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 It was current when produced, but is no longer maintained and may be outdated.

Components of Modified Kramer System 1. 1.Previous Experience (-1, 0,+1) 2. 2.Alternative Etiologic Candidate (-1, 0, +2) 3. 3.Timing (-2, 0, +1) 4. 4.Overdose (0, +1) 5. 5.Dechallenge (-1, 0, +1) 6. 6.Rechallenge (-1, 0, +1)

Interpretation of Range   -6 to -1 Remotely drug related   0 to +2 Possibly drug related   +3 to +5 Probably drug related   +6 to +7 Definitely drug related

Heartworm Preventive Year of Initial Approval Number of Deaths, Approval to 9/1/04 Number of Deaths, 6/1/01 to 9/1/04 Ivermectin Products Milbemycin Products Selamectin Moxidectin Tablets (ProHeart) Subtotal 219 MoxidectinSustained Release (ProHeart 6) Number of Reported Dog Deaths

Anaphylaxis/Anaphylactoid Reactions Heartworm Preventive (year of initial approval) Assessments Approval to 9/1/04 Ivermectin Products (1987)16 Milbemycin Products (1990)36 Selamectin (1999)45 Moxidectin Tablets (Proheart)(1997) 0 Subtotal 97 Moxidectin Sustained Release (ProHeart 6) (2001) 1820

Onset Times of Anaphylaxis/ Anaphylactoid Reactions (ProHeart 6)

Health Status of Dogs with Anaphylaxis/Anaphylactoid Reactions at Time of ProHeart 6 Administration GOOD1,741 GOOD1,741 Fair 69 Fair 69 Poor 3 Poor 3 Unknown 7 Unknown 7 Deaths: 54

Concomitant Status of Dogs with Anaphylaxis/Anaphylactoid Reactions at Time of ProHeart 6 Administration No concomitant816 No concomitant816 Concomitant731 Concomitant731 Unknown273 Unknown273

Convulsions Heartworm Preventive (year of initial approval) Assessments Approval to 9/1/04 Ivermectin Products (1987)131 Milbemycin Products (1990)194 Selamectin (1999)304 Moxidectin Tablets (ProHeart)(1997)1 Subtotal 630 Moxidectin Sustained Release (ProHeart 6) (2001) 378

Onset Times of Convulsions (ProHeart 6)

Mean Serum Moxidectin Levels Following a Single Injection

Health Status of Dogs with Convulsions Following ProHeart 6 Administration GOOD302 GOOD302 Fair 64 Fair 64 Poor 7 Poor 7 Unknown 5 Unknown 5 Deaths: 61

Concomitant Status of Dogs with Convulsions Following ProHeart 6 Administration No concomitant 87 No concomitant 87 Concomitant215 Concomitant215 Unknown 76 Unknown 76

Heartworm Preventive (year of initial approval) SGPT/ALT Elevations Liver Lesions Ivermectin Products (1987)389 Milbemycin Products (1990)388 Selamectin (1999)6913 Moxidectin Tablets (ProHeart) (1997) 00 Subtotal Moxidectin Sustained Release (ProHeart 6)(2001) Liver Problem Assessments Approval to 9/1/04

Health Status at Time of ProHeart 6 Injection for Dogs with Subsequent SGPT/ALT Elevations or Liver Lesions SGPT/ALT Elevations GOOD 149 GOOD 149 Fair 36 Fair 36 Poor 6 Poor 6 Unknown 1 Unknown 1 Deaths: 38 Liver Lesions GOOD 50 GOOD 50 Fair 13 Fair 13 Unknown 2 Unknown 2 Deaths: 47

Concomitant Status of Dogs with Elevated SGPT/ALT or Liver Lesions Following ProHeart 6 Administration SGPT/ALT Elevation No concomitant 50 No concomitant 50 Concomitant 112 Concomitant 112 Unknown 30 Unknown 30 Liver Lesions No concomitant 13 No concomitant 13 Concomitant 44 Concomitant 44 Unknown 8 Unknown 8

Onset Times of Elevated SGPT/ALT and Liver Lesions (ProHeart 6)

Hematologic Assessments Approval to 9/1/04 Heartworm Preventive (year of initial approval) Low Platelets IMHA Ivermectin Products (1987)1020 Milbemycin Products (1990)2616 Selamectin (1999)5015 Moxidectin Tablets (Proheart) (1997) 00 Subtotal Moxidectin Sustained Release (ProHeart 6) (2001)

