# Presentation: 731825

## Slide 1

## Components of Modified Kramer System

**Alternative Etiologic Candidate (-1, 0, +2)**
**Timing (-2, 0, +1)**
**Overdose (0, +1)**
**Dechallenge (-1, 0, +1)**
**Rechallenge (-1, 0, +1)**

***Components of Modified Kramer System***

## 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

## Number of Reported Dog Deaths

| 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 |
| Milbemycin Products | 1990 | 131 | 59 |
| Selamectin | 1999 | 171 | 110 |
| Moxidectin Tablets 
(ProHeart) | 1997 | 0 | 0 |
| Subtotal |  |  |            219 |
| MoxidectinSustained 
Release 
(ProHeart 6)           | 2001 | 485 | 485 |

**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

- GOOD		1,741
- Fair		     69
- Poor		       3
- Unknown	       7

**Deaths: 54**

## Concomitant Status of Dogs with Anaphylaxis/Anaphylactoid Reactions at Time of ProHeart 6 Administration

- No concomitant		816
- Concomitant			731
- Unknown			273

## 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

- GOOD		302
- Fair	   	  64
- Poor	    	    7
- Unknown   	    5

**Deaths: 61**

## Concomitant Status of Dogs with Convulsions Following ProHeart 6 Administration

- No concomitant 	  87
- Concomitant		215
- Unknown		  76

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

| Heartworm Preventive
(year of initial approval) | SGPT/ALT Elevations | Liver
Lesions |
| --- | --- | --- |
| Ivermectin Products (1987) | 38 | 9 |
| Milbemycin Products (1990) | 38 | 8 |
| Selamectin (1999) | 69 | 13 |
| Moxidectin Tablets 
(ProHeart) (1997) | 0 | 0 |
| Subtotal |             145 |            30 |
| Moxidectin Sustained
Release (ProHeart 6)(2001) | 192 | 65 |

**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
- Fair	   36
- Poor	     6
- Unknown     1

_**Liver Lesions**_
- GOOD	  50
- Fair	  13
- Unknown    2

**Deaths: 38**

**Deaths: 47**

## Concomitant Status of Dogs with Elevated SGPT/ALT or Liver Lesions Following ProHeart 6 Administration

_**SGPT/ALT Elevation**_
- No concomitant    50
- Concomitant	   112
- Unknown	             30

_**Liver Lesions**_
- No concomitant  13
- Concomitant	   44
- 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) | 10 | 20 |
| Milbemycin Products (1990) | 26 | 16 |
| Selamectin (1999) | 50 | 15 |
| Moxidectin Tablets (Proheart)
(1997) | 0 | 0 |
| Subtotal |                              86 | 51 |
| Moxidectin Sustained
Release (ProHeart 6) 
(2001) | 124 | 
67
 |

## 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
- Fair	       28
- Poor		4
- Unknown		1

_**IMHA**_
- GOOD	   56
- Fair            10
- Poor            1

**Deaths: 45**

**Deaths:** **34**

## Concomitant Status of Dogs with Low Platelets or IMHA Following ProHeart 6 Administration

_**LOW PLATELETS**_
- No concomitant    26
- Concomitant        76
- Unknown             22

_**IMHA**_
- No concomitant   19
- Concomitant	    34
- Unknown	     	    14

## Slide 22

## 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 6/30/02 | 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 ADEs and Number of Reported Dog Deaths ProHeart 6, by Year (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 | 1814 | 148
 |
| 7/1/03 to 6/30/04 | 1640 | 185
 |

## 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 6/30/02 | 704 | 110 | 23 | 9 | 26 | 14 |
| 7/1/02 to
6/30/03 | 544 | 126 | 52 | 15 | 28 | 24 |
| 7/1/03 to
6/30/04 | 487 | 118 | 92 | 37 | 52 | 26 |

## Reasons for Post-Marketing Surveillance

_**PRE-MARKETING**_
- Limited size
- Controlled population

_**POST-MARKETING**_
- Larger size
- More diverse population

## Post-Approval Concernsfor Drug Safety

- Frequency of events
- Severity of events
- Temporal association with administration
- Correlation with rising or peak serum levels
- Ongoing serious events despite regulatory measures

## Additional Considerations

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

## Slide 29

## 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
- Duramune Max 5/4L vaccine:	0.4
- 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
- Duramune Max 5/4L vaccine:	0.3
- 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

- Potential

- Probable

- Events classified as allergic excluded

- Neurologic, hematologic, and hepatic cases reviewed by experts

- Neoplasia cases reviewed by expert

## Analysis of Banfield Data

- Selection bias
- Information bias

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

- _Limitations_