reduced in patients with genetic variants. Therefore, the evidence is sufficient to determine that this testing results in a meaningful improvement in the net health outcome (consider alternate treatment or dosing strategies) in patients identified as CYP2C19 poor metabolizers. 

 

Selection and/or Dosing of Tetrabenazine

Huntington’s disease is an autosomal dominant genetic neurodegenerative disorder characterized by progressive cognitive and motor dysfunction, including chorea. In 2008, FDA approved tetrabenzine, a centrally acting vesicular monoamine transporter inhibitor, as an orphan drug for the treatment of chorea (abnormal involuntary movement) in Huntington disease, based on evidence from an RCT of improved chorea symptoms in ambulatory patients with Huntington disease.  Tetrabenazine’s primary metabolites are metabolized mainly by CYP2D6.  FDA labeling for tetrabenazine includes recommendations for genotyping for CYP2D6 in patients who are being considered for doses over 50 mg per day. The labeling states: “Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is poor metabolizer (PM), poor metabolizers should not be given daily doses greater than 50 mg.”

 

Selection and/or Dosing of Eliglustat   

Gaucher disease is a rare autosomal recessive lipid storage disease in which deficiency or absence of enzyme B-glucocerebrosidase leads to lysosomal accumulation of the glycosphingolipid glucosylceramide. Untreated, this accumulation can lead to a range of effects, including anemia and thrombocytopenia, splenomegaly, bone disease, pulmonary fibrosis, and central nervous system involvement. Gaucher disease has been treated through enzyme replacement, for which 3 drugs have been FDA approval as orphan drugs (imiglucerase, velaglucerase alfa, and taliglucerase alfa) or substrate reduction therapy, for which 2 drugs have FDA approval as orphan drugs (miglustat and eliglustat tartrate). Eliglustat (cerdelga) is an orally administered selective inhibitor of glucosylceramide synthase that received FDA approval in 2014 and has been found in 3 phase 3 clinical trials to lead to improvements in hematologic metrics and organomegaly.

 

Eliglustat (cerdelga) is metabolized by CYP2D6 and CYP3A. FDA labeling requires that patients be selected on the basis of CYP2D6 metabolizer status as determined by genotype, with recommendations based on genotype about dosage: CYP2D6 Ems (extensive metabolizers) or IMs (intermediate metabolizers) 84 mg orally twice daily; CYP2D6 PMs (poor metabolizers) 84 mg orally once daily.  Eliglustat (cerdelga) is not indicated in patients who are CYP2D6 ultra-rapid metabolizers, since they may not achieve adequate concentrations of eliglustat (cerdelga) to achieve a therapeutic effect.  

 

Selection and/or Dosing of Other Medications   

The evidence for cytochrome P450 (CYP450) genotyping in patients with various clinical conditions undergoing or being considered for treatment with a drug metabolized CYP450 enzyme(s) includes prospective and retrospective observational studies reporting associations with CYP450 metabolizer status and medication response or adverse effects. Most published studies of CYP450 pharmacogenomics are retrospective evaluations of CYP450 genotype association with intermediate (e.g., circulating drug concentrations) or, less often, final outcomes (e.g., adverse events or efficacy) and are largely small and underpowered or not designed to examine the clinical effects of homozygous variant poor metabolizers and of ultra-rapid metabolizers, where the strongest effects, if any, would be seen. The hazards associated with different metabolizer status are therefore uncertain.  Decision making regarding dose or medication selection changes in response to CYP450 metabolizer status is poorly defined, and outcome changes uncertain. As a result the evidence is insufficient to determine the effects of CYP450 genotyping for various clinical conditions on net health outcomes. Therefore, CYP450 genotyping including but not limited to the following indications would be considered investigational:

  • selection or dose of selective serotonin reuptake inhibitor (SSRI)
  • selection and dosing of serotonin norepinephrine reuptake inhibitors (SNRIs)
  • selection and dosing of tricyclic antidepressant medications
  • selection or dose of antipsychotic medications
  • selection or dosing of opioid analgesics
  • dose of efavirenz (common component of highly active antiretroviral therapy for HIV infection)
  • dose of immunosuppressant for organ transplantation
  • selection or dose of beta blockers
  • dosing and management of antituberculosis medications
  • selection or dosing of Tamoxifen

Testing for genetic polymorphisms has also been proposed for a wide array of other drugs, involving many different conditions and CYP450 enzyme(s).  At this time, the available literature addressing such testing is limited and insufficient to allow any assessment of clinical utility in the treatment of individuals. The outcomes that require further research attention include major adverse events, utilization of health resources, and time to clinically significant changes in condition using appropriate and validated measures.

While the potential of pharmacogenomics is intriguing for many clinical applications, it is not yet clear which are most likely to yield clinical benefit in the near future.  As this field evolves and matures, and if pre-prescription testing can be shown to be of clinical utility for specific drugs and individuals, it will be imperative to establish evidence-based guidelines for healthcare professionals delineating the most effective courses of action based on such genotype testing results. 

