Actionable Pharmacogenetics in FDA Labeling

Monday, August 15, 2016
Author: 

Sherri J. Willard Argyres, PharmD

Over the last several years, the Food and Drug Administration (FDA) has made a concerted effort to include pharmacogenetics in prescribing information when appropriate and maintains a list of drug labeling that contains pharmacogenetic information.

However, until recently, many of the labels with information related to pharmacogenetics have been purely informational, providing no clinically actionable direction regarding whether to test a patient, what to do with the pharmacogenetic information once in hand, or the clinical implications of pharmacogenetic testing. The clinician has been left to sort out whether to order a pharmacogenetic test and how to interpret the test results.

Although organizations such as the Clinical Pharmacogenetics Implementation Consortium have produced guidelines for interpreting pharmacogenetic test results, adoption of pharmacogenetics into routine clinical care has been slow.

Several articles are written annually about common barriers to the adoption of pharmacogenetics, including:

  • Limitations in the ability to order tests and receive results at the right time and the right place
  • Lack of information technology systems that can appropriately handle pharmacogenetic data
  • Limitations in reimbursement for pharmacogenetic testing and counseling
  • Lack of training for clinicians or access to genetic counseling resources

Nevertheless, the FDA and some guidelines have made clear that clinicians should consider employing pharmacogenetic-based decision making in clinical practice. To assist with this, in the chart below, I have provided some notable examples of drugs from the FDA’s Table of Pharmacogenetic Biomarkers in Drug Labeling for which pharmacogenetics must or may be considered in prescribing, particularly when pharmacogenetic test results are available.

List exclusions

Excluded from this list are examples that fall into these criteria:

  • Information in labeling does not call for action
  • Labeling that concerns a molecular targeted therapy
  • Labeling that addresses a predisposition for a disease state with a known genetic cause

In many cases of non-actionable associations, the influence of a genetic variant on a drug’s pharmacokinetic or pharmacodynamic properties has little or no known association with an efficacy or safety outcome. For example, patients who are CYP2D6 poor metabolizers exhibit a two- to five-fold increase in paroxetine AUC on average; however, specific effects on clinical outcomes have not been demonstrated.

Most targeted therapies have been designed to target the protein products from genetic mutations found in tumors, and these therapies require genetic testing of tumor tissue before their use. For example, researchers designed the tyrosine kinase inhibitor imatinib to target the constitutively active receptor tyrosine kinases found in patients with a variety of cancers.

Finally, whereas most pharmacogenetic associations are related to drug pharmacokinetics or pharmacodynamics, some listed in the FDA biomarker list are related to a physiological response to a drug aggravating a genetic disease or a genetic predisposition for a disease state. For example, the increased oxidative stress due to dapsone use can precipitate acute hemolytic anemia in a patient who, independent of the drug, has a predisposition for acute hemolytic anemia due to glucose-6-phosphate dehydrogenase (G6PD) deficiency. Another example: The increased risk of thromboembolism with oral contraceptive use can precipitate a thromboembolic event in a patient who, independent of the drug, is predisposed to clotting due to Factor V Leiden thrombophilia.

List inclusions

This list is limited to those genetic biomarkers associated with inter-individual differences in drug pharmacokinetic or pharmacodynamics parameters. It also addresses human leukocyte antigens (HLA), for which researchers have postulated individuals with certain HLA genotypes are at greater risk of drug-induced hypersensitivity reactions when a particular drug or class of drugs directly interfere in the immune system’s ability to distinguish between self and non-self.

