Biomarker Label Context Examples of other Drugs Associated with this Biomarker
  Representative Label
 
Drug  
C-KIT expression Gastrointestinal stromal tumor c-Kit expressionIn vitro, imatinib inhibits proliferation and induces apoptosis in gastro-intestinal stromal tumor (GIST) cells, which express an activating c-kit mutation.” “Gleevec is also indicated for the treatment of patients with Kit (CD117) positive unresectable and/or metastatic malignant gastrointestinal stromal tumors (GIST).” Imatinib mesylate  
CCR5 -Chemokine C-C motif receptor CCR5 is a receptor site on the human T-cell that HIV uses to bind to the cell allowing it to enter and begin replication.
 “SELZENTRY, in combination with other antiretroviral agents, is indicated for treatment experienced adult patients infected with only CCR5-tropic HIV-1 detectable, who have evidence of viral replication and HIV-1 strains resistant to multiple antiretroviral agents.”
“SELZENTRY blocks a specific receptor called CCR5 that CCR5-tropic HIV-1 uses to enter CD4 or T-cells in your blood. Your doctor will do a blood test to see if you have been infected with CCR5-tropic HIV-1 before prescribing SELZENTRY for you.” “Pharmacogenomics The impact of CCR5 promoter and coding sequence polymorphisms on the efficacy of maraviroc is being evaluated.”
Maraviroc
 
CYP2C19 Variants Diminished effectiveness in poor metabolizers. 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 precutaneous 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. (Boxed Warning)
CYP2C19 poor metabolizer status is associated with diminished response to Clopidogrel. The optimal dose regimen for poor metabolizers has yet to be determined. (Dosage and Administration-Pharmacogenetics) Based on Literature data, patients with genetically reduced CYP2C19 function have lower systemic exposure to the active metabolite of clopidogrel and diminished antiplatelet responses and generally exhibit higher cardiovascular event rates following myocardial infraction than do patients with normal CYP2C19 function. (Precautions-Pharmacogenetics) CYP2C19 is involved in the formation of both the active metabolite and the 2-oxo-clopidrogrel intermediate metabolite. Clopidrogrel active metabolite pharmacokinetic and antiplatelet effects as measured by ex vivo platelet aggregation assays, differ according to CYP2C19 genotypes. The prevalence of CYP2C19 alleles that result in intermediate and poor CYP2C19 metabolism differs according to race/ethinicity. (Clinical Pharmacology-Pharmacogenetics)
Clopidogrel  
CYP2C19 Variants with alternate context CYP2C19 Variants (Poor Metabolizers-PM and Extensive Metabolizers-EM) with genetic defect leads to change in drug exposure. “In vivo studies indicated that CYP2C19 is significantly involved in the metabolism of voriconazole. This enzyme exhibits genetic polymorphism. For example, 15-20% of Asian populations may be expected to be poor metabolizers. For Caucasians and Blacks, the prevalence of poor metabolizers is 3-5%. Studies conducted in Caucasian and Japanese healthy subjects have shown that poor metabolizers have, on average, 4-fold higher voriconazole exposure (AUCτ) than their homozygous extensive metabolizer counterparts. Subjects who are heterozygous extensive metabolizers have, on average, 2-fold higher voriconazole exposure than their homozygous extensive metabolizer counterparts.” Voriconazole Omeprazole[m1] 
Pantoprazole [m2]  
Esomeprazole[m3]   
diazepam[m4]  
Nelfinavir[m5]   
Rabeprazole[m6] 
CYP2C19 Variants with alternate context (no effect of Variants) 8.9 Metabolic Status In healthy subjects, patients with stable atherosclerosis, and patients with ACS receiving prasugrel, there was no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of prasugrel’s active metabolite or its inhibition of platelet aggregation. (8. Use in Special Populations) There is no relevant effect of genetic variation in CYP2B6, CYP2C9, CYP2C19, or CYP3A5 on the pharmacokinetics of 352 prasugrel’s active metabolite or its inhibition of platelet aggregation. (12 Clinical Pharmacology- 12.5 Pharmacogenomics) Whereas the pharmacokinetics of prasugrel’s active metabolite are not known to be affected by genetic variations in CYP2B6, CYP2C9, CYP2C19, or CYP3A5, the pharmacokinetics of clopidogrel’s active metabolite are affected by CYP2C19 genotype, and approximately 30% of Caucasians are reduced-metabolizers (14 Clinical Studies). Prasugrel  
CYP2C9 Variants CYP2C9 Variants PM and EM genotypes and drug exposure; “Patients who are known or suspected to be P450 2C9 poor metabolizers based on a previous history should be administered celecoxib with caution as they may have abnormally high plasma levels due to reduced metabolic clearance.” Celecoxib  
CYP2C9 Variants with alternate context CYP2C9 Variant genotypes and drug dose “The analysis suggested an increased bleeding risk for patients carrying either the CYP2C9*2 or CYP2C9*3 alleles. Patients carrying at least one copy of the CYP2C9*2 allele required a mean daily warfarin dose that was 17% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele. For patients carrying at least one copy of the CYP2C9*3 allele, the mean daily warfarin dose was 37% less than the mean daily dose for patients homozygous for the CYP2C9*1 allele.” Warfarin  
CYP2D6 Variants CYP2D6 Variants “Atomoxetine is metabolized primarily through the CYP2D6 enzymatic pathway. People with reduced activity in this pathway (PMs) have higher plasma concentrations of atomoxetine compared with people with normal activity (EMs).” Atomoxetine Venlafaxine;[m8] 
Risperidone;[m9] 
Tiotropium  bromide inhalation;[m10] 
Tamoxifen;[m11] 
Timolol Maleate;[m12] 