Testing Panels 

Several commercial laboratories market multi-test panels for genetic polymorphisms related to drug metabolizer status.  While the use of some individual tests included in these test panels may be reasonable under specific circumstances, the use of all the tests within a panel is rarely justified unless there is clinical evidence that the panel provides information that leads to meaningful impact on treatment.  At this time, the available published evidence addressing the use of such test panels is limited to a few panel and condition-specific studies. The results of these studies are limited by the study designs utilized by the investigators, with each having some combination of no blinding, small study population, retrospective methodology, selection bias, short follow-up periods, and subjective study outcomes.  The data from these studies is weak, and further investigation is warranted using better designed, larger study samples and double-blind randomized controlled methodology. The evidence is insufficient to determine the effects of the technology and net health outcomes. 

Practice Guidelines and Position Statements

 

Evaluation of Genomic Applications in Practice and Prevention (EGAPP)

 

CYP450 Genotyping to Predict Response to SSRIs Used to Treat Non-psychotic Depression in Adults: EGAPP™ Recommendation

In 2007, the independent Evaluation of Genomic Applications in Practice and Prevention (EGAPP™) Working Group  determined that there was not enough evidence to state whether CYP450 genotyping should or should not be used to help health care providers make decisions about beginning SSRI treatment in adults with non-psychotic depression. They discouraged use of such testing until more studies evaluating potential harms and benefits are conducted.

The EGAPP recommendation statement was based on the following key points from the evidence review:

  • In studies of people undergoing SSRI treatment, the results of their CYP450 genotyping did not show a clear relationship with the actual levels of the SSRI drug in their blood.
  • CYP450 genotyping results were not clearly related to how well the SSRI worked or the presence or severity of negative side effects.
  • No evidence was found to indicate that the use of CYP450 genotyping improved health outcomes or helped patients or doctors make decisions about the use of SSRI drugs.
  • The potential harms of CYP450 genotyping are:
    • Increased health care costs without clear benefit to the patient.
    • Patients may receive less effective treatment with SSRI drugs.
    • Genotyping information may be used inappropriately for managing other drugs metabolized by CYP450 enzymes 

 

American College of Cardiology Foundation (ACCF) and American Heart Association (AHA)

 

In 2010, the American College of Cardiology Foundation (ACCF) and the American Heart Association (AHA) issued a consensus statement on genetic testing for selection and dosing of clopidogrel, and their recommendation for practice included the following statements:

  • Adherence to existing ACCF/AHA guidelines for the use of antiplatelet therapy should remain the foundation for therapy. Careful clinical judgment is required to assess the importance of the variability in response to clopidogrel for an individual patient and its associated risk to the patient.
  • Clinicians must be aware that genetic variability in CYP enzymes alter clopidogrel metabolism, which in turn can affect its inhibition of platelet function. Diminished responsiveness to clopidogrel has been associated with adverse patient outcomes in registry experiences and clinical trials.
  • The specific impact of the individual genetic polymorphisms on clinical outcome remains to be determined.
  • Information regarding the predictive value of pharmacogenomic testing is very limited at this time; resolution of this issue is the focus of multiple ongoing studies. The selection of the specific test, as well as the issue of reimbursement, is both important additional considerations.
  • The evidence base is insufficient to recommend either routine genetic or platelet function testing at the present time.  Clinical judgement is required to assess clinical risk and variability in patients considered to be at increased risk. Genetic testing to determine if a patient is predisposed to poor clopidogrel metabolism (poor metabolizers) may be considered before starting clopidogrel therapy in patients believed to be at moderate or high risk for poor outcomes. This might include, among others, patients undergoing elective high risk PCI procedures (e.g. treatment of extensive and/or very complex disease). If such testing identifies a potential poor metabolizer, other therapies, particularly prasurgel for coronary patients should be considered.  
  • There are several possible therapeutic options for patients who experience an adverse event while taking clopidogrel in the absence of any concern about medication compliance.

 

In 2012, the American College of Cardiology Foundation  (ACCF) and the American Heart Association (AHA) issued and updated the guideline for the management of patients with unstable angina/non-ST-elevation myocardial infarction which stated the following:

 

Since the FDA announced a “Boxed Warning” on March 12, 2010, about the diminished effectiveness of clopidogrel in patients with an impaired ability to convert the drug into its active form, there has been interest in whether clinicians should perform routine testing in patients being treated with clopidogrel. The routine testing could be for genetic variants of the CYP2C19 allele and/or for overall effectiveness for inhibition of platelet activity.

 

The FDA label revision does not mandate testing for CYP2C19 genotypes or overall platelet function. The revision serves to warn clinicians that certain patient subgroups may exhibit reduced clopidogrel-mediated platelet inhibition and emphasizes that clinicians should be aware of alternative treatment strategies to tailor alternative therapies when appropriate.

 

Our recommendations for the use of genotype testing and platelet function testing seek to strike a balance between not imposing undue burden on clinicians, insurers, and society to implement these strategies in patients with unstable angina (UA) or non-ST-elevation myocardial infarction (NSTEMI) and that of acknowledging the importance of these issues to patients with UA/NSTEMI. Our recommendation that the use of either strategy may have some benefit should be taken in the context of the remarks in this update, as well as the more comprehensive analysis in the ACCF/AHA Clopidogrel Clinical Alert. The Class IIb recommendation of these strategies suggests that a selective, limited approach to platelet genotype assessment and platelet function testing is the more prudent course until better clinical evidence exists for us to provide a more scientific derived recommendation. 