Drug Gene Phenotype Efficacy or Safety Outcome of Concern Recommendation
Abacavir HLA-B HLA-B*57:01 High Risk Allele Increased risk of hypersensitivity reactions Alternative therapy
Aripiprazole CYP2D6 CYP2D6 Poor Metabolizer Increased risk of adverse effects (eg, extrapyramidal symptoms) Dosage adjustment
Atomoxetine CYP2D6 CYP2D6 Poor Metabolizer Increased risk of adverse reactions (eg, insomnia, decreased appetite, tremor) Dosage adjustment
Azathioprine TPMT Deficient Activity Increased risk of myelotoxicity Alternative therapy or dosage adjustment and increased monitoring
Azathioprine TPMT Intermediate Activity Increased risk of myelotoxicity Dosage adjustment and increased monitoring
Belinostat UGT1A1 Reduced Glucorindation Increased risk of dose-limiting toxicities (eg, fatigue, atrial fibrillation, and diarrhea) Dosage adjustment
Brexpiprazole CYP2D6 CYP2D6 Poor Metabolizer Increased risk of akasthisia Dosage adjustment
Capecitabine DPYD DPD Deficient Activity Increased risk of severe, life-threatening, or fatal adverse reactions (eg, mucositis, diarrhea, neutropenia, and neurotoxicity) Alternative therapy
Capecitabine DPYD DPD Intermediate Activity Increased risk of severe, life-threatening, or fatal adverse reactions (eg, mucositis, diarrhea, neutropenia, and neurotoxicity) Alternative therapy or dosage adjustment
Carbamazepine HLA-A HLA-A*31:01 High Risk Allele Increased risk of hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) and maculopapular exanthema (MPE) cutaneous reactions Alternative therapy
Carbamazepine HLA-B HLA-B*15:02 High Risk Allele Increased risk of Stevens Johnson syndrome/toxic epidermal necrolysis Alternative therapy
Celecoxib CYP2C9 CYP2C9 Poor Metabolizer Increased risk of cardiovascular or gastrointestinal adverse events Dosage adjustment or alternative therapy
Citalopram CYP2C19 CYP2C19 Poor Metabolizer Increased risk of QT prolongation Dosage adjustment
Clopidogrel CYP2C19 CYP2C19 Poor Metabolizer Increased risk of cardiovascular complications related to acute coronary syndrome or percutaneous coronary intervention Alternative therapy
Eliglustat CYP2D6 CYP2D6 Poor Metabolizer Increased risk of PR, QT, QRS prolongation Dosage adjustment
Eliglustat CYP2D6 CYP2D6 Poor Metabolizer Increased risk of therapeutic failure Alternative therapy
Flibanserin CYP2C19 CYP2C19 Poor Metabolizer Increased risk of hypotension, syncope, and central nervous system depression Increased monitoring
Fluorouracil DPYD DPD Deficient Activity Increased risk of severe, life-threatening, or fatal adverse reactions (eg, mucositis, diarrhea, neutropenia, and neurotoxicity) Alternative therapy
Fluorouracil DPYD DPD Intermediate Activity Increased risk of severe, life-threatening, or fatal adverse reactions (eg, mucositis, diarrhea, neutropenia, and neurotoxicity) Alternative therapy or dosage adjustment
Iloperidone CYP2D6 CYP2D6 Poor Metabolizer Increased risk of QT prolongation Dosage adjustment
Irinotecan UGT1A1 UGT1A1 Reduced Activity Increased risk of neutropenia and/or life threatening diarrhea Dosage adjustment
Mercaptopurine (6-MP) TPMT TPMT Deficient Activity Increased risk of myelosuppression Alternative therapy or dosage adjustment and increased monitoring
Oxcarbazepine HLA-B HLA-B*15:02 High Risk Increased risk of Stevens Johnson syndrome/toxic epidermal necrolysis Alternative therapy
Phenytoin/Fosphenytoin HLA-B HLA-B*15:02 High Risk Increased risk of Stevens Johnson syndrome/toxic epidermal necrolysis Alternative therapy
Pimozide CYP2D6 CYP2D6 Poor Metabolizer Inreased risk of QT prolongation Dosage adjustment
Thioguanine TPMT TPMT Deficient Activity Increased risk of myelosuppression Dosage adjustment and increased monitoring
Vortioxetine CYP2D6 CYP2D6 Poor Metabolizer Increased exposure to vortioxetine Dosage adjustment
Warfarin CYP2C9 CYP2C9 Poor Metabolizer Increased risk of bleeding Dosage adjustment
Warfarin VKORC1 VKORC Warfarin Sensitive Increased risk of bleeding Dosage adjustment

Sherri J. Willard Argyres, MA, PharmD, BCPS, is a senior clinical content specialist for Wolters Kluwer Clinical Drug Information.

Want to learn more about related topics? Check out these RxPerts Academy features on pharmacogenomics:

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