1. Previous Experience (-1, 0,+1)

2. Alternative Etiologic Candidate (-1, 0, +2)

3. Timing (-2, 0, +1)

4. Overdose (0, +1)

5. Dechallenge (-1, 0, +1)

6. Rechallenge (-1, 0, +1)

Components of Modified Kramer SystemComponents of Modified Kramer System

InterpretationInterpretation 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 1987 133 50

MilbemycinProducts 1990 131 59

Selamectin 1999 171 110Moxidectin Tablets (ProHeart) 1997 0 0

Subtotal 219MoxidectinSustainedRelease (ProHeart 6)

2001 485 485

Number of Reported Dog DeathsNumber of Reported Dog Deaths

Anaphylaxis/Anaphylaxis/AnaphylactoidAnaphylactoidReactionsReactions

Heartworm Preventive(year of initial approval)

Assessments Approval to 9/1/04

Ivermectin Products (1987)

Milbemycin Products (1990)

Selamectin (1999)

Moxidectin Tablets(Proheart)(1997)

Subtotal 97

Moxidectin SustainedRelease (ProHeart 6) (2001)

16

36

45

0

1820

Onset Times of Anaphylaxis/ Onset Times of Anaphylaxis/ AnaphylactoidAnaphylactoid Reactions (Reactions (ProHeartProHeart 6)6)

Time of Onset

<1 hr

1to<3

hr3to

<24 h

r<3

0 day

sun

know

n

Num

ber o

f Ass

essm

ents

0

200

400

600

800

1000Total = 1820

Health Status of Dogs with Health Status of Dogs with Anaphylaxis/Anaphylaxis/AnaphylactoidAnaphylactoid Reactions Reactions at Time of at Time of ProHeartProHeart 6 Administration6 Administration

GOODGOOD 1,7411,741FairFair 6969PoorPoor 33UnknownUnknown 77

Deaths: 54

Concomitant Status of Dogs with Concomitant Status of Dogs with Anaphylaxis/Anaphylaxis/AnaphylactoidAnaphylactoid Reactions at Reactions at

Time of Time of ProHeartProHeart 6 Administration6 Administration

No concomitantNo concomitant 816 816 ConcomitantConcomitant 731731UnknownUnknown 273273

ConvulsionsConvulsionsHeartworm 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 Onset Times of Convulsions ((ProHeartProHeart 6)6)

Time of Onset (Days)<1

1 to<

33 t

o<7

7 to<

1414

to<30

30 to

<90 >90Unk

nown

Num

ber o

f Ass

essm

ents

0102030405060708090

100110120

Total = 378

Mean Serum Mean Serum MoxidectinMoxidectin Levels Levels Following a Single Injection Following a Single Injection

Days0 5 10 15 20 25 30

Mox

idec

tin M

ean

Seru

m

Con

cent

ratio

n ( μ

g/L)

1

2

3

4

5

6

Health Status of Dogs with Health Status of Dogs with Convulsions Following Convulsions Following

ProHeartProHeart 6 Administration6 Administration

GOODGOOD 302302FairFair 6464PoorPoor 77Unknown Unknown 55

Deaths: 61

Concomitant Status of Dogs with Concomitant Status of Dogs with Convulsions Following Convulsions Following ProHeartProHeart 6 6

AdministrationAdministration

No concomitant No concomitant 8787ConcomitantConcomitant 215215UnknownUnknown 7676

Heartworm Preventive(year of initial approval)

SGPT/ALT Elevations

LiverLesions

Ivermectin Products (1987) 38 9

Milbemycin Products (1990) 38 8

Selamectin (1999) 69 13

Moxidectin Tablets (ProHeart) (1997) 0 0

Subtotal 145 30

Moxidectin SustainedRelease (ProHeart 6)(2001) 192 65

Liver Problem Assessments Liver Problem Assessments Approval to 9/1/04Approval to 9/1/04

Health Status at Time of Health Status at Time of ProHeartProHeart 6 6 Injection for Dogs with Subsequent Injection for Dogs with Subsequent