 

American Society of Clinical Oncology (ASCO)

 

In 2013, the American Society of Clinical Oncology (ASCO) issued a clinical practice guideline for the use of pharmacologic interventions for breast cancer risk reduction which states the following information:

  • Testing for CYP2D6 Allelic Variants in the Prevention Setting:  Since the last guideline, additional data have been generated on the relationship between functional allele variants in cytochrome P450 2D6 gene (CYP2D6), use of CYP2D6 inhibitors including selective serotonin reuptake inhibitors, and breast cancer incidence. Data from the NSABP-P1 and STAR trials do not support the use of CYP2D6 testing to identify women not likely to benefit from tamoxifen therapy for breast cancer prevention. 

National Comprehensive Cancer Network (NCCN)

Breast Cancer Risk Reduction Version 1.2017: It has been reported that certain CYP2D6 genotypes are markers of poor tamoxifen metabolism. Nevertheless, the consensus of the NCCN Breast Cancer Risk Reduction Panel is that further validation of this biomarker is needed before it can be used to select patients for tamoxifen therapy.

 

Regulatory Status

Diagnostic genotyping tests for certain CYP450 enzymes are now available. Some tests are offered as in-house laboratory developed test services, which do not require U.S. Food and Drug Administration (FDA) approval but which must meet Clinical Laboratory Improvement (CLIA) quality standards.

 

Several test kits for CYP450 genotyping have been cleared for marketing by the FDA (FDA product code: NTI). These include: 

  • The AmpliChip® (Roche Molecular Systems, Inc.) is an FDA-cleared test for CYP450 genotyping. The AmpliChip® is a microarray consisting of many DNA sequences complementary to 2 CYP450 genes and applied in microscopic quantities at ordered locations on a solid surface (chip). The AmpliChip® tests the DNA from a patient’s white blood cells collected in a standard anticoagulated blood sample for 29 polymorphisms and mutations for the CYP2D6 gene and 2 polymorphisms for the CYP2C19 gene. CYP2D6 metabolizes approximately 25% of all clinically used medications (e.g., dextromethorphan, beta-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. FDA cleared the test “based on results of a study conducted by the manufacturers of hundreds of DNA samples as well as on a broad range of supporting peer-reviewed literature.” According to FDA labeling, “Information about CYP2D6 genotype may be used as an aid to clinicians in determining therapeutic strategy and treatment doses for therapeutics that are metabolized by the CYP2D6 product.”
  • The xTAG® CYP2D6 Kit (Luminex Molecular Diagnostics, Toronto, ON) was cleared for marketing in August 2010 based on substantial equivalence to the AmpliChip CYP450 test. It is designed to identify a panel of nucleotide variants within the polymorphic CYP2D6 gene on chromosome 22.
  • The INFINITI CYP2C19 Assay (AutoGenomics Inc., Vista, CA) was cleared for marketing in October 2010 based on substantial equivalence to the AmpliChip CYP450 test. It is designed to identify variants within the CYP2C19 gene (*2, *3, and *17).
  • Verigene CYP2C19 Nucleic Acid Test (Nanosphere Inc., Northbrook, IL) , designed to identify variants within the CYP2C19 gene, was cleared for marketing in November 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.
  • The Spartan RX CYP2C19 Test System Spartan Bioscience, Redwood Shores, CA), designed to identify variants in the CYP2C19 gene (*2, *3, and *17 alleles), was cleared for marketing in August 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.
  • The xTAG® CYP2C19 Kit v3 (Luminex Molecular Diagnostics, Toronto, ON), designed to identify variants in the CYP2C19 gene (*2, *3, and *17 alleles) was cleared for marketing in September 2013 based on substantial equivalence to the INFINITI CYP2C19 Assay.

FDA approval 2008 Tetrabenazine (xanazine): Patients requiring doses above 50 mg per day should be genotyped for the drug metabolizing enzyme CYP2D6 to determine if the patient is a poor metabolizer (PM) or an extensive metabolizer (EM). Maximum daily dose in PMs: 50 mg with a maximum single dose of 25 mg; Maximum daily dose in Ems and intermediate metabolizers (IMs): 100 mg with a maximum single dose of 37.5 mg.

 

FDA Approval 2014 Cerdelga (eliglustat): Select patients using an FDA cleared test for determining CYP2D6 genotype: CYP2D6 Ems or IMs: 84 mg orally twice daily. CYP2D6 PMs: 84 mg orally once daily.

 

Prior Approval:

 

Not applicable.

 

Policy:

 

See also related medical policies:

  • 02.01.33  Genetic Testing for Warfarin Sensitivity
  • 02.04.54  Genetic Testing for Mental Health Conditions

 

CYP450 genotyping for CYP2C19 for the purpose of aiding in the choice of clopidogrel (plavix) versus alternative antiplatelet agents or in decisions on the optimal dosing for an individual at risk for adverse events and therefore requires assessment for CYP2C19 before undergoing treatment with clopidogrel (plavix) in order to identify his or her risk of poorly metabolizing clopidogrel (plavix) and his or her likelihood of exhibiting poor response to this drug may be considered medically necessary for any one of the following indications:

  • Patient with unstable angina; or
  • Patient with non-ST-elevation myocardial infarction; or
  • Patient who experiences recurrent acute coronary syndromes (unstable angina/myocardial infarction) despite ongoing therapy with clopidogrel (plavix); or
  • Patients undergoing high risk percutaneous coronary interventions (PCI) with extensive and/or very complex disease. 

