TABLE OF CONTENTS

[Introduction 2](#introduction)

[Definitions 2](#definitions)

[Adverse Event Reporting for Animal Drugs
4](#adverse-event-reporting-for-animal-drugs)

[Canine Heartworm Disease 7](#canine-heartworm-disease)

[Macrocyclic Lactones 8](#macrocyclic-lactones)

[ProHeart 6 Product Information 8](#proheart-6-product-information)

[Regulatory History of ProHeart 6 10](#regulatory-history-of-proheart-6)

[ADE Reports for ProHeart 6 and Other Heartworm Preventives
11](#ade-reports-for-proheart-6-and-other-heartworm-preventives)

[ProHeart 6 ADEs 16](#proheart-6-ades)

[Trends in ProHeart 6 ADE Reporting
19](#trends-in-proheart-6-ade-reporting)

[Clinical Manifestations 22](#clinical-manifestations)

[Anaphylaxis/Anaphylactoid Reactions
22](#anaphylaxisanaphylactoid-reactions)

[Convulsions 24](#convulsions)

[Liver Signs 26](#liver-signs)

[Hematologic Signs 30](#hematologic-signs)

[Conclusions 34](#conclusions)

[References 36](#references)

[Appendix A. Causality Assessment Algorithm for Adverse Drug Events
39](#appendix-a.-causality-assessment-algorithm-for-adverse-drug-events)

[Appendix B. Approved Monthly and 6-Month Heartworm Preventives
42](#appendix-b.-approved-monthly-and-6-month-heartworm-preventives)

[Appendix C. ProHeart 6 Label, May 2003
45](#appendix-c.-proheart-6-label-may-2003)

[Appendix D. Case Studies 47](#appendix-d.-case-studies)

[Anaphylaxis/Anaphylactoid Reactions
47](#anaphylaxisanaphylactoid-reactions-1)

[Convulsions 52](#convulsions-1)

[Liver Signs 61](#liver-signs-1)

[Hematologic Signs 65](#hematologic-signs-1)

#   {#section .unnumbered}

# **Introduction**

The Center for Veterinary Medicine (CVM) has the regulatory
responsibility for ensuring the safety of marketed animal drug products.
Prior to their approval, new animal drugs are subject to studies to
establish their safety and effectiveness under the labeled conditions of
use. Many of the common adverse events may become known prior to
approval. CVM maintains a post-approval monitoring system to detect
adverse events that occur after the new animal drug is approved. After
approval, the drug will be used in a larger and more diverse population.

This document describes CVM's method for evaluating adverse drug
experience reports associated with animal drugs and provides data on
adverse drug events reported for canine heartworm preventives. It
demonstrates that the number of reports of serious adverse drug events,
such as anaphylaxis, convulsions, liver abnormalities, immune-mediated
hemolytic anemia, thrombocytopenia, and death, is substantially higher
for ProHeart 6 (moxidectin sustained release) than for other heartworm
preventives. The frequency of ProHeart 6 adverse drug event reports, the
severity of the clinical manifestations within the reports, and the
temporal association with drug administration raise serious questions
about the safety of this heartworm prevention product. Fort Dodge, at
FDA\'s request, agreed to immediately cease production and recall
Proheart 6 from the market until the safety concerns associated with the
product are resolved.

# **Definitions**

**Adverse drug experience** **(ADE):** Any adverse event associated with
the use of a new animal drug, whether or not considered to be drug
related and whether or not the new animal drug was used in accordance
with the approved labeling ([CFR](../References/Ref%20514.3.doc)
[514.3.doc](../../../../../../../../D://References/Ref%20514.3.doc)
).^1^ Adverse drug experience includes, but is not limited to:

> \(1\) An adverse event occurring in animals in the course of the use
> of an animal drug product by a veterinarian or by a livestock producer
> or other animal owner or caretaker.
>
> \(2\) Failure of a new animal drug to produce its expected
> pharmacological or clinical effect (lack of expected effectiveness).
>
> \(3\) An adverse event occurring in humans from exposure during
> manufacture, testing, handling, or use of a new animal drug.

In this document the term "adverse drug event" is used interchangeably
with "adverse drug experience.

**Serious adverse drug experience:** An adverse event that is fatal, or
life threatening, or requires professional intervention, or causes an
abortion, or stillbirth, or infertility, or congenital anomaly, or
prolonged or permanent disability, or disfigurement.

**Unexpected adverse drug experience:** An adverse event that is not
listed in the current labeling for the new drug and includes any event
that may be symptomatically and pathophysiologically related to an event
listed on the labeling, but differs from the event because of greater
severity of specificity.

**ADE report:** An adverse drug experience report submitted by a sponsor
on Form [1932](../../../../../../../../D:/References/Form1932.pdf) or by
a veterinarian or consumer on Form
[1932a](../../../../../../../../D:/References/FDA1932A.pdf). ^2,\ 11^
Nearly all of the reports submitted to CVM by drug sponsors are
identified with a unique sponsor case number.

**Correspondence date:** The date an ADE report is postmarked.

**Clinical manifestation:** Equivalent to a clinical sign or outcome and
can be a primary, secondary, or tertiary clinical sign or outcome. A
report may contain several clinical manifestations.

**Causality assessment:** The evaluation and scoring of a clinical
manifestation using the modified Kramer algorithm. There is a causality
assessment score for every clinical manifestation in a report. Causality
assessment scores are grouped into causality assessment categories:

**[Causality Assessment]{.underline} [Causality
Assessment]{.underline}**

**[Scores]{.underline} [Categories]{.underline}**

**-9** Not applicable

**-8** Information lacking

**-7** No conclusion

**-1 to -6** Remotely drug-related

**0 to 2** Possibly drug-related

**3 to 5** Probably drug-related

**6 to 7** Definitely drug-related

If clinical manifestations in an ADE report cannot be attributed to a
single animal, an assessment could involve more than one animal. For
companion animals, there is usually one animal for each assessment.

**Episode:** The occurrence of one or more clinical manifestations in
the smallest number of animals to which the clinical manifestation(s)
can be uniquely ascribed. If clinical manifestations in an ADE report
cannot be attributed to a single animal, an episode could include more
than one animal. For companion animals, there is usually one animal in
each episode.

**Time of onset**: The duration of time between drug administration and
onset or detection of a clinical manifestation.

**Pharmacovigilance:** The science and activities relating to the
detection, assessment, understanding, and prevention of adverse effects
or any other drug-related problems (World Health Organization). ^27^

# 

# **Adverse Event Reporting for Animal Drugs** 

In the United States, the Center for Veterinary Medicine (CVM) approves
new animal drugs under Section 512 of the Federal Food, Drug, and
Cosmetic Act based on applications that include full reports of
investigations which have been made to show whether or not the drug is
safe and effective for use. Prior to their approval, new animal drugs
are subject to studies to establish their safety and effectiveness.
Thus, most of the common adverse events will become known during those
pre-approval studies. Post approval monitoring of adverse drug events is
a widely accepted method for monitoring the safety and effectiveness of
approved drugs when used in a larger, heterogeneous population.
^[2](../../../../../../../../D:/References/Brewer.htm)1^ Goals of CVM's
pharmacovigilance program include: (1) providing pertinent safety
information for the product label, (2) monitoring for unsafe or
defective products, and (3) monitoring for unsafe drug-use
practices.^[4](../../../../../../../../D:/References/Bataller.pdf)^

Post approval monitoring is critical to ensuring that drugs approved as
safe and effective continue to be so; however, it has some inherent
limitations. In the United States, reporting of adverse drug events by
physicians and veterinarians is entirely voluntary and accomplished
through passive reporting systems. It is well recognized that adverse
drug events are substantially under-reported.
**^[5](../../../../../../../../D:/References/Trontell.pdf),\ [6](../References/Funmilayo.pdf),\ [7](../../../../../../../../D:/References/Brown.pdf),\ [8](../../../../../../../../D:/References/The%20Clinical%20Impact%20of%20Adverse%20Event%20Reporting.doc),\ [9](../../../../../../../../D:/References/Kimmel.pdf),\ [10](../../../../../../../../D:/References/Sgro.pdf)[,\ 21](../../../../../../../../D:/References/Brewer.htm)^**
When an adverse drug event is reported, accurate assessment of the event
depends upon the general quality and completeness of the report.
Additional limitations in veterinary pharmacovigilance include the cost
and availability of diagnostic tests and the lack of comprehensive
post-mortem information. Veterinary clinical care is becoming more
sophisticated, and reports currently submitted to CVM are more
comprehensive than 10 years ago.
[^20^](../../../../../../../../D:/References/Keck.pdf)

In most cases, national ADE reporting rates can only be estimated
because the population at risk (number of patients exposed to a
particular product) is not precisely known. Furthermore, an ADE
reporting rate is **not** an incidence rate because ADEs are
substantially under-reported (numerator) and accurate data on the number
of exposed patients (denominator) is often lacking. ^28^ A reporting
rate that is high compared to the background incidence rate may signal a
problem with a product. However, 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.