SGPT/ALT Elevations or Liver LesionsSGPT/ALT Elevations or Liver Lesions

SGPT/ALT ElevationsSGPT/ALT Elevations

GOOD GOOD 149149

FairFair 3636PoorPoor 66Unknown 1Unknown 1

Liver LesionsLiver Lesions

GOODGOOD 5050

FairFair 1313Unknown 2Unknown 2

Deaths: 38 Deaths: 47

Concomitant Status of Dogs with Concomitant Status of Dogs with Elevated SGPT/ALT or Liver Lesions Elevated SGPT/ALT or Liver Lesions Following Following ProHeartProHeart 6 Administration6 Administration

SGPT/ALT ElevationSGPT/ALT Elevation

No concomitant 50No concomitant 50

ConcomitantConcomitant 112112UnknownUnknown 3030

Liver LesionsLiver Lesions

No concomitant 13No concomitant 13

ConcomitantConcomitant 4444UnknownUnknown 88

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

Time of Onset (Days)<1

1 to<

33 t

o<7

7 to<

1414

to<3

030

to<9

0>9

0Unk

nown

Num

ber o

f Ass

essm

ents

0

10

20

30

40

50Liver Lesions SGPT\ALT

Total = 67Total = 192

HematologicHematologic Assessments Assessments Approval to 9/1/04Approval to 9/1/04

Heartworm Preventive(year of initial approval) Low Platelets IMHA

Ivermectin Products (1987) 10

26

50

0

Subtotal 86 51

124

Milbemycin Products (1990)

20

16

15

0

Selamectin (1999)

Moxidectin Tablets (Proheart)(1997)

67Moxidectin SustainedRelease (ProHeart 6) (2001)

Onset Times for Low Platelets Onset Times for Low Platelets and IMHA (and IMHA (ProHeartProHeart 6)6)

Time of Onset (Days)<1

1 to<

33 t

o<7

7 to<

1414

to<3

030

to<9

0>9

0Unk

nown

Num

ber o

f Ass

essm

ents

0

10

20

30Platelets Total = 124IMHA Total = 67

Health Status at Time of Health Status at Time of ProHeartProHeart 6 Injection for Dogs with 6 Injection for Dogs with

Low Platelets or IMHALow Platelets or IMHA

LOW PLATELETS LOW PLATELETS

GOODGOOD 9191

FairFair 2828PoorPoor 44UnknownUnknown 11

IMHAIMHA

GOODGOOD 5656

Fair 10Fair 10Poor 1Poor 1

Deaths: 45 Deaths: 34

Concomitant Status of Dogs with Concomitant Status of Dogs with Low Platelets or IMHA Following Low Platelets or IMHA Following

ProHeartProHeart 6 Administration6 Administration

LOW PLATELETSLOW PLATELETS

No concomitant 26No concomitant 26

Concomitant 76Concomitant 76Unknown 22Unknown 22

IMHAIMHA

No concomitant 19No concomitant 19

ConcomitantConcomitant 3434UnknownUnknown 1414

Number of Number of ProHeartProHeart 6 ADE Reports 6 ADE Reports Received by CVM, by Year Received by CVM, by Year

(July 1, 2001 to June 30, 2004)(July 1, 2001 to June 30, 2004)

Period Initial Reports

Follow UpReports

Total Reports

7/1/01 to 6/30/02 1719 546 2265

7/1/02 to 6/30/03 1905 838 2743

7/1/03 to 6/30/04 1763 1076 2839

Number of Dogs with Reported Number of Dogs with Reported ADEsADEs and and Number of Reported Dog Deaths Number of Reported Dog Deaths

ProHeartProHeart 6, by Year 6, by Year (July 1, 2001 to June 30, 2004)(July 1, 2001 to June 30, 2004)

Period Number of Dogs Number of Deaths

7/1/01 to 6/30/02 1896 112

7/1/02 to 6/30/03 1814148

7/1/03 to 6/30/04 1640185

Number of Causality Assessments for Certain Number of Causality Assessments for Certain Reported Clinical Manifestations, Reported Clinical Manifestations, ProHeartProHeart 6, 6,

by Year (July 1, 2001 to June 30, 2004)by Year (July 1, 2001 to June 30, 2004)

