Genotype testing for polymorphisms can identify variants of specific genes associated with abnormal and normal drug metabolism.  This document addresses the use of such testing, based on the theory that individuals with certain gene variants may potentially be able to receive higher or lower doses of some drugs to improve the likelihood of achieving clinical goals as well as lessening the risk of adverse drug effects.

Medically Necessary: 

Genotype testing for genetic polymorphisms of Human Leukocyte Antigen B*1502 (HLAB*1502) to determine the drug-metabolizer status of individuals for whom the use of carbamazepine is being proposed is considered medically necessary when the criteria below have been met:

1. The individual is of Asian descent; and
2. There are no other alternatives to the use of carbamazepine. 

Genotype testing for identification of the CYP2C19 variant of Cytochrome P450 to determine the drug-metabolizer status of individuals: a) who are currently undergoing treatment with clopidogrel and have not been tested, or b) for whom the use of clopidogrel is being proposed, is considered medically necessary.

Investigational and Not Medically Necessary: 

Genotype testing for genetic polymorphisms to determine drug-metabolizer status is considered investigational and not medically necessary in all other circumstances, including but not limited to:

1. Individuals initiating therapy with the following drugs:
   • 5-fluorouracil (5-FU); or
   • Antidepressants or antipsychotics; or
   • Irinotecan; or
   • Phenytoin; or
   • Tamoxifen; or
   • Warfarin; or
2. Analysis of the following enzymes:
   • Cytochrome P450 (including CYP2C9) [except where noted above]; or
   • Dihydropyrimidine dehydrogenase (DPYD); or
   • Leukocyte Antigen B*1502 (HLAB*1502) [except where noted above]; or
   • Thymidylate synthetase (TYMS); or
   • Uridine diphosphate glucuronosyltransfrease 1A1 (UGT1A1); or
   • Vitamin K epoxide reductase subunit C1 (VKORC1).

Current evidence regarding the use of genotyping tests for the determination of drug metabolizer status indicates that while available testing methods may accurately identify genetic variations in an individual, there is insufficient data to demonstrate that such testing, and the clinical decisions made based on the testing, results in a significant impact on health outcomes.  Specifically, clinical trials have not yet adequately demonstrated that such testing results in either enhanced clinical effectiveness, or in decreased short-term or long-term serious adverse events.

Critical elements of assessing the effectiveness of such genetic tests include: 1) analytic (diagnostic) validity, 2) clinical validity, and 3) clinical utility.  Analytic validity measures the technical performance of the test, in terms of accurately identifying the genetic markers to be measured.  Clinical validity measures the strength of association between genetic test results and clinical parameters such as dose, therapeutic efficacy, or adverse events.  Clinical utility, the ultimate goal of genetic testing, measures the ability of the test to improve clinical outcomes, such as whether prescribing or dosing based on information from genetic testing improves therapeutic efficacy or adverse event rate as compared with treatment without genetic testing.

Therefore, when considering whether or not a test to determine drug metabolizer status is appropriate in the treatment of individuals prescribed certain medications, specific issues need to be evaluated, including:

• A specific mutation, or set of mutations, has been established in the scientific literature to be reliably associated with drug metabolism status; AND
• A biochemical or other non-genetic test is identified but the results are indeterminate, or the genetic status cannot be identified through such biochemical or other non-genetic testing; AND
• The results of the genetic test could impact the medical management of the individual with a resulting improvement in health outcomes.

There has been investigation into the role of HLAB*1502 mutations in the occurrence of toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome in ethnic Han Chinese individuals receiving treatment with the anticonvulsant drug carbamazepine.  A molecular study by Hung et al. (2006) identified this genetic variation as a contributor to this reaction.  Based on data reviewed by an expert panel, the FDA decided to place a black-box warning on the label of carbamazepine as follows:

Serious and sometimes fatal dermatologic reactions, including toxic epidermal necrolysis (TEN) and Stevens-Johnson syndrome (SJS), have been reported during treatment with carbamazepine. These reactions are estimated to occur in 1 to 6 per 10,000 new users in countries with mainly Caucasian populations, but the risk in some Asian countries is estimated to be about 10 times higher. Studies in patients of Chinese ancestry have found a strong association between the risk of developing SJS/TEN and the presence of HLA-B*1502, an inherited allelic variant of the HLA-B gene. HLA-B*1502 is found almost exclusively in patients with ancestry across broad areas of Asia. Individuals with ancestry in genetically at risk populations should be screened for the presence of HLA-B*1502 prior to initiating treatment with carbamazepine. Patients testing positive for the allele should not be treated with tegretol unless the benefit clearly outweighs the risk.