CVM currently receives about 25,000 adverse drug experience reports per
year. Approximately 99% of ADE reports are received from drug sponsors.
A sponsor of a new animal drug completes [Form]{.underline}
[1932](../../../../../../../../D:/References/Form1932.pdf) when it
receives a report (by telephone, mail or e-mail) of an adverse event
from a veterinarian or a consumer. Under the mandatory reporting
requirement of [CFR
21§514.80](../../../../../../../../D:/References/Ref%201%20514.80.doc)
(and formerly under CFR 21§510.300), sponsors are required to submit a
Form 1932 to FDA within 15 working days for each serious, unexpected
ADE. Under CFR 21§514.80, sponsors must report other ADEs in periodic
Drug Experience Reports, which are submitted every 6 months for the
first 2 years following product approval and yearly thereafter.
Approximately 1% of ADE reports come directly to CVM from pet owners and
veterinarians on [Form
1932a.](../../../../../../../../D:/References/FDA1932A.pdf) Each ADE
report contains one or more clinical manifestations, which are coded by
CVM according to a standard dictionary of clinical
terms.[^12^](../../../../../../../../D:/References/Dictionary%20Clin%20Tm.xls)

When an ADE report arrives at CVM, it is logged into the Document
Control Unit, assigned a submission number, and forwarded to the
Division of Surveillance for processing. CVM safety reviewers, who are
experienced clinical veterinarians, then review the individual ADE
reports. The safety reviewers enter all relevant information such as
age, breed, history, pre**-**existing problems, and concomitant drugs
into an Oracle database called the Submission Tracking and Reporting
System (STARS).

The reviewers evaluate each clinical manifestation reported using a
scoring system that has been previously described.
^[3](../../../../../../../../D:/References/Keller.pdf)[,\ 4,\ 13](../../../../../../../../D:/References/Hampshire.pdf)^
This system is a modified version of the Kramer algorithm, a human
adverse drug event
algorithm.^[14](#appendix-a.-causality-assessment-algorithm-for-adverse-drug-events),^
^25,\ 26^ This scoring system has the following 6 components:

1.  **Previous Experience with the Drug**

2.  **Alternative Etiologic Candidates**

**3. Timing of Events**

**4. Evidence of Overdose**

**5. Dechallenge** (whether the problem disappears after withdrawal of
the drug)

**6. Rechallenge** (whether the problem reappears when the drug is
reintroduced)

Consideration is given to information about age, breed, gender,
pre-existing conditions, and concomitant drugs. A summary causality
assessment score for each clinical manifestation is determined and
entered into the STARS database. The summary score corresponds to the
strength of the association between the drug and the clinical
manifestation and ranges between -9 and +7. Clinical manifestations with
summary scores of ≥0 are considered possibly, probably, or definitely
drug-related. When many ADE reports listing a particular clinical
manifestation have accrued for a particular drug, CVM assigns a higher
"previous experience" component score for that clinical manifestation in
subsequent ADE reports. Therefore, scores for a particular manifestation
may increase over time. Dechallenge and rechallenge components of Kramer
score usually don't apply with a sustained release product like ProHeart
6 so the maximum causality assessment score for such products is usually
+4 unless there is an overdose, in which case it can be +5. Detailed
information about the components of the algorithm used by CVM may be
found in [Appendix
A](#appendix-a.-causality-assessment-algorithm-for-adverse-drug-events).
Causality assessment scores for ineffectiveness can be as high as +6
because CVM uses a modified version of this algorithm for
ineffectiveness complaints. ^29^

Follow-up reports are an important part of pharmacovigilance. 21 CFR
514.80(b)(2)(ii). They generally arrive within a month or two after the
initial report. A new record is not created for follow-up reports; the
information in a follow-up report is added to that in the initial
report. In some cases, there may be more than 3 follow-up reports per
original ADE report. Follow-up reports provide significant new
information that may either strengthen or weaken the association between
an event and use of the drug. In addition, follow-up reports may provide
new clinical manifestations or outcomes to previously reported ones. For
example, in the absence of a follow-up report, a severe outcome such as
death may go unreported.

The severity and frequency of clinical manifestations in the STARS
database are continuously monitored by CVM. STARS data summaries may be
generated by cumulative experience or by detailed search criteria such
as age, time of onset, attending veterinarian opinion, gender, and
breed. The cumulative numbers of dogs with reported clinical
manifestations that had causality assessment scores of zero or above are
placed in the public domain on the [CVM
website](http://www.fda.gov/cvm/index/ade/adetoc.htm) by active
ingredient and route of administration.

When severity or frequency of reported ADEs for a given product are of
concern, the Division of Surveillance may request additional information
from the drug sponsor or organize an internal CVM product safety meeting
to review available data. At the product safety meeting, CVM determines
whether a label revision or any other action is indicated.

# **Canine Heartworm Disease**

Heartworm disease is a serious but preventable mosquito-borne parasitic
disease that primarily affects dogs and cats. It is caused by the
*Dirofilaria immitis* nematode. Dogs are usually asymptomatic until
maturation of heartworm larvae in the right atrium and pulmonary artery
causes cardiopulmonary effects. Typically, maturation of the larvae
takes about six months. The chances of contracting heartworm disease
without prophylaxis depend on exposure to mosquitos. Dogs are more
likely to become infected if they live in the Southeast, Gulf Coast, or
Mississippi River Valley near fresh or saltwater, are housed outside,
and are not receiving heartworm preventives. Dogs can survive a
heartworm infection by receiving appropriate treatment. There is a risk
of thromboembolism and death following adult heartworm treatment when
worms break loose from their location in the right heart, and there can
be side effects from the drugs that are commonly used to treat adult
heartworms. Additional information about canine heartworm disease can be
found through the American Heartworm Society.
^[3](../References/2003%20HW%20guidelines.doc)0,\ 31^

# **Macrocyclic Lactones** 

The macrocyclic lactones are natural fermentation products of
soil-dwelling bacteria of the genus *Streptomyces*. They have activity
against both internal and external parasites, specifically nematodes
(including heartworms) and arthropods. Macrocyclic lactones consist of
two major groups, the avermectins and the milbemycins. Moxidectin is a
member of the milbemycin group. The other macrocyclic lactones approved
for use in dogs include ivermectin, milbemycin oxime, and selamectin.
^32^ Known signs of macrocyclic lactone toxicity in mammals include
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.
^[3](../../../../../../../../D:/References/Edwards.pdf)2^

# **ProHeart 6 Product Information** 

ProHeart 6 is a sustained release microencapsulated preparation of
moxidectin. It is indicated for use in dogs at least 6 months of age and
older as a 6-month heartworm preventive. It is also approved for
treatment of existing larval and adult hookworm infections in dogs. It
is manufactured and sold by Fort Dodge Animal Health (FDAH), the
veterinary division of Wyeth Pharmaceuticals, under the new animal drug
application (NADA) number 141-189. ProHeart 6 is sold in multi-dose
vials. The [Freedom of Information
Summary](../../../../../../../../D:/References/FOIA%20141189.pdf)
describes conditions of approval for this product.
[^15^](../../../../../../../../D:/References/FOIA%20141189.pdf) A copy
of the current label for ProHeart 6 can be found in [Appendix
C](#appendix-c.-proheart-6-label-may-2003). ^16^ ProHeart 6 is the only
heartworm prevention product that is approved in the U.S. for parenteral
administration in dogs; it is administered subcutaneously (under the
skin). Following injection, mean ProHeart 6 blood levels peak 7-14 days
post-administration. Figure 1 shows mean moxidectin serum levels
following a single injection of ProHeart 6.
[^15^](../../../../../../../../D:/References/FOIA%20141189.pdf)

![](media/image1.wmf)Figure 1. Mean serum moxidectin concentrations
following a single injection of ProHeart 6 in dogs

The other major canine heartworm preventives (ivermectin, milbemycin,
and selamectin) are delivered as a monthly dose; ivermectin and
milbemycin are administered orally and selamectin is administered
topically. ProHeart, a once-a-month moxidectin tablet, is also
manufactured and sold by FDAH, but is not commonly used in dogs in the
United States. A listing of approved monthly and 6-month heartworm
prevention products and their indications can be found in [Appendix
B](#appendix-b.-approved-monthly-and-6-month-heartworm-preventives).

# **Regulatory History of ProHeart 6** 

ProHeart 6 was approved under NADA 141-189 on June 6, 2001 based on
pre-approval safety and effectiveness studies. Laboratory studies
revealed no serious adverse drug events in healthy dogs. In clinical
field studies, the following adverse reactions were reported in
approximately 1% of 280 dogs treated with ProHeart 6: vomiting,
diarrhea, listlessness, weight loss, seizures, injection site pruritus,
and increased body temperature. 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](#appendix-c.-proheart-6-label-may-2003): **Use with caution in
sick, debilitated or underweight animals**.

Since approval of ProHeart 6, three label revisions have been initiated
by the Division of Surveillance at CVM because of serious and unexpected
adverse drug reactions. The first label revision, which was approved on
June 13, 2002, added the post-approval reported clinical manifestations
of anaphylaxis/anaphylactoid reactions, depression/lethargy, urticaria,
and head/facial edema. The second revision, which was approved on
November 5, 2002, added post-approval reported cardiopulmonary signs
associated with administration of the product in heartworm positive
dogs. The third revision, which was approved on July 15, 2003, added a
[Client Information Sheet
(CIS](../../../../../../../../D:/References/Client%20Information%20about%20Proheart.doc))
and the phrase "and rare reports of death" to the post-approval adverse
reactions section of the label. Two "Dear Doctor" letters describing the
label revisions were disseminated by the sponsor to veterinarians. The
first letter described the anaphylaxis/anaphylactoid reaction
experiences reported and a precaution to test dogs for heartworms before
administration. The second "Dear Doctor" letter contained a combined
description of the second and third CVM initiated label changes. The
current label for ProHeart 6 can be found in [Appendix
C.](#appendix-c.-proheart-6-label-may-2003)

After a clinical manifestation is added to the Adverse Reactions section
of the product label, CVM safety reviewers may assign a higher value for
the "previous experience" component of a causality assessment score. CVM
did not re-evaluate ProHeart 6 ADE reports that were reviewed prior to
label changes, but if CVM had re-evaluated them, the causality
assessment scores would increase for clinical manifestations added to
the product label.