Period AnaphylactoidReactions Convulsion SGPT/ALT

ElevationLiver

LesionsLow

Platelets IMHA

7/1/01 to 6/30/02 704 110 23 9 26 14

7/1/02 to6/30/03

544 126 52 15 28 24

7/1/03 to6/30/04

487 118 92 37 52 26

Reasons for PostReasons for Post--Marketing Marketing SurveillanceSurveillance

PREPRE--MARKETINGMARKETING

Limited sizeLimited size

Controlled populationControlled population

POSTPOST--MARKETINGMARKETING

Larger sizeLarger size

More diverse More diverse populationpopulation

PostPost--Approval ConcernsApproval Concernsfor Drug Safetyfor Drug Safety

Frequency of eventsFrequency of eventsSeverity of eventsSeverity of eventsTemporal association with administrationTemporal association with administrationCorrelation with rising or peak serum levelsCorrelation with rising or peak serum levelsOngoing serious events despite regulatory Ongoing serious events despite regulatory measuresmeasures

Additional ConsiderationsAdditional Considerations

ProHeartProHeart 6 is used with the intent of 6 is used with the intent of preventing diseasepreventing disease

Other alternatives existOther alternatives existfewer reported serious adverse effectsfewer reported serious adverse effects

Analysis of Analysis of ProHeartProHeart 6 6 Adverse Events by Adverse Events by

Fort Dodge Animal HealthFort Dodge Animal Health

““Approximately 18 million doses of Approximately 18 million doses of ProHeartProHeart 6 have been sold with more 6 have been sold with more than 12 million doses administeredthan 12 million doses administered””

--Fort Dodge Animal Health (page 31)Fort Dodge Animal Health (page 31)

FDAH Allergy Event Reports per FDAH Allergy Event Reports per 10,000 doses sold (pages 3710,000 doses sold (pages 37--38)38)

ProHeartProHeart 6:6: 1.26 1.26 DuramuneDuramune Max 5/4L vaccine:Max 5/4L vaccine: 0.40.4RabvacRabvac 3 vaccine:3 vaccine: 0.50.5

Allergy event reporting rate for Allergy event reporting rate for ProHeartProHeart 6 is 6 is 2.5 to 3.1 times higher than for Fort 2.5 to 3.1 times higher than for Fort Dodge vaccinesDodge vaccines

FDAH NonFDAH Non--Allergy Event ReportsAllergy Event Reportsper 10,000 doses sold (pages 38per 10,000 doses sold (pages 38--39)39)

ProHeartProHeart 6:6: 1.19 1.19 DuramuneDuramune Max 5/4L vaccine:Max 5/4L vaccine: 0.30.3RabvacRabvac 3 vaccine:3 vaccine: 0.350.35

NonNon--allergy event reporting rate for allergy event reporting rate for ProHeartProHeart 6 6 is 3.4 to 4.0 times higher than for Fort is 3.4 to 4.0 times higher than for Fort Dodge vaccinesDodge vaccines

““The adverse event case fatality rate The adverse event case fatality rate associated with associated with ProHeartProHeart 6 reports is 6 reports is lower than many FDAH pharmaceuticals lower than many FDAH pharmaceuticals and similar to case fatality rates for the and similar to case fatality rates for the FDAH canine vaccine product lines FDAH canine vaccine product lines including including DuramuneDuramune Max 5/4L. Thus the Max 5/4L. Thus the incidence of death does not appear to be incidence of death does not appear to be causally related to causally related to ProHeartProHeart 66 usageusage..””

Fort Dodge Animal Health, Page 36Fort Dodge Animal Health, Page 36

Fort DodgeFort Dodge’’s Causality Analysis of Medical s Causality Analysis of Medical Events by Selected Body Systems (page 39)Events by Selected Body Systems (page 39)

Possible

Unlikely

Potential Probable

Events classified as allergic excluded

Neurologic, hematologic, and hepatic cases reviewed by

experts

Neoplasia cases reviewed by expert

Analysis of Analysis of BanfieldBanfield DataData

•• Selection biasSelection bias•• Information biasInformation bias

Table 4.4.2-1. Rate per 10,000 of Any Adverse Event by Treatment Category

LimitationsLimitations

ProHeart 6 HW Prev 1 HW Prev 2 No HW Treatment

Vaccine N NA Rate N NA Rate N NA Rate N NA Rate Yes 483,064 6,292 130.3 246,131 2,804 113.9 11,975 120 100.2 1,489,032 17,406 116.9 No 252,590 2,253 89.2 164,951 1,469 89.1 6,430 45 70.0 4,144,984 120,529 290.8 Total 735,654 8,545 116.1 411,082 4,273 103.9 18,405 165 89.4 5,634,016 137,935 244.8