Chen and colleagues conducted a study of 4877 carbamazepine-naive subjects who were genotyped for the HLA-B*1502 allele (2001).  B*1502 allele-positive subjects were given an alternative medication while negative patients were treated with carbamazepine.  The authors then compared the incidence of SJS and TEN in the study population to historical controls.  Results demonstrated that a mild, transient rash developed in 4.3% of B*1502 positive subjects; more widespread rash developed in 0.1% of subjects, who were hospitalized.  SJS–TEN did not develop in any of the HLA-B*1502–negative subjects receiving carbamazepine.  In contrast, the estimated historical incidence of carbamazepine-induced SJS–TEN (0.23%) would translate into approximately 10 cases among study subjects (P<0.001).

Other genetic mutations have also been investigated as having clinical impact on the outcomes of individuals who may undergo treatment with carbamazepine.  McCormack and others described a study investigating the association of the HLA-A*3101 allele and the incidence of carbamazepine-related complications (2011).  This study included 65 subjects who had experienced carbamazepine-related complications and 3987 control subjects.  An independent genome-wide association study demonstrated a significant association between subjects with the HLA-A*3101 allele and the incidence of carbamazepine-induced hypersensitivity reactions among subjects of Northern European ancestry.  Further study is warranted to understand the impact of genetic testing on the rate of occurrence of complications in subjects carrying the HLA-A*3101 allele.

Recent focus has been placed on the impact of drug metabolizer status testing for individuals prescribed clopidogrel.  Several published non-randomized controlled studies addressed the use of testing for genetic variants in CYP4502C19, ABCB1, CYP2A5, and P2RY12 (Collet, 2009; Mega, 2009; Simon, 2009).  These studies found that mutations in these genes, especially CYP2C19 variants, have significant effects on cardiovascular health outcomes.  Mega and colleagues conducted a study addressing the impact of CYP-450 gene variants on clinical response to clopidogrel treatment (2009).  This study included 162 healthy subjects and 1477 subjects with acute coronary disease being treated with clopidogrel.  Carriers of at least one CYP2C19 allele had a 32.4% reduction in the active metabolite of clopidogrel, a 9% decrease in maximal platelet aggregation response, and 300% increase in the risk of stent thrombosis, and relative increase of 53% in the composite primary efficacy outcome of the risk of death from cardiovascular causes, myocardial infarction, or stroke, as compared with noncarriers.

A study by Simon and others enrolled 2208 subjects with acute MI who were receiving clopidogrel therapy (2009).  The authors reported a significantly increased risk of adverse cardiovascular events in individuals with CYP2C19 variants when compared to those with no mutations (21.5% vs. 13.3%).  Among the 1535 participants who also underwent percutaneous coronary intervention during hospitalization, the rate of cardiovascular events among individuals with two CYP2C19 loss-of-function alleles was 3.58 times the rate among those with none.

In March 2010 the U.S. FDA announced that it was requiring a black-box warning on the label of clopidogrel that addresses the use of pharmacogenetic testing. The warning has four specific points:

• Effectiveness of Plavix depends on activation to an active metabolite by the cytochrome P450 (CYP) system, principally CYP2C19.
• Poor metabolizers treated with Plavix at recommended doses exhibit higher cardiovascular event rates following acute coronary syndrome (ACS) or percutaneous coronary intervention (PCI) than patients with normal CYP2C19 function. 
• Tests are available to identify a patient's CYP2C19 genotype and can be used as an aid in determining therapeutic strategy.
• Consider alternative treatment or treatment strategies in patients identified as CYP2C19 poor metabolizers.

Mega and colleagues published the findings of a large meta-analysis conducted in 2010.  This report included 9685 subjects who were treated with clopidogrel in 9 studies.  The findings included that subjects with one or two loss-of-function CYP2C19 alleles had a significantly increased risk of composite end-point events (HR 1.55, p=0.01; HR 1.76, p= 0.002, respectively.)  Additionally, these subjects had an increased risk of stent thrombosis when compared to non-carriers of loss-of-function alleles.