 
CYP2D6 with alternate context CYP2D6 PM and EM Variants and drug exposure and risk- “population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6. Fluoxetine, like other agents that are metabolized by P450IID6, inhibits the activity of this isoenzyme, and thus may make normal metabolizers resemble "poor metabolizers." Therapy with medications that are predominantly metabolized by the P450IID6 system and that have a relatively narrow therapeutic index should be initiated at the low end of the dose range if a patient is receiving fluoxetine concurrently or has taken it in the previous 5 weeks.” Fluoxetine HCL

Fluoxetine HCL and Olanzapine;[m13] 
Cevimeline hydrochloride[m14] 
Tolterodine;[m15] 
Terbinafine;[m16] 
Tramadol +
   Acetamophen [m17] 
Clozapine[m18] 
Aripiprazole;[m19] 
Metoprolol;[m20] 
Propranolol;[m21] 
Carvedilol[m22] 
Propafenone[m23] 
Thioridazine;[m24] 
Protriptyline HCl;[m25] 

Tetrabenazine [m26]

CYP2D6 (UM) with alternate context 5.9 Ultra-rapid Metabolizers of Codeine
Some individuals may be ultra-rapid metabolizers due to a specific CYP2D6*2x2 genotype. These individuals convert codeine into its active metabolite, morphine, more rapidly and completely than other people. This rapid conversion results in higher than expected serum morphine levels. Even at labeled dosage regimens, individuals who are ultra-rapid metabolizers may experience overdose symptoms such as extreme sleepiness, confusion, or shallow breathing.
The prevalence of this CYP2D6 phenotype varies widely and has been estimated at 0.5 to 1% in Chinese and Japanese, 0.5% to 1% in Hispanics, 1 to 10% in Caucasians, 3% in African Americans, and 16 to 28% in North Africans, Ethiopians, and Arabs. Data are not available for other ethnic groups. (Precautions 5)
When physicians prescribe codeine-containing drugs, they should choose the lowest effective dose for the shortest period of time and inform their patients about these risks and the signs of morphine overdose. [see Use in Specific Populations (8)]
Codeine sulfate

Fiorinal with Codeine (butalbital, aspirin, caffeine, and codeine phosphate)

