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 It was current when produced, but is no longer maintained and may be outdated.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. ProHeart 6 Adverse Drug Events: An Overview VMAC ProHeart 6 Meeting January 31, 2005 Lynn O. Post DVM, PhD FDA/CVM

3. Evaluation of Adverse Drug Events • Observational Studies • Advantages • Larger and more diverse population • Actual conditions of use • Disadvantages • Confounding factors • No well defined control group

4. Reporting Rate • Reporting rate • Numerator = total number of spontaneously reported ADEs Denominator number of exposed patients • ADE reporting rate is not an incidence rate • ADEs are substantially under-reported (numerator). • Accurate data on the number of exposed patients (denominator) is often lacking.

5. Reporting Rate Cont. • A high reporting rate compared to the background incidence rate may signal a problem with a product. • Because of under-reporting, the fact that a reporting rate is less than the background rate does not necessarily mean that the product in not associated with an increased risk of an adverse event.

6. Pre-approval History PH 6 • Approved under NADA 141-189 in June of 2001 • Laboratory Studies • No serious adverse drug events in healthy dogs • Clinical field studies • Vomiting, diarrhea, listlessness, weight loss, seizures, injection site pruritus, and increased body temperature

7. Pre-approval History PH 6 Cont. • The death of 3 dogs (2 geriatric dogs and 1 dog with a history of health problems) resulted in the following PRECAUTION statement on the label: • Use with caution in sick, debilitated or underweight animals.

8. Macrocyclic Lactone Toxicity • Macrocyclic lactone toxicity in mammals • Ivermectin, milbemycin oxime, and selamectin • Toxic Signs • Dilated pupils, vomiting, diarrhea, salivation, disorientation, lack of coordination, muscle twitching, tremors, depression, coma, and blindness. • Severe reactions can involve other neurologic signs such as seizures which have been added to the post-approval safety information on several macrocyclic lactone labels

9. Post Approval History PH 6 • Three label changes • June 13, 2002, added reported clinical manifestations of: anaphylaxis/anaphylactoid reactions, depression/lethargy, urticaria, and head/facial edema. • November 5, 2002, added cardiopulmonary signs associated with administration of the product in heartworm positive dogs

10. Post Approval History Cont. • July 15, 2003, added a Client Information Sheet and the phrase “and rare reports of death” • Two “Dear Doctor” Letters describing the three label changes (June 2002 and June 2003)

11. Annual Number of ProHeart 6 ADE Reports Received by CVM

12. Frequency of Initial and Follow-up ProHeart 6 Reports

13. Causality Assessments for All Clinical Manifestations Reported as PH 6 ADE’s *possibly, probably and definitely = positive causality (19676) **clinical manifestations that were considered definitely drug-related; all had causality assessment scores of +6 for heartworm ineffect

14. PH 6 Time of Onset*: Number of Causality Assessments *For those with known time of onset; causality ≥ 0

15. Moxidectin Mean Serum Concentration Following a Single Injection

16. Number of Dogs with Reported ADEs* *including “ineffect” for heartworms, hookworms, roundworms, fleas, ticks, and mites; causality ≥ 0

17. Number of Dog Deaths* *causality assessment ≥ 0