The results of two large placebo-controlled randomized controlled trials (RCTs) were published by Pare et al.  The two studies included a total of 5059 subjects randomized to receive either clopidogrel or placebo and followed for the occurrence of primary and secondary composite outcomes.  The authors concluded that "no significant difference in the effect of clopidogrel treatment on clinical outcomes was observed when patients were stratified according to metabolizer status."  However, some increase in efficacy was seen in subjects with gain-of-function alleles in terms of reduced ischemic events.

Perhaps the most studied area regarding the use of genotype polymorphism testing involves genetic variations in enzymes key to the metabolism and operation of the drug warfarin.  A significant amount of evidence has shown that the enzymes cytochrome P450 2C9 (CYP2C9) and vitamin K epoxide reductase enzyme subunit C1 (VKORC1) have the most significant role in warfarin metabolic variability (Higashi, 2002; Kirchheiner, 2005; Osman, 2006; Sconce, 2005.)  Some reports attribute approximately 55% of warfarin dose variability to these two variants (Wadelius, 2005; Sconce, 2005.)

A report published by McClain and colleagues, conducted for the American College of Medical Genetics (ACMG, 2007), evaluated the use of CYP4502C9 (CYP2C9) and VKORC1 testing of individuals receiving warfarin due to increased risk of thrombotic events.  The authors concluded the following:

• Analytic validity: Nearly all available data for analytic validity refer to two variants in the CYP2C9 gene; fewer data are available for the variants in the VKORC1 gene. Based on these data, analytic sensitivity and specificity are likely near 100%. Depending on methodology, 1% to 10% of samples may experience repeated assay failures resulting in inconclusive test results.
• Clinical validity: CYP2C9 and VKORC1 genotypes contribute significant and independent information to the stable warfarin dose and compared to the most common combination, some individuals with other genotype combinations will need more than the usual dose, while others would require less. Time to steady state warfarin levels varies by CYP2C9 genotype (3 to 5 days vs. 5 to 8 vs. 12 to 15 for the three most common genotypes). CYP2C9 positive predictive value (PPV) for serious bleeding events is estimated to be 7%; the negative predictive value (NPV) is 96%. Similar information for VKORC1 was not available.
• Clinical utility: The purpose of genetic testing in this clinical scenario is to predict an individual's likely stable warfarin dose by incorporating demographic, clinical, and genotype data (CYP2C9 and VKORC1), and initiating warfarin at that predicted dose as a way to limit high INR (International Normalized Ratio) values (over-anticoagulation) leading to an increased risk of serious bleeding events. No large study has yet confirmed such utility, although several randomized trials are currently underway

Caraco and colleagues (2007) describe a randomized controlled trial evaluating CYP2C9-guided warfarin therapy.  This study included 191 participants (n=96 controls, n=95 in the experimental groups) prescribed warfarin therapy.  While this study did find significant benefits in some secondary outcomes, such as time to stable dosing, more time spent in therapeutic range, and lower rates of minor bleeding, the small study population did not permit assessment of significant differences in serious bleeding, thrombotic events, major morbidity or mortality.  The authors state that further research is warranted.

A study by Anderson and colleagues (2007) indicates some promise for the use of genetic polymorphism testing for individuals receiving warfarin therapy.  In their randomized blinded study of 206 participants, the investigators compared pharmacogenetic-guided therapy vs. standard dosing methodology.  While the results indicated that the pharmacogenetic-guided therapy more closely approximated stable doses, resulting in significantly smaller and fewer dosing changes, the primary endpoint of reducing out-of-range INRs was not significantly different.  However, in a post-hoc subset analysis, the authors reported that in wild-type individuals and those with multiple variant carriers the differences were significant between groups.  These authors also indicate that additional research is warranted based upon their findings.

In February 2009 the International Warfarin Pharmacogenetics Consortium published a study that describes the development and modeling of two warfarin therapy algorithms that aid in the prediction of the ideal therapeutic dose.  The first algorithm uses both clinical and pharmacogenetic information from a retrospective cohort of 4043 individuals (2009).  The second algorithm uses the same population and methodology, excluding the pharmacogenetic data.  Using data from a separate retrospective cohort of 1009 individuals, the consortium created a model testing the use of these two algorithms against a standard fixed treatment approach of 5 mg warfarin/day.  While this study is of interest, it is only a model and does not provide real-world clinical results.  As has been discussed earlier, clinical validity data is needed for the proper evaluation of the clinical role of pharmacogenetic testing methods.  This report does not provide data on adverse events such as thromboembolic events or bleeding.  The next step is to see how this algorithm functions in a clinical setting with outcomes data reported.