Fioricet with Codeine (butalbital, acetaminophen, caffeine, and codeine phosphate)

Deletion of Chromosome 5q(del(5q)) Cytogenetic abnormality in management of Low- or Intermediate-1 risk myelodysplastic syndromes -“Lenalidomide is indicated for the treatment of patients with transfusion dependent anemia due to Low- or Intermediate-1-risk myelodysplastic syndromes associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.” Lenalidomide  
DPD Deficiency Deficiency of Dihydropyrimidine Dehydrogenase: “Rarely, unexpected, severe toxicity (eg, stomatitis, diarrhea, neutropenia and neurotoxicity) associated with 5-fluorouracil has been attributed to a deficiency of dihydropyrimidine dehydrogenase (DPD) activity. A link between decreased levels of DPD and increased, potentially fatal toxic effects of 5-fluorouracil therefore cannot be excluded. Capecitabine Fluorouracil Cream; [m27] 
Fluorouracil Topical Solution & Cream[m28] 
EGFR expression Epidermal Growth Factor Receptor presence or absence- “EGFR expression was determined using the EGFR pharmDxTM kit. In contrast to the 1% cut-off specified in the pharmDx kit instructions, a positive EGFR expression status was defined as having at least 10% of cells staining for EGFR. The pharmDx kit has not been validated for use in pancreatic cancer. An apparently larger effect, however, was observed in two subsets: patients with EGFR positive tumors (HR = 0.68) and patients who never smoked (HR = 0.42). Analysis of the impact of EGFR expression status on the treatment effect on clinical outcome is limited because EGFR status is known for 326 NSCLC study patients (45%).” Erlotinib  
EGFR expression with alternate Context Epidermal Growth Factor Receptor presence or absence- “Pretreatment assessment for evidence of EGFR expression is not required for patients with squamous cell carcinoma of head and neck (SCCHN).” Cetuximab
Head and Neck Cancer
Gefitinib[m29] 
EGFR expression with alternate Context Epidermal Growth Factor Receptor presence or absence- “Patients enrolled in the clinical studies were required to have immuno-histochemical evidence of positive EGFR expression using the DakoCytomation EGFR pharmDx™ test kit.” Cetuximab
Colorectal Cancer
Panitumab [m30] 
Gefitinib [m29] 
Familial Hypercholestremia (deficiency, and/or mutation, of receptors for low density lipoprotein -LDL) Dosage adjustment for Homozygous and heterozygous Familial Hypercholestremia “Doses should be individualized according to the recommended goal of therapy. Homozygous Familial Hypercholestremia (10-80mg/day)and heterozygous (10-20mg/day) Familial Hypercholestremia dose adjustment needed in pediatric patients.”  Atorvastatin
 
