Download In summary, the FDA Pharmacogenetic Biomarkers table is an

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Summary of the FDA Table of Pharmacogenomic Biomarkers in Drug Labeling
http://www.fda.gov/drugs/scienceresearch/researchareas/pharmacogenetics/ucm083378.htm
Kristen K. Reynolds, PhD
Sarah Schroer, PharmD
PGXL Laboratories
August 30, 2016
This is a list of medications approved by the FDA which have pharmacogenetic information in the product
labeling or the drug package insert. The table includes generic drug name, the therapeutic area with which the
drug is most commonly associated, the gene (biomarker) referenced in the package insert, and the section of
the drug label where that information can be found.
To date (list version 8/23/16), there are
164 unique drugs listed with some having
multiple entries for multi-gene information.
The table is periodically updated, so the
newest drugs with PGx information may
not yet be listed. For example, Rexulti
(brexpiprazole) was approved in July 2015
with CYP2D6 gene-dose information, but
was not added to the table until almost a
year later during an update.
You can follow a link to a medication’s
monograph directly from the FDA
biomarkers table by clicking on the drug’s
generic name listed in the table. The table
can be sorted by any of the column
headers for ease of use. Want to know
how many drugs have labels referencing
CYP2D6 in some way? Just sort by
biomarker.
The labeling section is a key aspect of this
list. It tells you exactly where to look in the
drug’s package insert to find the
information. This is where it gets
tricky…not all of the drugs in this table are DIRECTLY affected by the pharmacogenetic biomarker listed in the
table. The type and clinical relevance of biomarker information found in these different labels varies and
examples are described below.
©PGXL Laboratories 2016
1) SPECIFIC GENOTYPE-BASED DRUG DOSING: the pharmacogenetic biomarker (gene) listed in the table has
variants that affect the given drug’s safety or efficacy, and dosage
a) Example: aripiprazole CYP2D6 Poor Metabolizers should take half of the standard dose
In the Abilify monograph “Dosage and Administration” section (v 01-2016), this is what is found:
b) Example: citalopram CYP2C19 Poor Metabolizers should not exceed 20 mg/day
When one reviews in the Celexa (citalopram) package insert (v 07-2014) in the first section mentioned in
the biomarkers table, “Clinical Pharmacology,” a clear genotype-specific dosage is found:
©PGXL Laboratories 2016
2) NON-RELEVANT GENOTYPES: some labels have a gene biomarker listed in the FDA table, but the detail
shows that the gene is NOT relevant for that drug
a) Example: citalopram’s second entry for CYP2D6
In the “Clinical Pharmacology” section of the package insert, this is what is stated for CYP2D6:
This demonstrates that CYP2D6 has no relevance for citalopram. Thus, although there is information
about CYP2D6 poor metabolizers in the citalopram package insert, and it is listed in the FDA Biomarkers
Table, the citalopram-CYP2D6 drug-gene pair is not clinically meaningful.
b) Example: prasugrel has four entries – CYP2C19, CYP2C9, CYP3A5, CYP2B6
The “Use in Specific Populations” section in the Effient (prasugrel) insert says:
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.
Additionally, the section “Clinical Studies” indicates:
In TRITON-TIMI 38, prasugrel reduced ischemic events (mainly nonfatal MIs) and increased bleeding events
[see Adverse Reactions (6.1)] relative to clopidogrel. The findings are consistent with the intended greater
©PGXL Laboratories 2016
inhibition of platelet aggregation by prasugrel at the doses used in the study [see Clinical Pharmacology
(12.2)]. There is, however, an alternative explanation: both prasugrel and clopidogrel are pro-drugs that
must be metabolized to their active moieties. 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. Moreover, certain proton pump inhibitors, widely used in the
ACS patient population and used in TRITON-TIMI 38, inhibit CYP2C19, thereby decreasing formation of
clopidogrel’s active metabolite. Thus, reduced-metabolizer status and use of proton pump inhibitors may
diminish clopidogrel’s activity in a fraction of the population, and may have contributed to prasugrel’s
greater treatment effect and greater bleeding rate in TRITON-TIMI 38. The extent to which these factors
were operational, however, is unknown.