On several occasions, CVM discussed with the sponsor discrepancies in
reported adverse drug events and the lack of adequate follow-up
information contained in the ProHeart 6 ADE reports, generally through
teleconferences.
^[2](../References/April%202003TeleMemo%20ADE%20PH6.doc)2,\ [23,\ 24,](../References/3-13-02%20ADE%20teleconference%20with%20FDAH.pdf)^
CVM met with FDAH on January 14, 2004, July, 13, 2004 and September 1,
2004 to discuss the Center's concerns about the frequency and severity
of reported ADEs associated with Proheart 6. In addition to safety
issues, concerns with the current Good Manufacturing Practices (GMPs)
have been noted. In December 2003 FDA issued a [**Warning**
**Letter**](../References/Ref%2017%20Warn.%20Let.pdf) to FDAH for
violations occurring in the ProHeart 6 manufacturing facility. ^17^ An
August 2004 inspection found that the GMP violations had been corrected.
Two firm-initiated nation-wide recalls of ProHeart 6 have been made due
to GMP problems. The first recall occurred on [**April 27,
2004**](../References/Ref%2018%20Recall%20April%202004%20FDA.doc) for
failure to meet the 6-month dissolution time point. ^18^ The second
recall was issued on [**May 13,
2004**](../References/Ref%2019%20Recall%20July%202004.doc) because of
failure to meet GMPs and concerns about proper sterilization. ^19^ An
August 2004 inspection found the GMP violations had been corrected.

# **ADE Reports for ProHeart 6 and Other Heartworm Preventives** 

This section summarizes STARS searches conducted by CVM for ADEs
reported for marketed monthly and 6-month heartworm preventives with the
active ingredients: ivermectin, milbemycin, selamectin, and moxidectin.
Searches were conducted using correspondence dates for 2 time
periods: 1) product approval to September 1, 2004 and 2) June 1, 2001 to
September 1, 2004. Only ADEs (including death) considered to be
possibly, probably, or definitely related to the products are reported.

Table 1 indicates the number of dogs with reported ADEs for monthly and
6-month heartworm preventives and Table 2 shows the number of deaths
among the dogs. Table 1 and Table 2 include all ADEs and deaths
(possibly, probably, or definitely drug-related), including those
related to "ineffect" for heartworms, hookworms, roundworms, fleas,
ticks, and mites.

Table 1. Number of dogs with reported ADEs\* that are possibly,
probably, or definitely related to the use of marketed monthly or
6-month heartworm preventives.

+-------------------+-------------+----------------+------------------+
| Heartworm         | > **Year of | **Number of    | **Number of      |
| Preventive        | > Initial   | Dogs,**        | Dogs,**          |
|                   | >           |                |                  |
|                   |  Approval** | **Approval to  | **June 1, 2001   |
|                   |             | September 1,   | to September 1,  |
|                   |             | 2004**         | 2004**           |
+-------------------+-------------+----------------+------------------+
| Ivermectin and    | 1987        | 5667           | 4646             |
|                   |             |                |                  |
| Iv                |             |                |                  |
| ermectin/Pyrantel |             |                |                  |
|                   |             |                |                  |
| (all products)    |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Milbemycin and    | 1990        | 3243           | 2273             |
|                   |             |                |                  |
| Mil               |             |                |                  |
| bemycin/Lufenuron |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Selamectin        | 1999        | 9719           | 7681             |
+-------------------+-------------+----------------+------------------+
| Moxidectin        | 1997        | 12             | 1                |
| Tablets           |             |                |                  |
|                   |             |                |                  |
| (ProHeart)        |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Moxidectin        | 2001        | 5659           | 5659             |
| Sustained         |             |                |                  |
|                   |             |                |                  |
| Release (ProHeart |             |                |                  |
| 6)                |             |                |                  |
+-------------------+-------------+----------------+------------------+

\*including "ineffect" for heartworms, hookworms, roundworms, fleas,
ticks, and mites

**Table 2**. Number of reported dog deaths that are possibly, probably,
or definitely related to marketed monthly or 6-month heartworm
preventives.

+-------------------+-------------+----------------+------------------+
| Heartworm         | **Year of   | **Number of    | **Number of      |
|                   | Initial     | Deaths,**      | Deaths,**        |
| Preventive        | Approval**  |                |                  |
|                   |             | **Approval to  | **June 1, 2001   |
|                   |             | September 1,   | to September 1,  |
|                   |             | 2004**         | 2004**           |
+-------------------+-------------+----------------+------------------+
| Ivermectin and    | 1987        | 133            | 50               |
|                   |             |                |                  |
| Iv                |             |                |                  |
| ermectin/Pyrantel |             |                |                  |
|                   |             |                |                  |
| (all products)    |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Milbemycin and    | 1990        | 131            | 59               |
|                   |             |                |                  |
| Mil               |             |                |                  |
| bemycin/Lufenuron |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Selamectin        | 1999        | 171            | 110              |
+-------------------+-------------+----------------+------------------+
| Moxidectin        | 1997        | 0              | 0                |
| Tablets           |             |                |                  |
|                   |             |                |                  |
| (ProHeart)        |             |                |                  |
+-------------------+-------------+----------------+------------------+
| Moxidectin        | 2001        | 485            | 485              |
| Sustained         |             |                |                  |
|                   |             |                |                  |
| Release (ProHeart |             |                |                  |
| 6)                |             |                |                  |
+-------------------+-------------+----------------+------------------+

Selamectin had the highest number of dogs with ADE reports. Many of
these dogs had reports of ineffect for fleas, mites, and ticks and many
had mild local reactions or hair loss at the application site. Between
2001 and 2002, CVM worked with the sponsor of the selamectin product to
address serious ADEs that were observed in underweight and debilitated
animals. CVM collaborated with the sponsor to add a warning on the
label: "Do not use in sick, debilitated or underweight animals" and to
develop an in-clinic approach to educating prescribing veterinarians and
staff members. The reported safety-related ADEs decreased in frequency
and severity. Between 2002 and 2004 the sponsor was also asked to
conduct post-approval studies to address reports of ineffectiveness with
respect to heartworm prevention. In July 2004, the sponsor issued a Dear
Doctor Letter to veterinarians about these studies.

During the period of June 1, 2001 and September 1, 2004, there were more
than twice as many deaths reported among dogs that received ProHeart 6
than for all other heartworm preventives combined, even though ProHeart
6 sales represent 21-24% of the market (as reported by FDAH to CVM in
January and September, 2004).

Ineffectiveness complaints for heartworm prevention claims were reported
for all marketed products including ProHeart 6. CVM discussed this issue
at a recent national meeting. ^29\ Table\ 3^ shows the number dogs with
reported heartworm infections that are possibly, probably, or definitely
related to the ineffectiveness of marketed monthly or 6-month heartworm
preventives. Table 3 also illustrates the small number of deaths that
are possibly, probably, or definitely drug-related among those dogs.

Table 3. Number of dogs with reported heartworm infections that are
possibly, probably, or definitely related to the ineffectiveness of
marketed monthly or 6-month heartworm preventives and the number of
reported deaths possibly, probably, or definitely drug-related among
those dogs.

+--------------------+-----------+-------------------+-----------------+
| **Heartworm        | **Year of | **Number of       | **Number of     |
| Preventive**       | Initial   | Dogs,**           | Deaths,**       |
|                    | A         |                   |                 |
|                    | pproval** | **Approval to**   | **Approval to   |
|                    |           |                   | September 1,    |
|                    |           | **September 1,    | 2004**          |
|                    |           | 2004**            |                 |
+--------------------+-----------+-------------------+-----------------+
| Ivermectin and     | 1987      | 906               | 4               |
|                    |           |                   |                 |
| I                  |           |                   |                 |
| vermectin/Pyrantel |           |                   |                 |
|                    |           |                   |                 |
| (all products)     |           |                   |                 |
+--------------------+-----------+-------------------+-----------------+
| Milbemycin and     | 1990      | 1610              | 0               |
|                    |           |                   |                 |
| Mi                 |           |                   |                 |
| lbemycin/Lufenuron |           |                   |                 |
+--------------------+-----------+-------------------+-----------------+
| Selamectin         | 1999      | 2815              | 11              |
+--------------------+-----------+-------------------+-----------------+
| Moxidectin Tablets | 1997      | 2                 | 0               |
|                    |           |                   |                 |
| (ProHeart)         |           |                   |                 |
+--------------------+-----------+-------------------+-----------------+
| Moxidectin         | 2001      | 411               | 4               |
| Sustained          |           |                   |                 |
|                    |           |                   |                 |
| Release (ProHeart  |           |                   |                 |
| 6)                 |           |                   |                 |
+--------------------+-----------+-------------------+-----------------+

Table 4 and Table 5 show the number of causality assessments for serious
clinical manifestations reported among dogs administered monthly or
6-month heartworm preventives from product approval to September 1, 2004
and from June 1, 2001 to September 1, 2004, respectively. The number of
assessments for anaphylaxis/anaphylactoid reactions, convulsions, liver
lesions, elevations in SGPT/ALT (serum glutamic-pyruvic
transaminase/alanine transferase), low platelets (thrombocytopenia), and
immune-mediated hemolytic anemia (IMHA) were considerably higher for
ProHeart 6 than for other heartworm preventives. The number of
convulsions in dogs receiving selemectin was high between 2001 and 2002
but has been declining since the warning not to use this product in
sick, debilitated or underweight animals was placed on the label in
2002. The numbers of hematologic and liver signs also decreased for
selamectin.