G6PD Deficiency G6PD deficiency and risk “Rasburicase administered to patients with glucose- phosphate dehydrogenase (G6PD) deficiency can cause severe hemolysis. ELITK administration should be immediately and permanently discontinued in any patient developing hemolysis. It is recommended that patients at higher risk for G6PD deficiency (e.g., patients of African or Mediterranean ancestry) be screened prior to starting ELITEK therapy (see CONTRANDICATIONS and WARNINGS, Hemolysis).” Rasburicase Dapsone[m31] 
G6PD Deficiency with alternate Context G6PD deficiency and tolerance “Hemolytic reactions (moderate to severe) may occur in glucose-6-phosphate dehydrogenase (G-6-PD) deficient. If primaquine phosphate is prescribed for an individual with erythrocytic glucose-6-phosphatedehydrogenase (G-6-PD) deficiency or nicotinamide adenine dinucleotide (NADH) methemoglobin reductase deficiency, the person should be observed closely for tolerance.” Primaquine Chloroquine[m32] 
Her2/neu Over-expression Overexpresion of Her2/neu necessary for selection of patients appropriate for drug therapy “Detection of HER2 protein overexpression is necessary for selection of patients appropriate for HERCEPTIN therapy (see INDICATIONS).”
“HERCEPTIN should be used in patients whose tumors have been evaluated with an assay validated to predict HER2 protein overexpression (see PRECAUTIONS: HER2 Testing and CLINICAL STUDIES: HER2 Detection).”
Trastuzumab Lapatinib [m33] 
HLA-B*1502 allele presence “SERIOUS DERMATOLOGIC REACTIONS AND HLA-B*1502 ALLELE.” “Prior to initiating Tegretol therapy, testing for HLA-B*1502 should be performed in patients with ancestry in populations in which HLA-B*1502 may be present. In deciding which patients to screen, the rates provided above for the prevalence of HLA-B*1502 may offer a rough guide, keeping in mind the limitations of these figures due to wide variability in rates even within ethnic groups, the difficulty in ascertaining ethnic ancestry, and the likelihood of mixed ancestry. Tegretol should not be used in patients positive for HLA-B*1502 unless the benefits clearly outweigh the risks. Tested patients who are found to be negative for the allele are thought to have a low risk of SJS/TEN (see WARNINGS and PRECAUTIONS/Laboratory Tests).” ”For genetically at-risk patients (See WARNINGS), high-resolution ‘HLA-B*1502 typing’ is recommended. The test is positive if either one or two HLA-B*1502 alleles are detected and negative if no HLA-B*1502 alleles are detected.” Carbamazepine
 
HLA-B*5701 allele presence

WARNING: HYPERSENSITIVITY REACTIONS/LACTIC ACIDOSIS AND SEVERE HEPATOMEGALY
Patients who carry the HLA-B*5701 allele are at high risk for experiencing a hypersensitivity reaction to abacavir. Prior to initiating therapy with abacavir, screening for the HLA-B*5701 allele is recommended; this approach has been found to decrease the risk of hypersensitivity reaction. Screening is also recommended prior to reinitiation of abacavir in patients of unknown HLA-B*5701 status who have previously tolerated abacavir. HLA-B*5701-negative patients may develop a suspected hypersensitivity reaction to abacavir; however, this occurs significantly less frequently than in HLA-B*5701-positive patients. Regardless of HLA-B*5701 status, permanently discontinue ZIAGEN if hypersensitivity cannot be ruled out, even when other diagnoses are possible
Risk Factor: HLA-B*5701 Allele: Studies have shown that carriage of the HLA-B*5701 allele is associated with a significantly increased risk of a hypersensitivity reaction to abacavir.

Before starting ZIAGEN, tell your doctor about all of your medical conditions, including if you: have been tested and know whether or not you have a particular gene variation called HLA-B*5701. 

Abacavir  
KRAS mutation (Lack of Efficacy of Anti-EGFR Monoclonal Antibodies in Patients with mCRC Containing KRAS Mutations) Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. (Indication and Usage)
Lack of Efficacy of Anti-EGFR Monoclonal Antibodies in Patients With mCRC Containing KRAS Mutations
Retrospective analyses as presented in Table 2 across seven randomized clinical trials suggest that anti-EGFR-directed monoclonal antibodies are not effective for the treatment of patients with mCRC containing KRAS mutations. (Clinical Studies) Signal transduction through the EGFR results in activation of the wild-type KRAS protein. However, in cells with activating KRAS somatic mutations, the mutant KRAS protein is continuously active and appears independent of EGFR regulation. (Clinical Pharmacology-Mechanism of Action)
Panitumumab Cetuximab
NAT Variants N-acetyltransferase slow and fast acetylators and toxicity- “slow acetylation may lead to higher blood levels of the drug, and thus, an increase in toxic reactions.” Rifampin, isoniazid,  and pyrazinamide Isosorbide dinitrate and Hydralazine hydrochloride[m34] 
Philadelphia Chromosome-positive responders Philadelphia (Ph1) chromosome presence (effective) -“Busulfan is clearly less effective in patients with chronic myelogenous leukemia who lack the Philadelphia (Ph1) chromosome. Also, the so-called “juvenile” type of chronic myelogenous leukemia, typically occurring in young children and associated with the absence of a Philadelphia chromosome, responds poorly to busulfan. The drug is of no benefit in patients whose chronic myelogenous leukemia has entered a “blastic” phase.” Busulfan  
Philadelphia Chromosome- positive responders with alternate context Philadelphia (Ph1) chromosome presence (effective) “Dasatinib is indicated for the treatment of adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.” Dasatinib Nilotinib [m35]
PML/RAR alpha gene expression (Retinoic acid receptor responder and non-responders) PML/ RAR (alpha) fusion gene presence “Initiation of therapy with VESANOID may be based on the morphological diagnosis of acute promyelocytic leukemia (APL). Confirmation of the diagnosis of APL should be sought by detection of the t (15; 17) genetic marker by cytogenetic studies. If these are negative, PML/ RAR (alpha) fusion should be sought using molecular diagnostic techniques. The response rate of other AML subtypes to VESANOID has not been demonstrated; therefore, patients who lack the genetic marker should be considered for alternative treatment.”