In early 2008, based upon the information provided above, the ACMG published a position statement regarding the use of CYP2C9 and VKORC1 testing, which concluded:

The group determined that the analytical validity of these tests has been met, and there is strong evidence to support association between these genetic variants and therapeutic dose of warfarin. However, there is insufficient evidence, at this time, to recommend for or against routine CYP2C9 and VKORC1 testing in warfarin-naive patients. Prospective clinical trials are needed that provide direct evidence of the benefits, disadvantages, and costs associated with this testing in the setting of initial warfarin dosing…  Although the routine use of warfarin genotyping is not endorsed by this work group at this time, in certain situations, CYP2C9 and VKORC1 testing may be useful, and warranted, in determining the cause of unusual therapeutic responses to warfarin therapy.

However, selection criteria or specific algorithms were not described based upon clinical study evidence.

The Agency for Healthcare Research and Quality (AHRQ) published a technology assessment addressing the use of pharmacogenetic testing for warfarin and statin therapy (2008).  In this assessment it evaluated the available evidence regarding the clinical impact and outcomes related to the use of pharmacogenetic testing for variants of CYP2C9, VKORC1, and MTHFR.  The report concludes:

Overall, studies evaluating associations between the pharmacogenetic test results and the patient's response to therapy for non-cancer and cancer conditions showed considerable variation in study designs, study populations, medication dosages, and the type of medications. This variation warrants caution when interpreting our results. Data on the relationships among pharmacogenetic test results and patient- and disease-related factors and on the patient's response to therapy are limited. We found no data on the benefits, harms, or adverse effects from subsequent therapeutic management after pharmacogenetic testing. Detailed patient-level analyses are needed to adjust estimates for the effects of modifiers, such as age or tumor stage.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group published its recommendations regarding the use of UGT1A1 testing for individuals undergoing treatment with irinotecan (2009).  This paper concluded, "the evidence is currently insufficient to recommend for or against the routine use of UGT1A1 genotyping in patients with metastatic colorectal cancer who are to be treated with irinotecan, with the intent of modifying the dose as a way to avoid adverse drug reactions (severe neutropenia)."

Testing for genetic polymorphisms has also been proposed for a wide array of other drugs, involving many different conditions and enzymes.  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 health care professionals delineating the most effective courses of action based on such genotype testing results.  

Drug efficacy and toxicity vary substantially between 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.  It has been found that inherited DNA sequence variation (polymorphisms) in genes for drug-metabolizing enzymes may have a significant effect on the efficacy or toxicity of a drug.  This field of research is referred to as pharmacogenomics. 

It has been proposed that genotype testing for certain genes to detect polymorphisms will allow physicians to predict side effects to drugs and to tailor a drug regimen based on an individual's genetic make-up.  It may be that genotype testing will improve the choice of drug, or the dose of the drug, when the drug in question has a narrow therapeutic dose range, when the consequences of treatment failure are severe, and/or when serious adverse reactions are more likely in individuals with certain polymorphisms. 

One of the drugs where this approach has been most extensively investigated is for the anticoagulant drug warfarin.  This is because the most appropriate dose of warfarin for an individual varies widely, and individuals must be periodically monitored to ensure that a proper level of anticoagulation is maintained.  Warfarin is primarily metabolized by the enzymes in the CYP450 family, and is heavily impacted by the activity of vitamin K epoxide reductase.  Determination of polymorphisms of these genes has been proposed as an aid to help physicians tailor anticoagulant therapy.

The impact of polymorphisms has been the focus of study with a wide variety of drugs and for many diseases and conditions.  The use of this type of science is just starting to be investigated, and its impact on actual medical practice is not yet fully understood.

Cytochrome P450:  Refers to a family of 60 different enzymes involved in drug and toxin metabolism.

Genotype testing:  Determining the DNA sequence in genes.

Metabolize:  Refers to breaking down a drug so that it is no longer clinically active.

Polymorphisms:  Refers to genetic variation between individuals resulting in differences in gene expression, in this case differing activity of various enzymes.

Uridine diphosphate glucuronosyltransfrease 1A1 (UGT1A1): An enzyme that is involved in drug metabolism. 

Vitamin K epoxide reductase subunit C1 (VKORC1): An enzyme involved with the metabolism of vitamin K; its C1 subunit (VKORC1) is the target of the anticoagulant warfarin.