Note:  Per American Heart Association: Acute Coronary Syndrome is defined as those situations where the blood supplied to the heart muscle is suddenly blocked.

 

CYP450 genotyping for CYP2D6 to determine drug metabolizer status may be considered medically necessary for individuals with the following:

  • Huntington's disease being considered for treatment with a dosege of tetrabenazine (xenazine) greater than 50mg/day; or
  • Gaucher disease type I being considered for treatment with eliglustat (cerdelga) 

 

Repeat CYP450 genotype testing for CYP2C19, CYP2D6 for the above medically necessary indications is considered not medically necessary.

 

CYP450 genotyping for (CYP2C19, CYP2D6, CYP2C9, etc.) for the purpose of aiding in the choice of drug and/or dosing to increase efficacy and/or avoid toxicity including but not limited to the following drugs is considered investigational:

  • Selection or dosing of selective serotonin reuptake inhibitors (SSRI)
  • Selection or dosing of antipsychotic drugs
  • Selection or dosing of opioid analgesics
  • Selection and dosing of selective norepinephrine reuptake inhibitors (SNRIs)
  • Selection and dosing of tricyclic antidepressants
  • Dosing of efavirenz (common component of highly active antiretroviral therapy for HIV)
  • Dosing of immunosuppressants for organ transplantation
  • Selection or dose of beta blockers
  • Dosing and management of antituberculosis medications
  • Selection or dosing of Tamoxifen
  • Selection or dosing of Clopidogrel (Plavix) except as indicated above
  • Dosing of Tetrabenzine (Xenazine) except as indicated above
  • Dosing of Eliglustat (Cerdelga) except as indicated above

Testing for genetic polymorphisms has also been proposed for a wide array of other drugs, involving many different conditions and CYP450 enzyme(s).  At this time, the available literature addressing such testing is limited and insufficient to allow any assessment of clinical utility in the treatment of individuals. The outcomes that require further research attention include major adverse events, utilization of health resources, and time to clinically significant changes in condition using appropriate and validated measures. While the potential of pharmacogenomics is intriguing for many clinical applications, it is not yet clear which are most likely to yield clinical benefit in the near future.  As this field evolves and matures, and if pre-prescription testing can be shown to be of clinical utility for specific drugs and individuals, it will be imperative to establish evidence-based guidelines for healthcare professionals delineating the most effective courses of action based on such genotype testing results. The evidence is sufficient to determine the effects of this testing on net health outcomes and is considered investigational.

Testing Panels 
Use of genetic testing panels that include analysis of multiple CYP450 mutations and other gene polymorphisms for the purpose of aiding in the choice of drug and/or dosing to increase efficacy and/or avoid toxicity are considered investigational due to the lack of clinical evidence demonstrating an impact on improved health outcomes.

Several commercial laboratories market multi-test panels for genetic polymorphisms related to drug metabolizer status. While the use of some individual tests included in these test panels may be reasonable under specific circumstances, the use of all the tests within a panel is rarely justified unless there is clinical evidence that the panel provides information that leads to meaningful impact on treatment.  At this time, the available published evidence addressing the use of such test panels is limited to a few panel and condition-specific studies. The results of these studies are limited by the study designs utilized by the investigators, with each having some combination of no blinding, small study population, retrospective methodology, selection bias, short follow-up periods, and subjective study outcomes.  The data from these studies is weak, and further investigation is warranted using better designed, larger study samples and double-blind randomized controlled methodology. The evidence is sufficient to determine the effects of this testing on net health outcomes and is considered investigational.

 

Procedure Codes and Billing Guidelines:

  • To report provider services, use appropriate CPT* codes, Alpha Numeric (HCPCS level 2) codes, Revenue codes, and/or diagnosis codes.
  • 81225 CYP2C19 (cytochrome P450, family 2, subfamily C, polypeptide 19) (eg, drug metabolism), gene analysis common variants (eg *2, *3, *4, *8, *17) 
  • 81226 CYP2D6 (cytochrome P450, family 2, subfamily D, polypeptide 6) (eg. drug metabolism), gene analysis common variants (eg *2, *3, *4, *5, *6, *9, *10, *17, *19, *29, *35, *41, *1XN, *2XN, *4XN)  
  • 81227 CYP2C9 (cytochrome P450, family 2, subfamily C, polypeptide 9) (eg, drug metabolism), gene analysis, common variants (eg, *2, *3, *5, *6)
  • 81401 Molecular pathology procedure, level 2 (e.g. 2-10 SNPs, 1 methylated variant or 1 somatic variant (typically using non-sequencing target variant analysis], or detection of a dynamic mutation disorder/triplet repeat) includes:
    • CYP3A4 (cytochrome P450, family 3, subfamily A, polypeptide 4) (e.g. drug metabolism), common variants (e.g. *2, *3, *4, *5, *6)
    • CYP3A5 (cytochrome P450, family 3, subfamily A, polypeptide 5) (e.g. drug metabolism), common variants (e.g. *2, *3, *4, *5, *6)  
  • 81402 Molecular pathology procedure, Level 3 (e.g. > 10 SNPs, 2-10 methylated variants, or 2-10 somatic variants [typically using non-sequencing target variant analysis], immunoglobulin and T-cell receptor gene rearrangements, duplication/deletion variants of 1 exon, loss of heterozygosity [LOH], uniparental disomy [UPD] includes:
    • CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) (e.g. congenital adrenal hyperplasia, 21  hydroxylase deficiency), common variants (e.g. IVS2-13G, P3OL, I172N, exon 6 mutation cluster [I235N, V236E, M238K,], V281L, L307FfsX6, Q318X, R356W, P453S, G110VfsX21, 30-kb deletion variant) 
  • 81404 Molecular pathology procedure, Level 5 (e.g. analysis of 2-5 exons by DNA sequencing analysis, mutation scanning or duplication/deletion variants of 6-10 exons, or characterization of a dynamic mutation disorder/triplet repeat by Southern blot analysis) includes:
    • CYP1B1 (cytochrome P450,family 1, subfamily B, polypeptide 1), e.g. primary congenital glaucoma), full gene sequence
  • 81405 Molecular pathology procedure Level 6 (e.g. analysis of 6-10 exons by DNA sequence analysis, mutation scanning or duplication/deletion variants of 11-25 exons, regionally targeted cytogenomic array analysis) includes:
    • CYP11B1 (cytochrome P450, family 11, subfamily B, polypeptide 1) (e.g. congenital adrenal hyperplasia), full gene sequence
    • CYP17A1 (cytochrome P450, family 17, subfamily A, polypeptide 2) (e.g. congenital adrenal hyperplasia), full gene sequence
    • CYP21A2 (cytochrome P450, family 21, subfamily A, polypeptide 2) e.g. steroid 21-hydroxylase isoform, congenital adrenal hyperplasia), full gene sequence

 

Selected References:

  • JAMA, December 28, 2011-Vol 306, No24. Michael V. Holmes, MBBS, Msc, Pablo Perel, PhD, Tina Shah, PhD, Aroon D. Hingorani, PhD, Juan P. Casas, PhD. CYP2C19 Genotype, Clopidogrel Metabolism, Platelet Function, and Cardiovascular Events. A Systemic Review and Meta-Analysis
  • American Heart Association. Circulation Cardiovascular Interventions. Guillaume Pare and John W. Eikelboom. 2011; 4:514-521. CYP2C19 Genetic Testing Should not be Done in all Patients Treated with Clopidogrel who are Undergoing Percutaneous Coronary Intervention
  • Chest. Chest/141/2/February 2012 Supplement. John W. Eikelboom, MBBS; Jack Hirsh, M.D., FCCP; Frederick A. Spencer, M.D.; Trevor P. Baglin, MBChB, PhD; and Jeffrey I. Weitz, M.D., FCCP. Antiplatelet Drugs. Antithrombotic Therapy and Preventions of Thromobosis, 9th ed: Amerincan College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
  • Chest. Chest 2012; 141(2) (Suppl):e120S-151S. Jeffrey I.Weitz, M.D. FCCP; John W. Eikelboom, MBBS; and Meyer Michael Samama, M.D.. New Antithrombotic Drugs. Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence Based Clinical Practice Guidelines.
  • MedScape Reference Drugs, Diseases and Procedures. December 14, 2011. Clopidogrel Dosing and CYP2C19
  • ECRI. Test Intended as Clopidogrel Companion Diagnostic gets FDA Clearance as Guidance Test. Published 12/11/2012.
  • 2012 ACCF/AHA Focused Update of the Guideline for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction.
  • ACCF/AHA Clopidogrel Clinical Alert: Approaches to the FDA “Boxed Warning”. Journal of the American College of Cardiology Vol. 56, No. 4.2010
  • UpToDate Overview of Pharmacogenomics. Kelan Tantisira, M.D., MPH, Scott T. Weiss, M.D. MS. Topic Last Updated February 8, 2017.
  • UpToDate Clopidogrel Resistance and Clopiogrel Treatment Failure. Udaya S. Tantry, PhD, Charles H. Hennekens, M.D., DrPH, James L. Zehnder, M.D., Paul A. Gurbel, M.D.. Topic last updated November 2, 2016.  
  • Roche AmpliChip Ctyochrome P450 Genotype Testing and Affymetrix GeneChip Microarray Instrumentation System K042259.
  • PubMed. The AmpliChip CYP450 Genotyping test: Integrating a New Clinical Tool.
  • Tom Lynch, PharmD and Amy Price, M.D., The Effect of Cytochrome P450 Metabolism on Drug Response Interactions, and Adverse Effects. 2007 American Academy of Family Physicians.
  • ECRI. Hotline Response. Pharmacogenomic Testing to Guide Treatment of Behavioral Disorders. March 2014.
  • EGAPP. Recommendations from the EGAPP Working Group: Testing for Cytochrome P450 Polymorphisms in Adults with Nonpsychotic Depression Treated with Selective Serotonin Reuptake Inhibitors. December 2007.
  • Martin J. Lee KC. Pharmacogenomics of Antidepressants for Major Depressive Disorder. Ment Health Clin. 2012;1(9):17. Accessed August 25, 2014
  • KR Crews, et al. Clinical Pharmacogenetics Implementation Consortium Guidelines for Cytochrome P450 2D6 Genotype and Codeine Therapy: 2014.
  • MedScape. Pharmacogenomics of Opioids and Perioperative Pain Management. Pharmacogenomics. 2012;13 (15):1719-1740.
  • Jaekyu Shin, Pharm.D., Julie A. Johnson, Pharm.D. Pharmacogenetics of Beta Blockers. Phamacotherapy. 2007;27(6):874-887. 
  • Christoph Wyen, et.al. Cytochrome P450 2V6 (CYP2B6) and Constitutive Androstane Receptor (CAR) polymorphisms are Associated with Early Discontinuation of Efavirenz-Containing Regimens. Journal of Antimicrobial Chemotherapy 2011;66:2092-2098.
  • UpToDate. Isoniazid Hepatotoxicity. Anne M. Larson, M.D., FACP, Amy L. Graziani, PharmD. Topic Last Updated February 9, 2017. 
  • Y-Shin Huang, Recent Progress in Genetic Variation and Risk of Antituberculosis Drug Induced Liver Injury. ScienceDirect October 14, 2013.
  • UpToDate. Huntington Disease. Management. Oksana Suchowersky, M.D., FRCPC, FCCMG. Topic Last Updated October 27, 2016. 
  • Tetrabenazine in Huntington’s Disease Chorea. Clinical Medicine: Therapeutics.
  • American Society of Clinical Oncology: 2013 Use of Pharmacologic Interventions for Breast Cancer Risk Clinical Practice Guideline. Journal of Clinical Oncology 2013.49.3122   
  • NPS MedicineWise. Pharmacogenetics in Psychiatry – Promising But Not Yet Proven. Published in Health News and Evidence July 3, 2013.
  • National Comprehensive Cancer Network (NCCN) Breast Cancer Reduction Version 1.2017.
  • ECRI Genetic Testing Hotline Response. Pharmacogenetic Testing to Guide Treatment of Chronic Pain, Published March 2015.
  • Hou X, Shi J, Sun H. Gene polymorphism of cytochrome P450 2C19*2 and clopidogrel resistance reflected by platelet function assays: a meta-analysis. Eur J Clin Pharmacol. Sep 2014;70(9):1041-1047. PMID 24996381
  • Osnabrugge RL, Head SJ, Zijlstra F, et al. A systematic review and critical assessment of 11 discordant metaanalyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users. Genet Med. Jan 2015;17(1):3-11. PMID 24946154
  • Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011;343:d4588. PMID 21816733
  • Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. Dec 28 2011;306(24):2704-2714. PMID 22203539
  • Mao L, Jian C, Changzhi L, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. Oct 2013;106(10):517-527. PMID 24080325
  • Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. May 5 2012;379(9827):1705-1711. PMID 22464343
  • Desai NR, Canestaro WJ, Kyrychenko P, et al. Impact of CYP2C19 genetic testing on provider prescribing patterns for antiplatelet therapy after acute coronary syndromes and percutaneous coronary intervention. Circ Cardiovasc Qual Outcomes. Nov 2013;6(6):694-699. PMID 24192573