Table 4. Number of causality assessments for certain reported clinical
manifestations that are possibly, probably, or definitely related to the
use of marketed monthly or 6-month heartworm preventives, from approval
to September 1, 2004.

+-----------------+-----------+---------+--------+------+------+-----+
| Heartworm       | Ana       | Conv    | SG     | L    | Low  | I   |
| Preventive      | phylaxis/ | ulsions | PT/ALT | iver | P    | MHA |
|                 |           |         | Elev   |      | late |     |
| (year of        | Anap      |         | ations | Les  | lets |     |
| initial         | hylactoid |         |        | ions |      |     |
| approval)       |           |         |        |      |      |     |
|                 | Reactions |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+
| Ivermectin and  | 16        | 131     | 38     | 9    | 10   | 20  |
|                 |           |         |        |      |      |     |
| Iver            |           |         |        |      |      |     |
| mectin/Pyrantel |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| (all products)  |           |         |        |      |      |     |
| (1987)          |           |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+
| Milbemycin and  | 36        | 194     | 38     | 8    | 26   | 16  |
|                 |           |         |        |      |      |     |
| Milbe           |           |         |        |      |      |     |
| mycin/Lufenuron |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| \(1990\)        |           |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+
| Selamectin      | 45        | 304     | 69     | 13   | 50   | 15  |
| (1999)          |           |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+
| Moxidectin      | 0         | 1       | 0      | 0    | 0    | 0   |
| Tablets         |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| (Proheart)      |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| \(1997\)        |           |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+
| Moxidectin      | 1820      | 378     | 192    | 65   | 124  | 67  |
| Sustained       |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| Release         |           |         |        |      |      |     |
| (ProHeart 6)    |           |         |        |      |      |     |
|                 |           |         |        |      |      |     |
| \(2001\)        |           |         |        |      |      |     |
+-----------------+-----------+---------+--------+------+------+-----+

Table 5. Number of causality assessments for certain reported clinical
manifestations that are possibly, probably, or definitely related to the
use of marketed monthly or 6-month heartworm preventives, June 1, 2001
to September 1, 2004.

+----------------+-----------+---------+---------+-----+------+-----+
| Heartworm      | Ana       | Conv    | S       | Li  | Low  | I   |
| Preventive     | phylaxis/ | ulsions | GPT/ALT | ver | P    | MHA |
|                |           |         | ele     |     | late |     |
|                | Anap      |         | vations | l   | lets |     |
|                | hylactoid |         |         | esi |      |     |
|                |           |         |         | ons |      |     |
|                | Reactions |         |         |     |      |     |
+----------------+-----------+---------+---------+-----+------+-----+
| Ivermectin and | 13        | 69      | 10      | 2   | 5    | 8   |
|                |           |         |         |     |      |     |
| Iverm          |           |         |         |     |      |     |
| ectin/Pyrantel |           |         |         |     |      |     |
|                |           |         |         |     |      |     |
| (all products) |           |         |         |     |      |     |
+----------------+-----------+---------+---------+-----+------+-----+
| Milbemycin and | 20        | 107     | 26      | 5   | 10   | 9   |
|                |           |         |         |     |      |     |
| Milbem         |           |         |         |     |      |     |
| ycin/Lufenuron |           |         |         |     |      |     |
+----------------+-----------+---------+---------+-----+------+-----+
| Selamectin     | 37        | 234     | 45      | 8   | 30   | 8   |
+----------------+-----------+---------+---------+-----+------+-----+
| Moxidectin     | 0         | 0       | 0       | 0   | 0    | 0   |
| Tablets        |           |         |         |     |      |     |
|                |           |         |         |     |      |     |
| (ProHeart)     |           |         |         |     |      |     |
+----------------+-----------+---------+---------+-----+------+-----+
| Moxidectin     | 1820      | 378     | 192     | 65  | 124  | 67  |
| Sustained      |           |         |         |     |      |     |
|                |           |         |         |     |      |     |
| Release        |           |         |         |     |      |     |
| (ProHeart 6)   |           |         |         |     |      |     |
+----------------+-----------+---------+---------+-----+------+-----+

# **ProHeart 6 ADEs**

Between June 6, 2001 and September 1, 2004, ProHeart 6 ADEs were
reported for 6015 dogs (all causality assessment categories). There were
21,885 causality assessments conducted for clinical manifestations
reported among these dogs.

Table 6 shows the number of assessments by causality assessment
category. There were 19,676 assessments for clinical manifestations
determined by CVM to be possibly, probably, or definitely related to the
administration of ProHeart 6 (Table 6). These assessments were for
clinical manifestations in 5659 dogs (Table 1).

There were 637 dog deaths (all causality assessment categories) reported
on ProHeart 6 ADE reports and 485 deaths were determined by CVM to be
possibly or probably related to ProHeart 6 (Table 2).

Table 6. Number of causality assessments for clinical manifestations
reported as ProHeart 6 ADEs, by causality assessment category, June 6,
2001 to September 1, 2004.

  ---------------------------------- ------------------------------------
  **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**
  ---------------------------------- ------------------------------------

\*clinical manifestations that were considered definitely drug-related
all had causality assessment scores of +6 for heartworm ineffect

Among dogs with clinical manifestations that were possibly, probably, or
definitely related to the administration of ProHeart 6, 2585 had
concomitant drugs and/or vaccines and 2034 did not have concomitant
vaccines or drugs. The concomitant drug/vaccine status for the remainder
of the dogs is not known. There were 5548 episodes for the 5659 dogs
with clinical manifestations that were possibly, probably, or definitely
drug-related. The health status of these dogs was noted by the reporting
veterinarian as good in 4916 episodes, fair in 544 episodes, and poor in
52 episodes. The health status of dogs in 36 episodes was not reported.

Time of onset refers to the duration of time between drug administration
and onset or detection of a clinical manifestation. Table 7 shows the
number of causality assessments by time of onset and concomitant
drug/vaccine status for clinical manifestations that were determined to
be possibly, probably, or definitely related to ProHeart 6
administration.

Table 7. Number of causality assessments by time of onset\* and
concomitant drug/vaccine status for reported clinical manifestations
that are possibly, probably or definitely related to the use of ProHeart
6, June 6, 2001 to September 1, 2004.

  ------------------- ------------------ ----------------- -------------------
  **Time of Onset**   **Total Causality  **Assessments     **Assessments
                      Assessments^†^**   with Concomitant  without Concomitant
                                         Drugs and/or      Drugs or Vaccines**
                                         Vaccines**        

  \<3 hours           6613 (34.9%)       2710 (27.5%)      3043 (48.2%)

  3 to \< 24 hours    2546 (13.4%)       1291 (13.1%)      877 (13.9%)

  1 to \<3 days       2296 (12.1%)       1279 (13.0%)      660 (10.4%)

  3 to \<7 days       2178 (11.5%)       1399 (14.2%)      515 (8.2%)

  7 to \<14 days      1962 (10.4%)       1301 (12.2%)      370 (5.9%)

  14 to \<30 days     1395 (7.4%)        839 (8.5%)        332 (5.3%)

  1 to \<3 months     1291 (6.8%)        715 (7.3%)        354 (5.6%)

  [\>]{.underline}3   658 (3.5%)         322 (3.3%)        165 (2.6%)
  months                                                   

  **Total\***         **18939**          **9856**          **6316**
  ------------------- ------------------ ----------------- -------------------

**\***For those with known time of onset

**^†^** Includes causality assessments for dogs that had concomitant
drugs and/or vaccines, dogs that did not have concomitant drugs or
vaccines, and dogs with unknown concomitant drug/vaccine status

The majority of clinical manifestations occurred between 0 and 14 days,
when there were rising or peak serum moxidectin levels. Some dogs had no
adverse events on initial dosing but did after subsequent doses. CVM
encouraged the sponsor to investigate whether the drug could be causing
hypersensitivity reactions. Hypersensitivity reactions occur when there
is an exaggerated immune response to a foreign substance. Anaphylaxis is
one type of hypersensitivity reaction. Preliminary results from studies
investigating the possible association between ProHeart 6 and
hypersensitivity reactions were discussed at a meeting on January 14,
2004. FDAH postulated that reactions might be due to direct mast cell
degranulation.

# **Trends in ProHeart 6 ADE Reporting** 

CVM tracks the number of incoming original and follow-up ADE reports as
well as severity of reported ADE's. Often, severe ADE's will have
follow-up reports. Figure 2 shows the mean number of initial and
follow-up ProHeart 6 ADE reports received per day at CVM by calendar
quarter (90 to 92 day quarter). Data for the third quarter of 2004
represents the mean number of ADE reports per day across the first 62
days of the quarter. The reporting pattern has remained similar each
year, with a peak in the second quarter, coinciding with start of
heartworm prevention season (Figure 2).

![](media/image2.wmf)Figure 2. Mean number of initial and follow-up
ProHeart 6 reports received by CVM day, by calendar quarter\*.

> \*Data for the third quarter of 2004 represents the mean number of
> reports per day across the first 62 days of the quarter

The annual reporting period for a product is based on its approval date,
not the calendar year. Table 8 shows the annual number of initial and
follow-up ProHeart 6 ADE reports received by CVM from July 1, 2001 to
June 30, 2004. The table shows that the annual number of initial
ProHeart 6 ADE reports has not decreased over time.