Warfarin:  A commonly prescribed anticoagulant, i.e., blood thinner.

The following codes for treatments and procedures applicable to this document are included below for informational purposes.  Inclusion or exclusion of a procedure, diagnosis or device code(s) does not constitute or imply member coverage or provider reimbursement policy.  Please refer to the member's contract benefits in effect at the time of service to determine coverage or non-coverage of these services as it applies to an individual member. 

When Services may be Medically Necessary when criteria are met: 

When Services may also be Medically Necessary when criteria are met: 

When Services are Investigational and Not Medically Necessary:
For the procedure codes listed above when criteria are not met, or when the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary.

When Services are Investigational and Not Medically Necessary: 

When Services are also Investigational and Not Medically Necessary:
When the code describes a procedure indicated in the Position Statement section as investigational and not medically necessary. 

Future ICD-10 coding (effective 10/01/2013)
A draft of ICD-10 Coding related to this document, as it might look today, is available for reference and comments at: Appendix 1: Future ICD-10 coding

Peer Reviewed Publications:

1. Aithal GP, Day CP, Kesteven PJ, Daly AK. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications.  Lancet. 1999; 353(9154):717-719.
2. Anderson JL, Horne BD, Stevens SM, et al.; Couma-Gen Investigators. Randomized trial of genotype-guided versus standard warfarin dosing in patients initiating oral anticoagulation. Circulation. 2007; 116(22):2563-2570.
3. Caldwell MD, Berg RL, Zhang KQ, et al. Evaluation of genetic factors for warfarin dose prediction. Clin Med Res. 2007; 5(1):8-16.
4. Caraco Y, Blotnick S, Muszkat M. CYP2C9 genotype-guided warfarin prescribing enhances the efficacy and safety of anticoagulation: a prospective randomized controlled study. Clin Pharmacol Ther. 2008; 83(3):460-470.
5. Carlquist JF, Horne BD, Muhlestein JB, et al. Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. J Thromb Thrombolysis. 2006; 22(3):191-197.
6. Chen P, Lin J,  Lu CS, et al. Carbamazepine-induced toxic effects and HLA-B*1502 screening in Taiwan. N Engl J Med. 2011; 364(12):1126-1133.
7. 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. 2009; 373(9660):276-278.
8. Gage BF, Eby C, Milligan PE, et al.  Use of pharmacogenomics and clinical factors to predict the maintenance of dose of warfarin.  Thromb Haemost 2004; 91(1):86-94.
9. Goetz MP, Rae JM, Suman VJ, et al. Pharmacogenetics of tamoxifen biotransformation is associated with clinical outcomes of efficacy and hot flashes. J Clin Oncol. 2005; 23(36):9312-9318.
10. Han JY, Lim HS, Shin ES, et al.  Comprehensive analysis of UGT1A polymorphisms predictive for pharmacokinetics and treatment outcome in patients with non-small-cell lung cancer treated with irinotecan and cisplatin. J Clin Oncol. 2006; 24(15):2237-2244.
11. Herman D, Peternel P, Stegnar M, et al. The influence of sequence variations in factor VII, gamma-glutamyl carboxylase and vitamin K epoxide reductase complex genes on warfarin dose requirement. Thromb Haemost. 2006; 95(5):782-787.
12. Higashi MK, Veenstra DL, Kondo LM, et al.  Association between CYP2C9 genetic variants and anticoagulation-related outcomes during warfarin therapy.  JAMA. 2002; 287(13):1690-1698.
13. Higgins MJ, Rae JM, Flockhart DA, et al. Pharmacogenetics of tamoxifen: who should undergo CYP2D6 genetic testing? J Natl Compr Canc Netw. 2009; 7(2):203-213.
14. Hung SI, Chung WH, Jee SH, et al. Genetic susceptibility to carbamazepine-induced cutaneous adverse drug reactions. Pharmacogenet Genomics. 2006; 16(4):297-306.
15. Ingelman-Sundberg M. Genetic polymorphisms of cytochrome P450 2D6 (CYP2D6): clinical consequences, evolutionary aspects and functional diversity. Pharmacogenomics J. 2005; 5(1):6-13.