In other words, none of the four genetic biomarkers listed for prasugrel should be used to predict
prasugrel safety or efficacy.
c) Example: nefazodone CYP2D6 Poor Metabolizers
The “Precautions” section of the nefazodone package insert (Teva Pharmaceuticals v 01-2016) states:
CYP2D6 Isozyme – A subset (3% to 10%) of the population has reduced activity of the drug-metabolizing
enzyme CYP2D6. Such individuals are referred to commonly as “poor metabolizers” of drugs such as
debrisoquin, dextromethorphan, and the tricyclic antidepressants. The pharmacokinetics of nefazodone
and its major metabolites are not altered in these “poor metabolizers.” Plasma concentrations of one
minor metabolite (mCPP) are increased in this population; the adjustment of nefazodone dosage is not
required when administered to “poor metabolizers.” Nefazodone and its metabolites have been shown in
vitro to be extremely weak inhibitors of CYP2D6. Thus, it is not likely that nefazodone will decrease the
metabolic clearance of drugs metabolized by this isozyme.
Thus, nefazodone is not significantly impacted by CYP2D6 genetic variability, which is consistent with
primary literature citing that nefazodone is metabolized primarily via CYP3A4.
3) DRUG INTERACTIONS: some labels include pharmacogenetic information that apply to drug interactions
rather than the primary metabolism of the given drug
a) Example: paroxetine CYP2D6 Extensive Metabolizers
The Pexeva (paroxetine) package insert (v 5-2014) “Drug Interactions” section mentions the following
with regard to CYP2D6 EXTENSIVE Metabolizers:
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Drugs Metabolized by Cytochrome CYP2D6: Many drugs, including most drugs effective in the treatment of MDD
(paroxetine, other SSRIs, and many tricyclics), are metabolized by the cytochrome P450 isozyme CYP2D6. Like other
agents that are metabolized by CYP2D6, paroxetine may significantly inhibit the activity of this isozyme. In most
patients (>90%), this CYP2D6 isozyme is saturated early during paroxetine dosing. In one study, daily dosing of
paroxetine (20 mg qd) under steady-state conditions increased single dose desipramine (100 mg) Cmax, AUC, and T1/2
by an average of approximately 2-, 5-, and 3-fold, respectively. Concomitant use of paroxetine with risperidone, a
CYP2D6 substrate, has also been evaluated. In one study, daily dosing of paroxetine 20 mg in patients stabilized on
risperidone (4 to 8 mg/day) increased mean plasma concentrations of risperidone approximately 4-fold, decreased 9hydroxyrisperidone concentrations approximately 10%, and increased concentrations of the active moiety (the sum of
risperidone plus 9-hydroxyrisperidone) approximately 1.4-fold. The effect of paroxetine on the pharmacokinetics of
atomoxetine has been evaluated when both drugs were at steady state. In healthy volunteers who were extensive
metabolizers of CYP2D6, paroxetine 20 mg daily was given in combination with 20 mg atomoxetine every 12 hours. This
resulted in increases in steady state atomoxetine AUC values that were 6- to 8-fold greater and in atomoxetine Cmax
values that were 3- to 4-fold greater than when atomoxetine was given alone. Dosage adjustment of atomoxetine may
be necessary and it is recommended that atomoxetine be initiated at a reduced dose when it is given with paroxetine.
This is an important example. Paroxetine is metabolized by CYP2D6 and this drug-gene pair is clinically
relevant. Poor Metabolizers of CYP2D6 may need a 50% lower than average dosage of paroxetine to
decrease the risk of side effects (CPIC Guidelines, Hicks et al. Clin Pharmacol Ther 2015;98(2):127-34).
However, this dose reduction in CYP2D6 Poor Metabolizers is NOT what the FDA Biomarkers table refers
to; that dose reduction is not in the drug package insert, but rather, is found in recent primary literature.
The FDA Biomarkers table cites a portion of the paroxetine package insert describing drug-drug
interactions with paroxetine in CYP2D6 Extensive Metabolizers. This entire section describes paroxetine
as known inhibitor of CYP2D6, which is clinically significant, but not with regard to the CYP2D6-genotype
differences for paroxetine dosing itself.
In summary, the FDA Pharmacogenetic Biomarkers table is an excellent resource for many drugs with
pharmacogenetic relevance. Its limitations include frequency of table updates, updates being limited to drug
labeling without regard for newer (post-market) clinical data, lack of consistency for the type of
pharmacogenetic information included, and genetic markers listed for drugs which may not be directly affected
by that gene. Package insert citations for all drug-gene pairs listed should be carefully reviewed in order to avoid
accidental misinterpretation.
The PGXL PRIMER system accounts for these known pharmacogenetic markers, as well as established drug-drug
interactions to provide the most comprehensive reports to guide therapeutic management decisions.
©PGXL Laboratories 2016