Table 8. Number of ProHeart 6 ADE reports received by CVM, by year (July
1, 2001 to June 30, 2004).

  ---------------------- -------------- ----------------- ----------------
  Period                 Initial        Follow-up reports Total reports
                         reports                          

  July 1, 2001-June 30,  1719           546               2265
  2002                                                    

  July 1, 2002-June 30,  1905           838               2743
  2003                                                    

  July 1, 2003-June 30,  1763           1076              2839
  2004                                                    
  ---------------------- -------------- ----------------- ----------------

Table 9 shows the number of assessments over time for
anaphylaxis/anaphylactoid reactions, convulsions, elevated SGPT/ALT,
liver lesions, low platelets, and immune-mediated hemolytic anemias
(IMHA) that were possibly or probably related to ProHeart 6
administration. The annual number of assessments for
anaphylaxis/anaphylactoid reactions decreased, but still remained
relatively high in 2003-2004. The number of assessments for convulsions
ranged between 110 and 126 annually. Assessments for the other clinical
manifestations shown in Table 10 have increased over time. The clinical
manifestations shown in Table 9 are described in more detail in the next
section.

Table 9. Number of causality assessments for certain reported clinical
manifestations that are possibly or probably related to the use of
ProHeart 6, by year (July 1, 2001 to June 30, 2004).

+-----------+------------+----------+----------+-------+--------+------+
| Period    | An         | Con      | SGPT/ALT | Liver | Low    | IMHA |
|           | aphylaxis/ | vulsions | E        |       | Pla    |      |
|           |            |          | levation | Le    | telets |      |
|           | Ana        |          |          | sions |        |      |
|           | phylactoid |          |          |       |        |      |
|           |            |          |          |       |        |      |
|           | Reactions  |          |          |       |        |      |
+-----------+------------+----------+----------+-------+--------+------+
| July 1,   | 704        | 110      | 34       | 9     | 26     | 14   |
| 2001 -    |            |          |          |       |        |      |
| June 30,  |            |          |          |       |        |      |
| 2002      |            |          |          |       |        |      |
+-----------+------------+----------+----------+-------+--------+------+
| July 1,   | 544        | 126      | 52       | 15    | 28     | 24   |
| 2002 -    |            |          |          |       |        |      |
| June 30,  |            |          |          |       |        |      |
| 2003      |            |          |          |       |        |      |
+-----------+------------+----------+----------+-------+--------+------+
| July 1,   | 487        | 118      | 92       | 37    | 52     | 26   |
| 2003 -    |            |          |          |       |        |      |
| June 30,  |            |          |          |       |        |      |
| 2004      |            |          |          |       |        |      |
+-----------+------------+----------+----------+-------+--------+------+

Table 10 shows by year the number of dogs with ADEs that were possibly,
probably, or definitely related to ProHeart 6 and the number of dog
deaths that were possibly or probably related to ProHeart 6 by year. A
label revision, which was approved on July 15, 2003, required the
sponsor to add "and rare reports of death" to the post approval
experience section of the product label and to send a [**Dear Doctor
Letter**](../refs/Ref%2038.%20DDr%207-22-03.pdf). Despite these changes,
the number of reported deaths, possibly or probably related to ProHeart,
6 increased each year since the product was marketed (Table 10). In
addition, the number of dogs with heartworm infections that were
possibly, probably, or definitely related to the ineffectiveness of
ProHeart 6 also increased (Table 11).

Table 10. Number of dogs with reported ADEs that are possibly, probably,
or definitely related to ProHeart 6 and number of reported dog deaths
that are possibly or probably related to ProHeart 6, by year (July 1,
2001 to June 30, 2004).

  ------------------------- ---------------------- -----------------------
  Period                    Number of Dogs         Number of Deaths

  July 1, 2001 - June 30,   1896                   112
  2002                                             

  July 1 2002 - June 30,    1814                   148
  2003                                             

  July 1 2003 - June 30,    1640                   185
  2004                                             
  ------------------------- ---------------------- -----------------------

Table 11. Number of dogs with reported heartworm infections that are
possibly, probably, or definitely related to the ineffectiveness of
ProHeart 6, by year (July 1, 2001 to June 30, 2004).

  ---------------------------------- ------------------------------------
  Period                             Number of Dogs

  July 1, 2001 - June 30, 2002       8

  July 1 2002 - June 30, 2003        164

  July 1 2003 - June 30, 2004        208
  ---------------------------------- ------------------------------------

#  

# **Clinical Manifestations**

This section provides additional information on
anaphylaxis/anaphylactoid reactions, convulsions, SGPT/ALT elevations,
liver lesions, thrombocytopenia, and immune-mediated hemolytic anemia
reported as ProHeart 6 ADEs. STARS searches were done using
correspondence dates of June 6, 2001 (date of ProHeart 6 approval) to
September 1, 2004. Because only one clinical manifestation is addressed
within each subsection, the number of assessments is equal to the number
of episodes. Case examples for each clinical manifestation can be found
in [Appendix D.](#appendix-d.-case-studies)

## [Anaphylaxis/Anaphylactoid Reactions]{.underline} 

[Table 12]{.underline} shows causality assessment categories for 1828
reported episodes of anaphylaxis/anaphylactoid reactions in dogs that
received ProHeart 6. CVM determined that approximately one-half of the
anaphylaxis/anaphylactoid reactions were probably drug-related and
approximately one-half were possibly drug-related. The opinion of
reporting veterinarians that ProHeart 6 caused the episodes were: high
(1338), medium (374), low (94), and unknown (22).

Table 12. Number of assessments for anaphylaxis/anaphylactoid reactions
reported as ProHeart 6 ADEs, by causality assessment category, June 6,
2001 to September 1, 2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              913

  Possibly drug-related              907

  Remotely drug-related              5

  Information Lacking                3

  **Total**                          **1828**
  ---------------------------------- ------------------------------------

For the 1820 episodes of anaphylaxis/anaphylactoid reactions determined
to be possibly or probably drug-related, the reporting veterinarians
indicated that at the time of ProHeart 6 administration, the health
status of the dogs was: good (1741), fair (69), and poor (3). The health
status of dogs in the remaining 7 episodes is not known. In 816
episodes, dogs did not have concomitant drugs or vaccines and in 731
episodes, dogs had concomitant drugs and/or vaccines. The concomitant
status for dogs in 273 episodes is not known. shows the number of
anaphylaxis/anaphylactoid reaction assessments by time of onset. Eighty
(80) percent of the episodes occurred within 3 hours of ProHeart 6
administration. Among the 1837 dogs involved in the 1820 episodes, there
were at least 54 deaths that were possibly or probably related to
ProHeart 6.

Table 13. Number of assessments by time of onset for anaphylaxis/
anaphylactoid reactions possibly or probably related to ProHeart 6
administration, June 6, 2001 to September 1, 2004.

  --------------------------------- -------------------------------------
  **Time of Onset**                 **Number of Assessments**

  \< 15 minutes                     374 (20.5%)

  15 minutes to \<1 hour            575 (31.6%)

  1 to \<3 hours                    508 (27.9%)

  3 to \< 24 hours                  296 (16.3%)

  1 to \<3 days                     37 (2.0%)

  3 to \<7 days                     8 (0.4%)

  7 to \<14 days                    14 (0.8%)

  14 to \<30 days                   3 (0.2%)

  [\>]{.underline}1 month           1 (0.1%)

  Unknown                           4 (0.2%)

  **Total**                         **1820**
  --------------------------------- -------------------------------------

The first ProHeart 6 label revision, which was approved on June 13,
2002, added to the product label the post-approval reported clinical
manifestations of anaphylaxis/anaphylactoid reactions,
depression/lethargy, urticaria, and head/facial edema. Although
anaphylaxis/anaphylactoid reactions have declined (Table 9), they remain
an ongoing problem with ProHeart 6. For the single marketing year of
July 1, 2003 to June 30, 2004, there were 487 reported episodes with
anaphylaxis/anaphylactoid reactions that were possibly or probably
related to ProHeart 6 (Table 9). In contrast, there were only 97
reported episodes with anaphylaxis/anaphylactoid reactions that were
possibly, probably, or definitely related to all monthly heartworm
preventives combined for all marketing years (Table 4).

On January 14, 2004, the sponsor stated that anaphylactic reactions may
be due in part to minimum residue solvents and that the elimination of
these solvents might reduce these reactions. However, CVM continued to
receive ADE reports for anaphylaxis/anaphylactoid reactions with zero
residual solvent lots.

## [Convulsions]{.underline}

Seizures[^1] were listed on the original ProHeart 6 product label
because one dog in the clinical field trial experienced an increase in
seizure frequency post-injection. Table 14 shows causality assessment
categories for 405 reported episodes of convulsions in dogs following
the administration of ProHeart 6. CVM determined that the majority of
the convulsions were possibly (348) or probably (30) drug-related. The
opinion of reporting veterinarians that ProHeart 6 caused the episodes
were: high (88), medium (156), low (142), and unknown (19).

Table 14. Number of assessments for convulsions reported as ProHeart 6
ADEs, by causality assessment category, June 6, 2001 to September 1,
2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              30

  Possibly drug-related              348

  Remotely drug-related              23

  Information Lacking                4

  **Total**                          **405**
  ---------------------------------- ------------------------------------

For the 378 episodes of convulsions determined to be possibly or
probably drug-related, the reporting veterinarians indicated that at the
time of ProHeart 6 administration, the health status of the dogs was:
good (302), fair (64), and poor (7). The health status of dogs in the
remaining 5 episodes is not known. In 87 episodes, dogs did not have
concomitant drugs or vaccines and in 215 episodes, dogs had concomitant
drugs and/or vaccines. The concomitant status for dogs in 76 episodes is
not known.

