1,How New Insights into Pharmacogenomics Lead to Revisions of Product Labels,Shiew-Mei Huang, Ph.D. Deputy Director for Science Office of Clinical Pharmacology & Biopharmaceutics CDER, FDA huangscder.fda.gov,Advisory Committee for Pharmaceutical Science -Clinical Pharmacology Subcommittee- November 14, 2005 Rockville, MD,2,21 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.”,3,Drug and Biologics/Device Labeling Recommendations- Section Content,Topic 1A backgrounder: http:/www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4194B1_00_TOC.htm,4,All clinically relevant information on effect of polymorphic variation in drug metabolizing enzymes, transporters, receptors and/or other proteins on pharmacokinetics, pharmacodynamics, clinical responses (both safety and efficacy),Clinical Studies Section,Clinical Pharmacology Section,OR,1,5,When the information has important implications for safe and effective use, the consequences of the genetic differences and/or recommendations may be placed in,Indications and Usage,AND/ OR,Dosage & Administration,Precautions/ Warnings,Contra- indications,Boxed Warning,Clinical Studies,Adverse Reactions,HIGHLIGHTS,2,Laboratory Testing,6,If a drug is indicated only for a population with a certain genetic makeup, and a genotypic or phenotypic test needs to be conducted prior to prescription and administration,2.1,Example: Herceptin,7,Trastuzumab (Herceptin),INDICATIONS & USAGE indicated formetastatic breast cancer whose tumor overexpress the HER2 protein Patients whose tumor evaluated with an assay validated to predict HER2,http:/www.fda.gov/cder/foi/label/2005/009218s101lbl.pdf,Required,8,If dose recommendations are different for subgroups of patients with different genetic makeup,2.2,Example: irinotecan,9,Irinotecan,CLINICAL PHARMACOLOGY Metabolism and Excretion: SN-38 is subsequently conjugated predominantly by the enzyme UDP-glucuronosyl transferase 1A1 (UGT1A1) to form a glucuronide metabolite. UGT1A1 activity is reduced in individuals with genetic polymorphisms that lead to reduced enzyme activity such as the UGT1A1*28 polymorphism. Approximately 10% of the North American population is homozygous for the UGT1A1*28 allele. In a prospective study, in which irinotecan was administered as a single-agent on a once-every-3-week schedule, patients who were homozygous for UGT1A1*28 had a higher exposure to SN-38 than patients with the wild-type,Descriptive info- rationale,10,Irinotecan,DOSAGE AND ADMINISTRATION - Dosage in Patients with Reduced UGT1A1 Activity When administered in combination with other agents, or as a single-agent, a reduction in the starting dose by at least one level of CAMPTOSAR should be considered for patients known to be homozygous for the UGT1A1*28 allele (See CLINICAL PHARMACOLOGY and WARNINGS). However, the precise dose reduction in this patient population is not known and subsequent dose modifications should be considered based on individual patient tolerance to treatment (see tables 10-13).,Action- Recommendations,11,If individuals with certain genetic makeup are more sensitive to one of the severe adverse events,2.3,Example: irinotecan,12,Irinotecan,WARNINGS Patients with Reduced UGT1A1 Activity Individuals who are homozygous for the UGT1A1*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 UGT1A1*28 allele (see DOSAGE however, clinical results have been variable and such patients have been shown to tolerate normal starting doses.,13,If individuals with certain genetic makeup are more sensitive to one of the life threatening adverse events that may not be managed via dose reduction,2.4,Example: thioridazine,14,Thioridazine,CONTRAINDICATIONS elevated levels of thioridazine would be expected to augment the prolongation of the QTc interval associated with thioridazine and may increase the risk of serious, potentially fatal, cardiac arrhythmias, such as torsade de pointes-type arrhythmias. . Therefore, thioridazine is contraindicated . in patients, comprising about 7% of the normal population, who are known to have a genetic defect leading to reduced levels of activity of P450 2D6 (see WARNINGS and PRECAUTIONS ).,Action- Recommendations,15,If individuals with certain genetic makeup had a higher rate of adverse reactions,2.5,Example: atomoxetine,16,Atomoxetine,ADVERSE EVENT,ADR PM EM decreased appetite 23% 16% insomnia 13% 7% sedation 4% 2% depression 6% 2% tremor 4% 1% early morning awakening 3% 1% pruritus 2% 1% mydriasis 2% 1%,Descriptive info-,17,When a specific laboratory test is available.,2.6,Examples: atomoxetine azathioprine,