Tretinoin

Arsenic Oxide [m36] 
Protein C deficiencies (hereditary or acquired) Hereditary or acquired deficiencies of protein C or its cofactor, protein S, has been associated with tissue necrosis following warfarin administration. “Not all patients with these conditions develop necrosis, and tissue necrosis occurs in patients without these deficiencies. Inherited resistance to activated protein C has been described in many patients with venous thrombosis-embolic disorders but has not yet been evaluated as a risk factor for tissue necrosis. The risk associated with these conditions, both for recurrent thrombosis and for adverse reactions, is difficult to evaluate since it does not appear to be the same for everyone. Decisions about testing and therapy must be made on an individual basis.” Warfarin  
TPMT Variants Thiopurine methyltransferase deficiency or lower activity due to mutation at increased risk of myelotoxicity. TPMT testing is recommended and consideration be given to either genotype or phenotype patients for TPMT.” Azathioprine Thioguanine[m37] 
Mercaptopurine [m38] 
UGT1A1
Variants
UGT1A1 mutation in patients, exposure to drug and hence their susceptibility to toxicity. “Individuals who are homozygous for the UGT1A*28 allele are at increased risk for neutropenia following initiation of camptosar treatment. A reduced initial dose should be considered for patients known to be homozygous for the UGT1A*28 allele. Heterozygous patients may be at increased risk of neutropenia; however clinical results have been variable and such patients have been shown to tolerate normal starting doses.” Irinotecan  
UGT1A1 variants with alternate context Pharmacogenomics (safety)
“Tasigna can increase bilirubin levels. A pharmacogenetic analysis of 97 patients evaluated the polymorphisms of UGT1A1 and its potential association with hyperbilirubinemia during Tasigna treatment. In this study, the (TA)7/(TA)7 genotype was associated with a statistically significant increase in the risk of hyperbilirubinemia relative to the (TA)6/(TA)6 and (TA)6/(TA)7 genotypes. However, the largest increases in bilirubin were observed in the (TA)7/(TA)7 genotype (UGT1A1*28) patients [See Warnings and Precautions
(5.5)].”
Nilotinib  
Urea Cycle Disorder (UCD) Deficiency Urea cycle disorders – “Prior to the initiation of valproate therapy, evaluation for UCD should be considered.” Valproic acid Sodium Phenylacetate and Sodium Benzoate; sodium phenyl butyrate
Vitamin K epoxide reductase (VKORC1) Variants Vitamin K epoxide reductase (VKOR) Variant- ““Certain single nucleotide polymorphisms in the VKORC1 gene (especially the -1639G).A allele) have been associated with lower dose requirements for warfarin.  About 55% of the variability in warfarin dose could be explained by the combination of VKORC 1 and CYP2C9 genotypes, age, height, body weight, interacting drugs, and indication for warfarin therapy in Caucasian patients. Similar observations have been reported in Asian patients.” Warfarin