Updating Information in the Approved Label for 6-Mercaptopurine: Introduction Lawrence J. Lesko, Ph.D., FCP Director, Office of Clinical Pharmacology and Biopharmaceutics Center for Drug Evaluation and Research Food and Drug Administration

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Updating Information in the Approved Label for
6-Mercaptopurine Introduction Lawrence J.
Lesko, Ph.D., FCPDirector, Office of Clinical
Pharmacology and BiopharmaceuticsCenter for Drug
Evaluation and ResearchFood and Drug
Administration

• Pediatric Oncology Subcommittee
  MeetingRockville, MarylandJuly 15, 2003

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FDA Goals for Pediatric Therapeutics

• Identify opportunities to improve the quality of
  therapeutics related to the use of
  already-marketed drugs
• Update product labels where new data is relevant
  to the safe and effective use of the drug
• Place information in product labels as a
  mechanism to disseminate important information
  about drug use

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These Goals Are Consistent with Label Regulations

• 21 CFR 201.57
• if evidence is available to support the safety
  and effectiveness of the drug only in selected
  subgroups of the larger population with a
  disease, the labeling shall describe the evidence
  and identify specific tests needed for selection
  or monitoring of patients who need the drug

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Pharmacogenetics--The Science
Pharmacogenetics is the study of genetically
determined variability in drug metabolism and
responses to drugs, including adverse events and
desired effects.Variability occurs because of
variations in DNA such as polymorphisms in single
gene, or limited set of multiple genes,
sequencesthat influence enzyme or receptor
activity.
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Integrating Pharmacogenetics Into Therapeutics Is
An Agency-Wide Initiative
Certain new therapies will be developed along
with genetic or phenotypic tests that can
identify an appropriate treatment population and
detect patients who need different doses or are
prone to certain toxic effects. Development of
these test and therapy combinations must be
facilitated because they have the potential to
maximize drug benefits while minimizing
toxicity.Mark McClellan, M.D.Commissioner,
FDAWashington Drug Letter, April 13, 2003
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Example of a New Drug--Atomoxetine (StraterraR)
Approved to Treat ADHD in Children2D6 Genetic
Polymorphism
Human PK A fraction of the population are PMs
resulting in Drug-Drug Interactions Inhibitors
of CYP2D6 in EMs increase exposuresimilar to
PMs Adverse Reactions The following ADRs were
either twice as frequent or statistically
significantly more frequent in PMs compare to
EMs... Laboratory Tests Laboratory tests are
available to identify CYP 2D6 PMs
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CDER Has Focused on Both New And Approved Drugs
Genetic contributions to variability in toxicity
include differences in metabolism, e.g.,
thiopurine methyltransferase, and use of genetic
tests for metabolizer status to predict
dosing.Janet Woodcock, M.D.Director, CDERFDA
Science Board MeetingApril 9, 2003
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6-Mercaptopurine (6MP) and Childhood Acute
Lymphoblastic Leukemia (ALL)

• ALL is a life-threatening disease and 6MP can
  cause life-threatening toxicities
• Dose titration (dosing size, duration and
  intensity) is major determinant of long-term EFS
  and myelosuppressive effects
• 6MP is metabolized to pharmacologically active
  thiopurine nucleotides by thiopurine
  methyltransferase (TPMT)
• TPMT activity shows trimodal variation in the
  general population

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Use of 6MP IMS Database
IMS Health NDTI, cited in Pamer CA report,
October 2002
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TPMT Genetic Polymorphism

• Well-documented, causal link between TPMT
  polymorphism and clinical effects, including
  toxicity
• Genotypes with reduced (10 of the population) or
  no (0.3 of the population) activity are at a
  substantially increased risk of myelosuppression
  and secondary cancer
• Pharmacogenetic tests are available and feasible
  to use for identifying these patients and guide
  optimal dosing

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Pharmacogenetic Tests

• TPMT genotype predicts no or very low enzyme
  activity
• TPMT 2 ( 5), 3A (85) and 3C (5)
• results in excess accumulation of RBC TGN/MeTIMP
• TPMT phenotype measures enzyme activity
• RBC TPMT activity
• RBC TGN/MeTIMP activity

Genotype and/or phenotype tests are adjunct
measures of thiopurine pharmacology not intended
to replace monitoring of clinical tolerance
(e.g, complete blood count)
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Prior Discussions of TPMT Polymorphism and 6MP
Therapeutics Without Asking for Specific
Recommendations

• Pediatric Subcommittee of the Oncology Drug
  Advisory Committee, November 28, 2001
• http//www.fda.gov/ohms/dockets/ac01docsbc.html
• Clinical Pharmacology Subcommittee of the
  Advisory Committee for Pharmaceutical Sciences,
  October 22, 2002
• The Pink Sheet, p.37, November 4, 2002

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Current Package Insert
Warning Section. There are individuals with an
inherited deficiency of the enzyme TPMT who may
be unusually sensitive to the myelosuppressive
effects of 6MP and prone to developing rapid bone
marrow suppression following initiation of
treatment. Substantial dosage reductions may be
required to avoid the development of
life-threatening bone marrow suppression in these
patients. This toxicity may be more in patients
treated with concomitant allopurinol.
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Current Package Insert-Continued
Dosage Section. Purinethol is administered
orally. The dosage which will be tolerated and
be effective varies from patient to patient, and
therefore careful titration is necessary to
obtain the optimum therapeutic effect without
incurring excessive, unintended toxicity.
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First Goal for Today
Question 1What additional information should
be added to the product label for 6MP regarding
pharmacogenetics?
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Additional Information

• Prevalence of patients that have little or no
  TPMT activity (0.3) or reduced activity (10)
• An additional statement in the Warnings (or
  Dosage) sections that patients with hereditary
  deficiency of TPMT activity may be unusually
  sensitive to the myelosuppressive effects of 6MP
  and at greater risk of toxicity

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Additional Information-Continued

• A statement that laboratory tests (phenotype
  and/or genotype) are available to determine the
  TPMT status of patients and some information
  regarding the use of these tests
• Recommendations for adjustment of doses in
  patients identified as having little or no, or
  reduced, TPMT activity

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Second Goal for Today
Question 2If pharmacogenetic information is
added to the label, what other testing
information, if any, about genotyping or
phenotyping for TPMT activity in patients would
you consider necessary to include in the product
label?
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Additional Testing Information

• Recommendation for testing for the status of TPMT
  activity before initiating 6MP treatment
• Recommendation for testing for TPMT activity
  status within the first week of initiating 6MP
  treatment
• Recommendation for testing for TPMT activity
  status if the patient develops severe
  myelosuppression
• Description of what information testing for the
  status of TPMT activity could provide

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Next Speakers

• Richard M. Weinshilboum, M.D., Professor of
  Medicine and Pharmacology, Mayo Medical School
• Naomi Winick, M.D., Pediatric Oncology, The
  University of Texas Southwestern Medical Center
  at Dallas
• Howard L. McLeod, Pharm.D., Washington University
  Medical School, Division on Oncology