U.S. Food and Drug Administration

1. U.S. Food and Drug Administration Notice: Archived Document The content in this document is provided on the FDA’s website for reference purposes only. It was current when produced, but is no longer maintained and may be outdated.

2. A Controlled Epidemiological Study:The Safety Profile of ProHeart 6 & Two Monthly Heartworm Preventivesin Dogs Purdue University Larry Glickman, VMD, DrPH Nita Glickman, PhD, MPH George Moore, DVM, MS, DACVIM COMSYS David Hasza, PhD January 31, 2004

3. Banfield Pet Hospital Locations

4. Advantages of Banfield Medical Recordsfor Drug AE Post-Marketing Surveillance • Banfield serves ~ 2% of US dog population • Representative of dog breeds nationally • Electronic data warehouse: all medical records standardized & computerized • Routine quality assurance record review • Routine review of all deaths for causality • More complete ascertainment of AEs • Follow-up calls to all clients after each visit • All drugs/vaccines warranted

5. Methods • All dog visits (encounters): Jan 1, 2002 to Aug 31, 2004 • Each encounter evaluated for potential AEs over subsequent 30 days • Each encounter categorized as: • ProHeart 6 (yes/no) • monthly heartworm preventive (yes/no) • vaccine (yes/no) • none of the above • AE rates calculated per 10,000 encounters and 10,000 days at risk • AE rates evaluated both with and without adjustment for potential confounding factors, such as age, concurrent vaccine use, etc.

6. Rate per 10,000 of Any AEby Treatment Category Total Number of Encounters = 6,800,061

7. Doses Dispensed by MonthProHeart Alone or With Vaccine

8. AE Rateper 10,000 by Treatment Group

9. Liver AE Rateper 10,000 Days at Risk

10. AE Rateper 10,000 by Treatment Group

11. AE Rateper 10,000 by Treatment Group

12. Allergic AE Rateper 10,000 Days at Risk

13. Mast Cell Tumor AE Rateper 10,000 Days at Risk

14. Significant Risk Factors for Liver AEsMultivariate Model (p < 0.05)

15. Risk of Liver Diseaseby Age for ProHeart 6 Risk(1yr old) = 0.854*1.043 = 0.89; Risk(7yr old) = 0.853*1.043**7 = 1.14 Risk(age yrs) = OR(ProHeart6) * OR(ProHeart6*age interaction)**age

16. Significant Risk Factors for Allergic AEsMultivariate Model (p < 0.05)

17. Significant Risk Factors for CancerMultivariate Model (p < 0.05)

18. Significant Risk Factors for DeathMultivariate Model (p < 0.05)

19. Conclusions • Safety profile of ProHeart 6 similar to 2 monthly heartworm preventives, except: • Biologically unexplained and small increased risk of mast cell tumor following ProHeart 6 administration • 23% increased risk of death following most commonly used monthly heartworm preventive (heartworm 1) • AEs probably underestimated for monthly heartworm preventives vs. injectable heartworm preventives because: • DVMs less likely to observe AEs with oral products • Owners less likely to administer oral products

20. Conclusions (continued) • This controlled epidemiological study: • Adjusted for effects of concurrent vaccination and other potential confounding factors • Unlike passive reporting systems, calculated incidence rates and compared AEs between heartworm preventives • Utilized recorded medical events rather than unfiltered and potentially biased reports from DVMs and dog owners • Tested causal hypotheses generated by spontaneous reports to FDA and FDAH

21. Conclusions (continued) • The safety profile of ProHeart 6 in this controlled epidemiological study was favorable compared with 2 monthly heartworm preventives • Therefore, we conclude there is no scientific rationale for the continued withdrawal of ProHeart 6 from the market