16. Innocenti F, Undevia SD, Iyer L, et al.  Genetic variants in the UDP-glucuronosyltransferase 1A1 gene predict the risk of severe neutropenia of irinotecan. J Clin Oncol. 2004; 22(8):1382-1388.
17. International Warfarin Pharmocogenetics Consortium. Estimation of the warfarin dose with clinical and pharmacogenetic data. N Engl J Med. 2009; 360(8):753-764.
18. Ismail R, Teh LK. The relevance of CYP2D6 genetic polymorphism on chronic metoprolol therapy in cardiovascular patients. J Clin Pharm Ther. 2006; 31(1):99-109.
19. Joffe HV, Xu R, Johnson FB, et al.  Warfarin dosing and cytochrome P450 2C9 polymorphisms.  Thromb Haemost. 2004; 91(6):1123-1128.
20. Kirchheiner J, Brockmoller J. Clinical consequences of cytochrome P450 2C9 polymorphisms. Clin Pharmacol Ther. 2005; 77(1):1-16.
21. Margaglione M, Colaizzo D, Andrea G, et al.  Genetic modulation of oral anticoagulation with warfarin.  Thromb Haemost. 2000; 84(5):775-778.
22. McCormack M, Alfirevic A, Bourgeois S, et al. HLA-A*3101 and carbamazepine-induced hypersensitivity reactions in Europeans.  N Engl J Med. 2011; 364(12):1134-1143.
23.  Mega JL, Close SL, Wiviott SD, et al. Cytochrome P-450 polymorphisms and response to clopidogrel. N Engl J Med. 2009; 360(4):354-362.
24. Mega JL, Simon T, Collet JP, et al. Reduced-function CYP2C19 genotype and risk of adverse clinical outcomes among patients treated with clopidogrel predominantly for PCI: a meta-analysis. JAMA. 2010; 304(16):1821-1830.  
25. Millican EA, Lenzini PA, Milligan PE, et al. Genetic-based dosing in orthopedic patients beginning warfarin therapy. Blood. 2007; 110(5):1511-1515.
26. Muszkat M, Blotnik S, Elami A, et al. Warfarin metabolism and anticoagulant effect: a prospective, observational study of the impact of CYP2C9 genetic polymorphism in the presence of drug-disease and drug-drug interactions. Clin Ther. 2007; 29(3):427-437.
27. Osman A, Enström C, Arbring K, et al. Main haplotypes and mutational analysis of vitamin K epoxide reductase (VKORC1) in a Swedish population: a retrospective analysis of case records. J Thromb Haemost. 2006; 4(8):1723-1729.
28. Paré G, Mehta SR, Yusuf S, et al. Effects of CYP2C19 genotype on outcomes of clopidogrel treatment. N Engl J Med. 2010; 363(18):1704-1714.
29. Sanderson S, Emery J, Higgins J. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med. 2005; 7(2):97-104.
30. Schelleman H, Chen Z, Kealey C, et al. Warfarin response and vitamin K epoxide reductase complex 1 in African Americans and Caucasians. Clin Pharmacol Ther. 2007; 81(5):742-747.
31. Schroth W, Goetz MP, Hamann U, et al. Association between CYP2D6 polymorphisms and outcomes among women with early stage breast cancer treated with tamoxifen. JAMA. 2009; 302(13):1429-1436.
32. Sconce EA, Khan TI, Wynne HA, et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood. 2005; 106(7):2329-33.
33. Shams ME, Arneth B, Hiemke C, et al. CYP2D6 polymorphism and clinical effect of the antidepressant venlafaxine. J Clin Pharm Ther. 2006; 31(5):493-502.
34. Simon T, Verstuyft C, Mary-Krause M, et al. The French Registry of Acute ST-Elevation and Non–ST-Elevation Myocardial Infarction (FAST-MI) Investigators. Genetic determinants of response to clopidogrel and cardiovascular events. N Engl J Med. 2009; 360(4):363-375.  
35. Swaisland HC, Cantarini MV, Fuhr R, Holt A. Exploring the relationship between expression of cytochrome P450 enzymes and gefitinib pharmacokinetics. Clin Pharmacokinet. 2006; 45(6):633-644.
36. Tan SH, Lee SC, Goh BC, Wong J. Pharmacogenetics in breast cancer therapy. Clin Cancer Res. 2008; 14(24):8027-8041.
37. Tran A, Jullien V, Alexandre J, et al. Pharmacokinetics and toxicity of docetaxel: role of CYP3A, MDR1, and GST polymorphisms. Clin Pharmacol Ther. 2006; 79(6):570-580.
38. Wadelius M, Chen LY, Downes K, et al. Common VKORC1 and GGCX polymorphisms associated with warfarin dose. Pharmacogenomics J. 2005; 5(4):262-270.
39. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med. 2005; 352 (21):2211-2221.
40. Zhu Y, Shennan M, Reynolds KK, et al. Estimation of warfarin maintenance dose based on VKORC1 (-1639 G>A) and CYP2C9 genotypes. Clin Chem. 2007; 53(7):1199-1205.