Table 15 shows the number of convulsion assessments by time of onset.
Approximately one-half of the convulsion episodes occurred within 3 days
after the administration of ProHeart 6. Among the 381 dogs involved in
the 378 episodes, there were at least 61 deaths that were possibly or
probably related to ProHeart 6.

**Table 15**. Number of assessments by time of onset for convulsions
possibly or probably related to ProHeart 6 administration, June 6, 2001
to September 1, 2004.

  ---------------------------------- ------------------------------------
  **Time of Onset**                  **Number of Assessments**

  \<3 hours                          62 (16.4%)

  3 to \<24 hours                    51 (13.5%)

  1 to \<3 days                      74 (19.6%)

  3 to \<7 days                      66 (17.5%)

  7 to \<14 days                     43 (11.4%)

  14 to \<30 days                    31 (8.2%)

  1 to \<3 months                    29 (7.7%)

  [\>]{.underline}3 months           13 (3.4%)

  Unknown                            9 (2.4%)

  **Total**                          **378**
  ---------------------------------- ------------------------------------

[]{.mark}

[]{.mark}

There were more episodes with convulsions during the period of June 1,
2001 to September 1, 2004 for ProHeart 6 (Table 5) than for ivermectin
products, for milbemycin products, or for selamectin products since
their approvals (Table 4). The clinical manifestation "convulsions" was
the most commonly reported neurologic sign among dogs treated with
ProHeart 6. However, there were an additional 484 dogs with other types
of neurologic signs that were possibly or probably related to ProHeart
6. Other neurologic signs reported include, but are not limited to
ataxia, trembling, nervousness, confusion, and paresis.

## [Liver Signs]{.underline}

Between June 6, 2001 and September 1, 2004, there were more than 294
dogs reported to have liver-related clinical manifestations that were
determined to be possibly or probably related to ProHeart 6. Elevated
SGPT/ALT and liver lesions noted on pathology reports were the most
commonly reported liver-related clinical manifestations and will be the
focus of this discussion.

> *SGPT/ALT Elevations*

*Table 16* shows the number of assessments, by causality assessment
category, for SGPT/ALT elevations reported in 222 dogs following the
administration of ProHeart 6. CVM determined that the majority of
SGPT/ALT elevations were possibly (190) or probably (2) drug-related.
The opinion of reporting veterinarians that ProHeart 6 caused the
elevations were: high (49), medium (97), low (71), and unknown (5).

Table 16. Number of assessments for SGPT/ALT elevations reported as
ProHeart 6 ADEs, by causality assessment category, June 6, 2001 to
September 1, 2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              2

  Possibly drug-related              190

  Remotely drug-related              30

  Information Lacking                0

  **Total**                          **222**
  ---------------------------------- ------------------------------------

For the 192 SGPT/ALT elevations determined to be possibly or probably
drug-related, the reporting veterinarians indicated that at the time of
ProHeart 6 administration, the health status of the dogs was: good
(149), fair (36), and poor (6). The health status of 1 dog is not known.
Fifty (50) dogs did not receive concomitant drugs or vaccines and 112
dogs received concomitant drugs and/or vaccines. The concomitant status
for 30 dogs is not known. Table 17 shows the number of assessments for
SGPT/ALT elevations by time of onset. Approximately 58% of SGPT/ALT
elevations occurred between 1 and 14 days after the administration of
ProHeart 6. The 192 SGPT/ALT elevations occurred in 192 dogs. There were
at least 38 deaths among the dogs that were possibly or probably related
to ProHeart 6.

Table 17. Number of assessments by time of onset for SGPT/ALT elevations
possibly or probably related to ProHeart 6 administration, June 6, 2001
to September 1, 2004.

  ---------------------------------- ------------------------------------
  **Time of Onset**                  **Number of Assessments**

  \<3 hours                          11 (5.7%)

  3 to \<24 hours                    11 (5.7%)

  1 to \<3 days                      31 (16.1%)

  3 to \<7 days                      40 (20.8%)

  7 to \<14 days                     41 (21.4%)

  14 to \<30 days                    26 (13.5%)

  1 to \<3 months                    16 (8.3%)

  [\>]{.underline}3 months           13 (6.8%)

  Unknown                            3 (1.6%)

  **Total**                          **192**
  ---------------------------------- ------------------------------------

> *Liver Lesions*

*Table 18* shows the number of assessments, by causality assessment
category, for liver lesions reported in dogs following the
administration of ProHeart 6. CVM determined that the majority of liver
lesions (65) were possibly drug-related. The opinion of reporting
veterinarians that ProHeart 6 caused the elevations were: high (16),
medium (30), low (39), and unknown (3).

Table 18. Number of assessments for liver lesions reported as ProHeart 6
ADEs, by causality assessment category, June 6, 2001 to September 1,
2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              0

  Possibly drug-related              65

  Remotely drug-related              23

  Information Lacking                0

  **Total**                          **88**
  ---------------------------------- ------------------------------------

For the dogs with liver lesions determined to be possibly drug-related,
the reporting veterinarians indicated that at the time of ProHeart 6
administration, the health status of the dogs was: good (50) and fair
(13). The health status of 2 dogs is not known. Thirteen (13) dogs did
not have concomitant drugs or vaccines and 44 dogs had concomitant drugs
and/or vaccines. The concomitant status for 8 dogs is not known.

Table 19 shows the time of onset for liver lesions possibly related to
ProHeart 6 administration. Among the 65 dogs with liver lesions, at
least 47 deaths were possibly or probably related to ProHeart 6.
Necrosis or hepatocellular vacuolization was mentioned in some of these
pathology reports.
[**^d47^**](../../../../../../../../D:/Data%20searches/d47%20PR-LiverCVMreport.pdf)

**Table 19.** Number of assessments by time of onset for liver lesions
possibly related to ProHeart 6 administration, June 6, 2001 to September
1, 2004.

  ---------------------------------- ------------------------------------
  **Time of Onset**                  **Number of Assessments**

  \<3 hours                          2 (3.1%)

  3 to \<24 hours                    7 (10.8%)

  1 to \<3 days                      8 (12.3%)

  3 to \<7 days                      5 (7.7%)

  7 to \<14 days                     10 (15.4%)

  14 to \<30 days                    9 (13.8%)

  1 to \<3 months                    15 (23.1%)

  [\>]{.underline}3 months           8 (12.3%)

  Unknown                            1 (1.5%)

  **Total**                          **65**
  ---------------------------------- ------------------------------------

There were more assessments for SGPT/ALT elevations and liver lesions
for ProHeart 6 in the period June 1, 2001 to September 1, 2004 (Table 5)
than there were for all monthly heartworm preventives combined for all
marketing years (Table 4). Furthermore, Table 9 shows that the number of
assessments for these two signs have increased over time for ProHeart 6.

## [Hematologic Signs]{.underline}

Several hematologic signs (clinical manifestations) were reported as
ADEs for ProHeart 6. There were 551 dogs with hematologic signs possibly
or probably related to ProHeart 6. Anemia (low red blood cell count) and
thrombocytopenia (low platelet count) were among the most commonly
reported hematologic signs. A number of dogs had both thrombocytopenia
and hemolytic anemia.

> ***Immune-Mediated Hemolytic Anemia***

There were 225 dogs with anemia that was possibly or probably related to
ProHeart 6. Some of these dogs were reported to have immune-mediated
hemolytic anemia (IMHA), a life-threatening condition that occurs when
an immune response causes the destruction of red blood cells.^33^

Table 20 shows the number of assessments, by causality assessment
category, for IMHA reported in dogs following the administration of
ProHeart 6. CVM determined that the majority of IMHAs were possibly (66)
or probably (1) drug-related. The opinion of reporting veterinarians
that ProHeart 6 caused the anemias were: high (20), medium (28), low
(19), and unknown (3).

Table 20. Number of assessments for IMHAs reported as ProHeart 6 ADEs,
by causality assessment category, June 6, 2001 to September 1, 2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              1

  Possibly drug-related              66

  Remotely drug-related              2

  Information Lacking                1

  **Total**                          **70**
  ---------------------------------- ------------------------------------

For the 67 dogs with IMHA that was possibly or probably drug-related,
the reporting veterinarians indicated that at the time of ProHeart 6
administration, the health status of the dogs was: good (56), fair (10),
and poor (1). Nineteen (19) dogs did not have concomitant drugs or
vaccines and 34 dogs had concomitant drugs and/or vaccines. The
concomitant drug/vaccine status for 14 dogs is not known. Table 21 shows
the time of onset for IMHAs possibly or probably related to ProHeart 6
administration. Approximately one-half the IMHAs occurred between 1 week
and 1 month following the administration of ProHeart 6. Among the 67
dogs with IMHA, there were at least 34 deaths that were possibly or
probably related to ProHeart 6.

Table 21. Number of assessments by time of onset for IMHAs possibly or
probably related to ProHeart 6 administration, June 6, 2001 to September
1, 2004.