Onset Times for Low Platelets and IMHA (ProHeart 6)

Health Status at Time of ProHeart 6 Injection for Dogs with Low Platelets or IMHA LOW PLATELETS GOOD 91 GOOD 91 Fair 28 Fair 28 Poor4 Poor4 Unknown1 Unknown1 Deaths: 45 IMHA GOOD 56 GOOD 56 Fair 10 Fair 10 Poor 1 Poor 1 Deaths: 34

Concomitant Status of Dogs with Low Platelets or IMHA Following ProHeart 6 Administration LOW PLATELETS No concomitant 26 No concomitant 26 Concomitant 76 Concomitant 76 Unknown 22 Unknown 22IMHA No concomitant 19 No concomitant 19 Concomitant 34 Concomitant 34 Unknown 14 Unknown 14

Number of ProHeart 6 ADE Reports Received by CVM, by Year (July 1, 2001 to June 30, 2004) Period Initial Reports Follow Up Reports Total Reports 7/1/01 to 6/30/ /1/02 to 6/30/ /1/03 to 6/30/

Number of Dogs with Reported ADEs and Number of Reported Dog Deaths ProHeart 6, by Year (July 1, 2001 to June 30, 2004) PeriodNumber of DogsNumber of Deaths 7/1/01 to 6/30/ /1/02 to 6/30/ /1/03 to 6/30/

Number of Causality Assessments for Certain Reported Clinical Manifestations, ProHeart 6, by Year (July 1, 2001 to June 30, 2004) Period Anaphylactoid Reactions Convulsion SGPT/ALT Elevation Liver Lesions Low Platelets IMHA 7/1/01 to 6/30/ /1/02 to 6/30/ /1/03 to 6/30/

Reasons for Post-Marketing Surveillance PRE-MARKETING Limited size Limited size Controlled population Controlled populationPOST-MARKETING Larger size Larger size More diverse population More diverse population

Post-Approval Concerns for Drug Safety Frequency of events Frequency of events Severity of events Severity of events Temporal association with administration Temporal association with administration Correlation with rising or peak serum levels Correlation with rising or peak serum levels Ongoing serious events despite regulatory measures Ongoing serious events despite regulatory measures

Additional Considerations ProHeart 6 is used with the intent of preventing disease ProHeart 6 is used with the intent of preventing disease Other alternatives exist Other alternatives exist fewer reported serious adverse effects fewer reported serious adverse effects

Analysis of ProHeart 6 Adverse Events by Fort Dodge Animal Health

“Approximately 18 million doses of ProHeart 6 have been sold with more than 12 million doses administered” -Fort Dodge Animal Health (page 31)

FDAH Allergy Event Reports per 10,000 doses sold (pages 37-38) ProHeart 6:1.26 ProHeart 6:1.26 Duramune Max 5/4L vaccine:0.4 Duramune Max 5/4L vaccine:0.4 Rabvac 3 vaccine:0.5 Rabvac 3 vaccine:0.5 Allergy event reporting rate for ProHeart 6 is 2.5 to 3.1 times higher than for Fort Dodge vaccines

FDAH Non-Allergy Event Reports per 10,000 doses sold (pages 38-39) ProHeart 6:1.19 ProHeart 6:1.19 Duramune Max 5/4L vaccine:0.3 Duramune Max 5/4L vaccine:0.3 Rabvac 3 vaccine:0.35 Rabvac 3 vaccine:0.35 Non-allergy event reporting rate for ProHeart 6 is 3.4 to 4.0 times higher than for Fort Dodge vaccines

“ The adverse event case fatality rate associated with ProHeart 6 reports is lower than many FDAH pharmaceuticals and similar to case fatality rates for the FDAH canine vaccine product lines including Duramune Max 5/4L. Thus the incidence of death does not appear to be causally related to ProHeart 6 usage.” Fort Dodge Animal Health, Page 36 Fort Dodge Animal Health, Page 36

Fort Dodge’s Causality Analysis of Medical Events by Selected Body Systems (page 39) Possible Unlikely PotentialProbable Events classified as allergic excluded Neurologic, hematologic, and hepatic cases reviewed by experts Neoplasia cases reviewed by expert

Analysis of Banfield Data Selection bias Selection bias Information bias Information bias Table Rate per 10,000 of Any Adverse Event by Treatment Category Limitations