Government Agency, Medical Society, and Other Authoritative Publications:

1. Agency for Healthcare Research and Quality. Technology Assessment: Reviews of Selected Pharmacogenetic Tests for Non-Cancer and Cancer Conditions. November 12, 2008.  Available at: http://www.cms.gov/medicare-coverage-database/details/technology-assessments-details.aspx?TAId=61&bc=BAAgAAAAAAAA&. . Accessed on March 18, 2011.
2. Agency for Healthcare Research and Quality (AHRQ). Testing for Cytochrome P450 Polymorphisms in Adults with Non-Psychotic Depression Treated With Selective Serotonin Reuptake Inhibitors (SSRIs). January 2007. Available at: http://www.ahrq.gov/clinic/tp/cyp450tp.htm. Accessed March 19, 2011.
3. Blue Cross Blue Shield Association. TEC Special Report: Genotyping for Cytochrome P450 Polymorphisms to Determine Drug-Metabolizer Status. TEC Assessment. 2004; 19(9).
4. Blue Cross Blue Shield Association. TEC Special Report: Cardiovascular Pharmacogenomics. TEC Assessment. 2007; 22(7).
5. Blue Cross Blue Shield Association. TEC Special Report: Pharmacogenomics of Cancer–Candidate Genes. TEC Assessment. 2007; 22(5).
6. Blue Cross Blue Shield Association. TEC CYP2D6 Pharmacogenomics of Tamoxifen Treatment. TEC Assessment. 2008; 23(1).
7. Centers for Medicare and Medicaid Services National Coverage Determination for Pharmacogenomic Testing for Warfarin Response. NCD #90.1. Effective August 3, 2009.
8. Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Working Group.  Recommendations from the EGAPP Working Group: can UGT1A1 genotyping reduce morbidity and mortality in patients with metastatic colorectal cancer treated with irinotecan? Genet Med. 2009; 11(1):15-20.
9. Flockhart DA, O'Kane D, Williams MS, et al.  ACMG Working Group on Pharmacogenetic Testing of CYP2C9, VKORC1 Alleles for Warfarin Use. Pharmacogenetic testing of CYP2C9 and VKORC1 alleles for warfarin. Genet Med. 2008; 10(2):139-150. Available at: http://www.acmg.net/AM/Template.cfm?Section=Policy_Statements&Template=/CM/HTMLDisplay.cfm&ContentID=3721. Accessed on March 19, 2011.
10. McClain MR, Palomaki GE, Piper M, et al. A rapid ACCE1 review of CYP2C9 and VKORC1 allele testing to inform warfarin dosing in adults at elevated risk for thrombotic events to avoid serious bleeding. August 20, 2007. Available at: http://www.acmg.net/AM/Template.cfm?Section=Home3&Template=/CM/ContentDisplay.cfm&ContentID=2263. Accessed on March 4, 2010.
11. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Breast Cancer (V.2.2011). October 23, 2009. Available at: http://www.nccn.org/professionals/physician_gls/PDF/breast.pdf.  Accessed on March19, 2011.

5-fluorouracil (5-FU)
Adrucil^®
AmpliChip™ Cytochrome P450 (CYP450) Genotype Test
Camptosar^®
Carac^®
Carbatrol^®
Coumadin^®
Cytochrome P450 (CYP450)
Cytochrome P450 2C9 (CYP2C9)
Dilantin^®
Efudex^®
Equetro^®
Fluoroplex^®
Invader^®
Jantoven^®
Nolvadex^®
Plavix^®
Polymorphisms, Drug Testing|
Tegretol^®
TheraGuide 5-FU™
Verigene^® Warfarin Metabolism Nucleic Acid Test
Vitamin K Epoxide Reductase
Vitamin K Epoxide Reductase Subunit C1 (VKORC1)
VKORC1

The use of specific product names is illustrative only.  It is not intended to be a recommendation of one product over another, and is not intended to represent a complete listing of all products available.