  --------------------------------- -------------------------------------
  **Time of Onset**                 **Number of Assessments**

  \<24 hours                        2 (3.0%)

  1 to \<3 days                     2 (3.0%)

  3 to \<7 days                     6 (9.0%)

  7 to \<14 days                    15 (22.4%)

  14 to \<30 days                   18 (26.9%)

  1 to \<3 months                   18 (26.9%)

  [\>]{.underline}3 months          6 (9.0%)

  Unknown                           0

  **Total**                         **67**
  --------------------------------- -------------------------------------

> *Thrombocytopenia*

Thrombocytopenia refers to a low platelet count. In dogs,
thrombocytopenia is frequently caused by the destruction of platelets by
an immune response (immune-mediated thrombocytopenia). ^33^

^Table\ 22^ shows the number of assessments, by causality assessment
category, for thrombocytopenia reported in dogs following the
administration of ProHeart 6. There were 135 reported episodes with
thrombocytopenia following ProHeart 6 administration. CVM determined
that the majority were possibly (123) or probably (1) drug-related. The
opinion of reporting veterinarians that ProHeart 6 caused the low
platelet counts were: high (21), medium (61), low (48), and unknown (5).

Table 22. Number of assessments for thrombocytopenias reported as
ProHeart 6 ADEs, by causality assessment category, June 6, 2001 to
September 1, 2004.

  ---------------------------------- ------------------------------------
  **Causality Assessment Category**  **Number of Assessments**

  Probably drug-related              1

  Possibly drug-related              123

  Remotely drug-related              10

  Information Lacking                1

  **Total**                          **135**
  ---------------------------------- ------------------------------------

For the 124 thrombocytopenia episodes possibly or probably related to
ProHeart 6, the reporting veterinarians indicated that at the time of
ProHeart 6 administration, the health status of the dogs was: good (91),
fair (28), and poor (4). The health status for the dog(s) in one episode
is not known. In 26 episodes, the dogs did not have concomitant drugs or
vaccines and in 76 episodes, the dogs had concomitant drugs and/or
vaccines. The concomitant drug/vaccine status for dogs in 22 episodes is
not known.

Table 23 shows the time of onset for thrombocytopenia possibly or
probably related to ProHeart 6 administration. The times of onset for
thrombocytopenia are similar to those for IMHA. Forty-three (43) percent
of thrombocytopenias occurred between 1 week and 1 month following
ProHeart 6 administration. The 124 thrombocytopenia episodes involved
125 dogs. There were at least 45 deaths among these dogs that were
possibly or probably related to ProHeart 6.

Table 23. Number of assessments by time of onset for thrombocytopenia
possibly or probably related to ProHeart 6 administration, June 6, 2001
to September 1, 2004.

  ---------------------------------- ------------------------------------
  **Time of Onset**                  **Number of Assessments**

  \<24 hours                         2 (1.6%)

  1 to \<3 days                      11 (8.9%)

  3 to \<7 days                      25 (20.2%)

  7 to \<14 days                     29 (23.4%)

  14 to \<30 days                    24 (19.4%)

  1 to \<3 months                    23 (18.5%)

  [\>]{.underline}3 months           8 (6.5%)

  Unknown                            2 (1.6%)

  **Total**                          **124**
  ---------------------------------- ------------------------------------

There were more assessments for IMHA and thrombocytopenia for ProHeart 6
in the period June 1, 2001 to September 1, 2004 (Table 6) than there
were for all monthly heartworm preventives combined for all marketing
years (Table 5). Table 9 shows that the number of assessments for low
platelets has increased over time for ProHeart 6.

# **Conclusions** 

CVM has the responsibility for ensuring the safety of animal drugs. The
sponsor of an animal drug product has the responsibility to demonstrate
that the product is safe and effective prior to approval. Prior to their
approval, new animal drugs are subject to studies to establish their
safety and effectiveness under the labeled conditions of use. Most of
the common adverse events may become known prior to approval. CVM has a
post-approval monitoring system to detect adverse drug events that occur
after marketing, i.e., when an animal drug is used in a larger and more
diverse population.

If CVM determines that a marketed animal drug product is likely to be
causing serious adverse effects, it must evaluate what steps are
necessary to address the issues raised by the adverse event reports.
ProHeart 6 is used primarily to prevent heartworm infections in dogs.
There are alternative products that are approved for use in dogs to
prevent heartworm infections. The frequency of ProHeart 6 adverse drug
events, the severity of the events, which include death, and the
temporal association with administration of ProHeart 6 raise serious
questions about the safety of this heartworm preventive product. These
adverse drug events are particularly striking when compared to other
marketed heartworm preventive products, including Fort Dodge Animal
Health's monthly heartworm preventive. In working with FDAH to address
the adverse events associated with ProHeart 6, CVM has requested three
label revisions. Despite these changes, the agency has continued to
receive a large number of serious adverse drug events related to
ProHeart 6. Therefore, CVM has concluded that there are serious
questions regarding the continued safety of ProHeart 6. Fort Dodge, at
FDA\'s request, agreed to immediately cease production and recall
Proheart 6 from the market until the safety concerns associated with the
product are resolved.

# **References**

1.  United States Code of Federal Regulations, 21, Part 500-599. Office
    of the Federal Register, National Archives and Records
    Administration, U.S. Government Printing Office, Washington, DC
    2004.

2.  Form 1932. U.S. Government Printing Office. Washington, DC.

3.  Keller WC, Bataller N, Oeller DS. Processing and evaluation of
    adverse drug experience reports at the Food and Drug Administration
    Center for Veterinary Medicine. JAVMA 1998; 213(2):208-211. 

4.  Bataller N, Keller WC. Monitoring adverse reactions to veterinary
    drugs. Pharmacovigilance. Veterinary Clinics of North Am Food Anim
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5.  Trontell A. Expecting the unexpected---drug safety,
    pharmacovigilance, and the prepared mind. New England Journal of
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6.  Funmilayo O. Adverse drug reactions, a review of relevant factors.
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7.  Brown SD. Recognizing, reporting and reducing adverse drug
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8.  U.S. FDA Website, MedWatch
    <http://www.fda.gov/medwatch/articles/medcont/medcont.htm#toc>.

9.  Kimmel SE, Sekeres MA, Berlin JA, et al. Adverse events after
    protamine administration in patients undergoing cardiopulmonary
    bypass: risks and predictors of under-reviewing. Journal of Clinical
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10. Sgro C, Clinard F, Ouazir K, et al. Incidence of drug-induced
    hepatic injuries: a French population-based study. Hepatology
    2002;36(2):451-5.

11. Form 1932A. U.S. Government Printing Office. Washington, DC.

12. Dictionary of Clinical Terms at CVM Division of Surveillance 7519
    Standish Pl., Rockville, MD 20855.

13. Hampshire VA, Dotty FM, Post LO, et al.2004. Adverse drug event
    reports at the United States Food and Drug Administration Center for
    Veterinary Medicine. JAVMA 2004;225(4):536-540.

14. ADE algorithm: reference document. Hampshire:\\desktop
    files\\Training\\algorithm. 7915 Standish Pl., Rm. 2426, Rockville,
    MD 20855.

15. NADA 141189 Freedom of Information Summary, Center for Veterinary
    Medicine 7915 Standish Pl., Rockville, MD 20855.

16. Label File; NADA 141-189, CVM DS/ FDA/CVM 7519 Standish Pl., 20855.

17. Warning Letter from Charles Sedgwick, Kansas City District FDA
    Office to Tom Corcoran March 31, 2004. Web version at:
    [**http://www.fda.gov/foi/warning_letters/g4602d.pdf. Accession date
    10/31/04**](http://www.fda.gov/foi/warning_letters/g4602d.pdf. Accession date 10/31/04)

18. Recall Enforcement Report 6/9/04.
    [**http://www.fda.gov/bbs/topics/enforce/2004/ENF00851.html.
    Accession date
    10/31/-4**](http://www.fda.gov/bbs/topics/enforce/2004/ENF00851.html. Accession date 10/31/-4)

19. Recall Enforcement Report 7/21/04.
    [**http://www.fda.gov/bbs/topics/enforce/2004/ENF00857.html.
    Accession date
    10/31/04**](http://www.fda.gov/bbs/topics/enforce/2004/ENF00857.html. Accession date 10/31/04)

20. Keck G and Ibrahim C. Veterinary Pharmacovigilance: between
    regulation and science. J Vet Pharmacol and Therapeutics
    2001;24:369-373.

21. Brewer T, Colditz GA. Postmarketing surveillance and adverse drug
    reactions: current perspectives and future needs. JAMA 1999;281(9):
    824-829.

22. Telememo in CVM records from Martine Hartogensis to Fort Dodge
    Animal Health. April 10, 2003.

23. Telememo in CVM records from Martine Hartogensis to Fort Dodge
    Animal Health March 13 &14, 2002.

24. Telememo in CVM records from Martine Hartogensis to Fort Dodge
    Animal Health. April 24 & 30, 2002.

25. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the
    operational assessment of adverse drug reactions. I. Background,
    description and instructions for use. JAMA1979;242(7):623-632.

26. Hutchinson TA, Leventhal JM, Kramer MS, et al. An algorithm for the
    operational assessment of adverse drug reactions. II. Demonstration
    of reproducibility and validity. JAMA 1979;242(7):633-638.

27. World Health Organization. The importance of pharmacovigilance:
    safety monitoring of medicinal products. 2002.
    <http://www.who.int/medicines/library/qsm/ip_booklet.pdf>

28. Rodriquez EM, Staffa JA, Graham DJ. The role of databases in
    postmarketing surveillance. Pharmacoepidemiology and Drug Safety
    2001;10:407-410.