  • Hodgson K, Tansey K, Dernovsek MZ, et al. Genetic differences in cytochrome P450 enzymes and antidepressant treatment response. J Psychopharmacol. Feb 2014;28(2):133-141. PMID 24257813
  • Chang M, Tybring G, Dahl ML, et al. Impact of Cytochrome P450 2C19 Polymorphisms on Citalopram/Escitalopram Exposure: A Systematic Review and Meta-Analysis. Clin Pharmacokinet. Sep 2014;53(9):801-811. PMID 25154506
  • Waade RB, Hermann M, Moe HL, et al. Impact of age on serum concentrations of venlafaxine and escitalopram in different CYP2D6 and CYP2C19 genotype subgroups. Eur J Clin Pharmacol. Aug 2014;70(8):933-940. PMID 24858822
  • de Vos A, van der Weide J, Loovers HM. Association between CYP2C19*17 and metabolism of amitriptyline, citalopram and clomipramine in Dutch hospitalized patients. Pharmacogenomics J. Oct 2011;11(5):359-367. PMID 20531370
  • Jornil J, Jensen KG, Larsen F, et al. Risk assessment of accidental nortriptyline poisoning: the importance of cytochrome P450 for nortriptyline elimination investigated using a population-based pharmacokinetic simulator. Eur J Pharm Sci. Oct 9 2011;44(3):265-272. PMID 21854846
  • Jovanovic N, Bozina N, Lovric M, et al. The role of CYP2D6 and ABCB1 pharmacogenetics in drug-naïve patients with first-episode schizophrenia treated with risperidone. Eur J Clin Pharmacol. Nov 2010;66(11):1109-1117. PMID 20563569
  • Almoguera B, Riveiro-Alvarez R, Lopez-Castroman J, et al. CYP2D6 poor metabolizer status might be associated with better response to risperidone treatment. Pharmacogenet Genomics. Nov 2013;23(11):627-630. PMID 24026091
  • van der Weide K, van der Weide J. The Influence of the CYP3A4*22 Polymorphism and CYP2D6 Polymorphisms on Serum Concentrations of Aripiprazole, Haloperidol, Pimozide, and Risperidone in Psychiatric Patients. J Clin Psychopharmacol. Jun 2015;35(3):228-236. PMID 25868121
  • Ciccacci C, Di Fusco D, Marazzi MC, et al. Association between CYP2B6 polymorphisms and Nevirapineinduced SJS/TEN: a pharmacogenetics study. Eur J Clin Pharmacol. Nov 2013;69(11):1909-1916. PMID 23774940
  • Oluka MN, Okalebo FA, Guantai AN, et al. Cytochrome P450 2B6 genetic variants are associated with plasma nevirapine levels and clinical response in HIV-1 infected Kenyan women: a prospective cohort study. AIDS Res Ther. 2015;12:10. PMID 25878720
  • Lu Y, Fuchs EJ, Hendrix CW, et al. Cytochrome P450 3A5 Genotype Impacts Maraviroc Concentrations in Healthy Volunteers. Drug Metab Dispos. Aug 12 2014. PMID 25117426
  • Lesche D, Sigurdardottir V, Setoud R, et al. CYP3A5*3 and POR*28 genetic variants influence the required dose of tacrolimus in heart transplant recipients. Ther Drug Monit. Dec 2014;36(6):710-715. PMID 24739669
  • Rojas L, Neumann I, Herrero MJ, et al. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. Pharmacogenomics J. Feb 2015;15(1):38-48. PMID 25201288
  • Han N, Yun HY, Hong JY, et al. Prediction of the tacrolimus population pharmacokinetic parameters according to CYP3A5 genotype and clinical factors using NONMEM in adult kidney transplant recipients. Eur J Clin Pharmacol. Jan 2013;69(1):53-63. PMID 22660440
  • Boughton O, Borgulya G, Cecconi M, et al. A published pharmacogenetic algorithm was poorly predictive of tacrolimus clearance in an independent cohort of renal transplant recipients. Br J Clin Pharmacol. Sep 2013;76(3):425-431. PMID 23305195
  • Xue L, Zhang WW, Ding XL, et al. Population pharmacokinetics and individualized dosage prediction of cyclosporine in allogeneic hematopoietic stem cell transplant patients. Am J Med Sci. Dec 2014;348(6):448-454. PMID 25247760
  • Batty JA, Hall AS, White HL, et al. An investigation of CYP2D6 genotype and response to metoprolol CR/XL during dose titration in patients with heart failure: a MERIT-HF substudy. Clin Pharmacol Ther. Mar 2014;95(3):321-330. PMID 24193112
  • Holmes DR, Jr., Dehmer GJ, Kaul S, et al. ACCF/AHA clopidogrel clinical alert: approaches to the FDA "boxed warning": a report of the American College of Cardiology Foundation Task Force on clinical expert consensus documents and the American Heart Association endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol. Jul 20 2010;56(4):321-341. PMID 20633831
  • FDA Center for Drug Evaluation and Research. Summary Review for Regulatory Action: Cerdelga/eliglustat tartrate. 2014
  • FDA. Highlights of Prescribing Information: Xenazine (tetrabenazine). 2015
  • UpToDate. Gaucher Disease: Treatment. Derralynn Hughes, M.D., Topic last updated July 13, 2015.
  • Cerdelga (eliglustat).
  • Seeringer A, Kirchheiner J. Pharmacogenetics-guided dose modifications of antidepressants. Clin Lab Med. Dec 2008;28(4):619-626. PMID 19059066
  • Frere C, Cuisset T, Morange PE, et al. Effect of cytochrome p450 polymorphisms on platelet reactivity after treatment with clopidogrel in acute coronary syndrome. Am J Cardiol. Apr 15 2008;101(8):1088-1093. PMID 18394438
  • Aleil B, Jacquemin L, De Poli F, et al. Clopidogrel 150 mg/day to overcome low responsiveness in patients undergoing elective percutaneous coronary intervention: results from the VASP-02 (Vasodilator-Stimulated Phosphoprotein-02) randomized study. JACC Cardiovasc Interv. Dec 2008;1(6):631-638. PMID 19463377
  • Gladding P, Webster M, Zeng I, et al. The pharmacogenetics and pharmacodynamics of clopidogrel response: an analysis from the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv. Dec 2008;1(6):620-627. PMID 19463375
  • Gladding P, Webster M, Zeng I, et al. The antiplatelet effect of higher loading and maintenance dose regimens of clopidogrel: the PRINC (Plavix Response in Coronary Intervention) trial. JACC Cardiovasc Interv. Dec 2008;1(6):612-619. PMID 19463374
