# Presentation: 396950

## ProHeart 6 Adverse Drug Events: An Overview

- VMAC ProHeart 6 Meeting
- January 31, 2005
- Lynn O. Post DVM, PhD
- FDA/CVM

## 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

## 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.

## 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.

## 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

## 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**.

## 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

## 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

## Post Approval History Cont.

- July 15, 2003, added a _[Client Information Sheet ](file:///D:/Heartworm/refs/Client%20Information%20about%20Proheart.doc)__ and the phrase “and rare reports of death” _
- Two “Dear Doctor” Letters describing the three label changes (June 2002 and June 2003)

## Annual Number of ProHeart 6 ADE Reports Received by CVM

| Period | Initial reports | Follow-up reports | Total reports |
| --- | --- | --- | --- |
| July 1, 2001-June 30, 2002 | 1719 | 546 | 2265 |
| July 1, 2002-June 30, 2003 | 1905 | 838 | 2743 |
| July 1, 2003-June 30, 2004 | 1763 | 1076 | 2839 |

## Frequency of Initial and Follow-up ProHeart 6 Reports  

##  Causality Assessments for All Clinical Manifestations Reported as PH 6 ADE’s 

| Causality Assessment Category* | Number of Assessments |
| --- | --- |
| Definitely drug-related | 32** |
| Probably drug-related | 4310 |
| Possibly drug-related | 15334 |
| Remotely drug-related | 2026 |
| Information Lacking | 183 |
| Total | 21885 |

- *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

## PH 6 Time of Onset*: Number of Causality Assessments

*****For those with known time of onset; causality ≥ 0

## Moxidectin Mean Serum  Concentration Following a Single Injection 

## Number of Dogs with Reported ADEs* 

| Monthly and  6 Month 
Heartworm Preventives
(Year of Initial Approval) | Number of Dogs
Approval to 9/1/04  | Number of Dogs
9/6/01 to 9/1/04 |
| --- | --- | --- |
| Ivermectin Products (1987) | 5667 | 4646 |
| Milbemycin Products (1990) | 3243 | 2273 |
| Selamectin (1999) | 9719 | 7681 |
| Moxidectin Tablets (1997)
(ProHeart) | 12 | 1 |
| Moxidectin Sustained 
Release (2001)
(ProHeart 6)           | 5659 | 5659  |

- *including “ineffect” for heartworms, hookworms, roundworms, fleas, ticks, and mites; causality ≥ 0

## Number of Dog Deaths*

| Monthly and  6 Month 
Heartworm Preventives
(Year of Initial Approval) | Number of Deaths 
Approval to 9/1/04 | Number of Deaths
6/6/01 to 9/1/04 |
| --- | --- | --- |
| Ivermectin Products (1987) | 133 | 50 |
| Milbemycin Products (1990) | 131 | 59 |
| Selamectin (1999) | 171 | 110 |
| Moxidectin Tablets (1997)
(ProHeart) | 0 | 0 |
| Moxidectin Sustained 
Release (2001)
(ProHeart 6)           | 485 | 485 |

- *causality assessment ≥ 0