  • Gurbel PA, Antonino MJ, Bliden KP, et al. Platelet reactivity to adenosine diphosphate and long-term ischemic event occurrence following percutaneous coronary intervention: a potential antiplatelet therapeutic target. Platelets. Dec 2008;19(8):595-604 PMID 19012177
  • Hou X, Shi J, Sun H. Gene polymorphism of cytochrome P450 2C19*2 and clopidogrel resistance reflected by platelet function assays: a meta-analysis. Eur J Clin Pharmacol. Sep 2014;70(9):1041-1047. PMID 24996381
  • Gladding P, Webster M, Ormiston J, et al. Antiplatelet drug nonresponsiveness. Am Heart J. Apr 2008;155(4):591-599. PMID 18371464
  • Simon T, Verstuyft C, Mary-Krause M, et al. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. Jan 22 2009;360(4):363-375. PMID 19106083
  • Mega JL, Close SL, Wiviott SD, et al. Cytochrome p-450 polymorphisms and response to clopidogrel. N Engl J Med. Jan 22 2009;360(4):354-362. PMID 19106084
  • Collet JP, Hulot JS, Pena A, et al. Cytochrome P450 2C19 polymorphism in young patients treated with clopidogrel after myocardial infarction: a cohort study. Lancet. Jan 24 2009;373(9660):309-317. PMID 19108880
  • Shuldiner AR, O'Connell JR, Bliden KP, et al. Association of cytochrome P450 2C19 genotype with the antiplatelet effect and clinical efficacy of clopidogrel therapy. JAMA. Aug 26 2009;302(8):849-857. PMID 19706858
  • Sibbing D, Stegherr J, Latz W, et al. Cytochrome P450 2C19 loss-of-function polymorphism and stent thrombosis following percutaneous coronary intervention. Eur Heart J. Apr 2009;30(8):916-922. PMID 19193675
  • Sibbing D, Koch W, Gebhard D, et al. Cytochrome 2C19*17 allelic variant, platelet aggregation, bleeding events, and stent thrombosis in clopidogrel-treated patients with coronary stent placement. Circulation. Feb 2 2010;121(4):512-518. PMID 20083681
  • Tiroch KA, Sibbing D, Koch W, et al. Protective effect of the CYP2C19 *17 polymorphism with increased activation of clopidogrel on cardiovascular events. Am Heart J. Sep 2010;160(3):506-512. PMID 20826260
  • Pare G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. Oct 28 2010;363(18):1704-1714. PMID 20979470
  • Osnabrugge RL, Head SJ, Zijlstra F, et al. A systematic review and critical assessment of 11 discordant meta-analyses on reduced-function CYP2C19 genotype and risk of adverse clinical outcomes in clopidogrel users. Genet Med. Jan 2015;17(1):3-11. PMID 24946154
  • Bauer T, Bouman HJ, van Werkum JW, et al. Impact of CYP2C19 variant genotypes on clinical efficacy of antiplatelet treatment with clopidogrel: systematic review and meta-analysis. BMJ. 2011;343:d4588. PMID 21816733
  • Holmes MV, Perel P, Shah T, et al. CYP2C19 genotype, clopidogrel metabolism, platelet function, and cardiovascular events: a systematic review and meta-analysis. JAMA. Dec 28 2011;306(24):2704-2714. PMID 22203539
  • Mao L, Jian C, Changzhi L, et al. Cytochrome CYP2C19 polymorphism and risk of adverse clinical events in clopidogrel-treated patients: a meta-analysis based on 23,035 subjects. Arch Cardiovasc Dis. Oct 2013;106(10):517-527. PMID 24080325
  • Roberts JD, Wells GA, Le May MR, et al. Point-of-care genetic testing for personalisation of antiplatelet treatment (RAPID GENE): a prospective, randomised, proof-of-concept trial. Lancet. May 5 2012;379(9827):1705-1711. PMID 22464343
  • Desai NR, Canestaro WJ, Kyrychenko P, et al. Impact of CYP2C19 genetic testing on provider prescribing patterns for antiplatelet therapy after acute coronary syndromes and percutaneous coronary intervention. Circ Cardiovasc Qual Outcomes. Nov 2013;6(6):694-699. PMID 24192573
  • Bennett LL, Turcotte K. Eliglustat tartrate for the treatment of adults with type 1 Gaucher disease. Drug Des Devel Ther. 2015;9:4639-4647. PMID 26345314
  • UpToDate. Personalized Medicine. Benjamin A. Raby M.D., MPH. Topic last updated April 19, 2017.
  • UpToDate. Mechanisms of Action of Selective Estrogen Receptor Modulators and Down Regulators. Suzanne A.W. Fuqua PhD, Rachel Schiff PhD. Topic last updated October 24, 2016.
  • UpToDate. Selective Serotonin Reuptake Inhibitors: Pharmacology, Administration and Side Effects. Michael Hirsch M.D., Robert J. Birnbaum M.D., PhD. Topic last updated August 22, 2016.
  • Serontonin-Norepinephrine Reuptake Inhibitors (SNRIs): Pharmacology, Administration, and Side Effects. Craig Nelson M.D., Topic last updated April 4, 2016.

 

Policy History:

  • July 2017 - Annual Review, Policy Revised
  • July 2016 - Annual Review, Policy Revised
  • August 2015 - Annual Review, Policy Revised
  • September 2014 - Annual Review, Policy Revised
  • October 2013 - New Policy

Wellmark medical policies address the complex issue of technology assessment of new and emerging treatments, devices, drugs, etc.   They are developed to assist in administering plan benefits and constitute neither offers of coverage nor medical advice. Wellmark medical policies contain only a partial, general description of plan or program benefits and do not constitute a contract. Wellmark does not provide health care services and, therefore, cannot guarantee any results or outcomes. Participating providers are independent contractors in private practice and are neither employees nor agents of Wellmark or its affiliates. Treating providers are solely responsible for medical advice and treatment of members. Our medical policies may be updated and therefore are subject to change without notice.

 

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