29. Hampshire VA. Evaluation of Heartworm Preventative Product
    Ineffectiveness Complaints at the FDA Center for Veterinary
    Medicine. 2004 Annual American Heartworm Association Meeting,
    Philadelphia, PA. July 24, 2004.

30. American Heartworm Society
    <http://www.heartwormsociety.org/CanineHeartwormInfo.htm> accession
    date Dec 18, 2004.

31. Knight DW. 1999 Guidelines for the Diagnosis, Prevention, and
    Management of Heartworm (Dirofilaria Immitis) Infection in Dogs.
    1999 Web posting of the American Heartworm Society.

32. Edwards, G. 2003. Ivermectin: Does P-Glycoprotein play a role in
    neurotoxicity? Filaria Journal 2 (Suppl I): 58.

33. Dunn JK. Diseases of the Haematopoietic System. In: Canine Medicine
    and Therapeutics. ed. Chandler EA and Thompson JB. 3^rd^ edition.
    London, Blackwell Scientific Publications; pp. 425-443.

34. Uchida K. Detection of Autoantibody from Pug Dogs with Necrotizing
    Encephalitis (Pug Dog Encephalitis). Vet Path 1999:36:301-307.

# **Appendix A. Causality Assessment Algorithm for Adverse Drug Events**

**1. Previous Experience With Drug:**

**+1** CM generally recognized to occur in this species at the dosage
received.

**0** CM is not generally recognized to occur in this species at the
dosage received but has been previously reported in veterinary and/or
human medicine.

Drug has limited accumulated clinical experience (time and/or quantity
marketed).

**-1** CM previously unreported and drug has substantial accumulated
clinical experience (time and/or quantity marketed).

**2. Alternative Etiologic Candidates:**

**+2** There is **no** good candidate or no change in a candidate which
can explain the CM, exclusive of drug administration.

**0** An alternative candidate(s) exists, but not a good one(s) which
can **well** explain the CM.

CM commonly occurs spontaneously in this type of patient and situation,
usually in the absence of any recognizable alternative candidate(s).

**-1** There **is** a good candidate or a change in a candidate which
can well explain the CM, exclusive of drug administration.

**3. Timing of Events:**

**+1** Timing was consistent and as expected for this type of CM to this
drug.

**0** Do not know what timing to expect.

**-2** Timing was inconsistent for this type of CM to this drug.

**4. Evidence of Overdose:**

**+1** CM is clearly a dose-related type of manifestation, **and** there
is unequivocal evidence that the amount of drug received was an overdose
for this animal.

**0** CM is not a dose related type of manifestation **or** there in no
evidence of an overdose.

**5. Dechallenge:**

**+1** CM diminished or disappeared after discontinuation of suspect
drug or administration of a **specific** antidote.

> CM is known to be dose-related, and CM diminished or disappeared after
> dosage reduction.

**0** Dechallenge difficult, impossible, or inappropriate to assess.

A non-specific agent or maneuver (non-antidotal was administered that
was directed against the CM and that usually produces the degree and
rate of improvement observed in the case.

CM characteristically transient and episodic, and there is no
established pattern episodes (regardless of what occurs after
discontinuing the drug).

> CM known to be dose-related, and CM did not diminish or disappear
> after dosage was reduced.

**-1** CM did **not** diminish or disappear after discontinuation of
suspect drug.

CM improved without dechallenge **and** the improvement **cannot** be
attributed to the development of tolerance.

**6. Rechallenge:**

**+1** CM unequivocally recurred or exacerbated after rechallenge.

**0** There was no rechallenge attempted.

> A non-specific agent or maneuver (non-antidotal) was administered that
> obscured the response of the CM.

CM failed to recur or exacerbate on rechallenge, **but** the dosage or
duration of drug administration on rechallenge was substantially less
than that suspected of causing the original CM.

Recurrence or exacerbation of CM was impossible to assess because it was
progressing or was at a level of severity that any further increase
would be difficult to appreciate.

**-1** CM failed to recur or exacerbate on rechallenge.

The component scores above are then summed to reach a final causal
score:

**[Scores]{.underline} [Category of Association]{.underline}**

**-9** Not applicable

**-8** Information lacking

**-7** No conclusion

**-1 to -6** Remotely drug-related

**0 to 2** Possibly drug-related

**3 to 5** Probably drug-related

**6 to 7** Definitely drug-related

**-1** Ineffectiveness - Remotely drug-related

**0 to 1** Ineffectiveness - Possibly drug-related

**3** Ineffectiveness - Probably drug-related

**6** Ineffectiveness - Definitely drug-related

#  **Appendix B. Approved Monthly and 6-Month Heartworm Preventives**

+-----+--------+--------+---------------------------------+----+-----+
| **P | **     | *      | **Indications for Dogs**        | ** | *   |
| rod | Active | *Route |                                 | NA | *Ap |
| uct | Ing    | of     |                                 | DA | pro |
| Nam | redien | Admi   |                                 | /A | val |
| e** | t(s)** | nistra |                                 | NA | Dat |
|     |        | tion** |                                 | DA | e** |
|     |        |        |                                 | ** |     |
+-----+--------+--------+---------------------------------+----+-----+
| Hea | Iver   | Oral   | For use in dogs to prevent      | 1  | 4/  |
| rtg | mectin |        | canine heartworm disease.       | 38 | 7/1 |
| ard |        |        | Heartgard® prevents heartworm   | -4 | 987 |
|     |        |        | disease by eliminating the      | 12 |     |
|     |        |        | tissue stage of heartworm       |    |     |
|     |        |        | larvae (*Dirofilaria immitis*)  |    |     |
|     |        |        | for a month (30 days) after     |    |     |
|     |        |        | infection.                      |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Hea | Iver   | Oral   | For use in dogs to prevent      | 1  | 8/  |
| rtg | mectin |        | canine heartworm disease by     | 40 | 9/1 |
| ard |        |        | eliminating the tissue stage of | -8 | 989 |
| Che |        |        | heartworm larvae (*Dirofilaria  | 86 |     |
| wab |        |        | immits)* for one month (30      |    |     |
| les |        |        | days) after infection .         |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Hea | Iver   | Oral   | For use in dogs to prevent      | 1  | 1/1 |
| rtg | mectin |        | canine heartworm disease by     | 40 | 5/1 |
| ard | and    |        | eliminating the tissue stage of | -9 | 993 |
| P   | Py     |        | heartworm larvae (*Dirofilaria  | 71 |     |
| lus | rantel |        | immits)* for one month (30      |    |     |
|     | P      |        | days) after infection andfor    |    |     |
|     | amoate |        | the treatment and control of    |    |     |
|     |        |        | ascarids (*Toxocara canis,      |    |     |
|     |        |        | Toxascaris leonina*) and        |    |     |
|     |        |        | hookworms (*Ancylostoma         |    |     |
|     |        |        | caninum, Uncinaria              |    |     |
|     |        |        | stenocephala*, *Ancylostoma     |    |     |
|     |        |        | braziliense)*.                  |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Adv | Iver   | Oral   | Advantage DUO                   | 1  | 9/2 |
| ant | mectin |        | (imidacloprid/ivermectin) is    | 41 | 7/2 |
| age | and    |        | indicated for the prevention of | -2 | 002 |
| Duo | Imidac |        | heartworm disease caused by     | 08 |     |
|     | loprid |        | *Dirofilaria immitis*, kills    |    |     |
|     |        |        | adult fleas and is indicated    |    |     |
|     |        |        | for the treatment of flea       |    |     |
|     |        |        | infestations (*Ctenocephalides  |    |     |
|     |        |        | felis*). Advantqge DUO is       |    |     |
|     |        |        | recommended for dogs eight      |    |     |
|     |        |        | weeks of age or older.          |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Iv  | Iver   | Oral   | For use in dogs to prevent      | 2  | 1   |
| erh | mectin |        | canine heartworm disease.       | 00 | 1/3 |
| art |        |        | IVERHART tablets prevent        | -2 | 0/2 |
|     |        |        | heartworm disease by            | 70 | 001 |
|     |        |        | eliminating the tissue stage of |    |     |
|     |        |        | heartworm larvae (*Dirofilaria  |    |     |
|     |        |        | immitis*) for one month (30     |    |     |
|     |        |        | days) after infection.          |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| I   | Iver   | Oral   | For use in dogs to prevent      | 2  | 6/1 |
| ver | mectin |        | canine heartworm disease by     | 00 | 8/2 |
| mec |        |        | eliminating the tissue stage of | -2 | 004 |
| tin |        |        | heartworm larvae (*Dirofilaria  | 97 |     |
| Ch  |        |        | immits)* for a month (30 days)  |    |     |
| ewa |        |        | after infection.                |    |     |
| ble |        |        |                                 |    |     |
| T   |        |        |                                 |    |     |
| abl |        |        |                                 |    |     |
| ets |        |        |                                 |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| **P | **     | *      | **Indications for Dogs**        | ** | *   |
| rod | Active | *Route |                                 | NA | *Ap |
| uct | Ing    | of     |                                 | DA | pro |
| Nam | redien | Admi   |                                 | /A | val |
| e** | t(s)** | nistra |                                 | NA | Dat |
|     |        | tion** |                                 | DA | e** |
|     |        |        |                                 | ** |     |
+-----+--------+--------+---------------------------------+----+-----+
| Iv  | Iver   | Oral   | For use in dogs to prevent      | 2  | 5/3 |
| erh | mectin |        | canine heartworm diseases by    | 00 | 0/2 |
| art | and    |        | eliminating the tissue stage of | -3 | 001 |
| P   | Py     |        | heartworm larvae (*Dirofilaria  | 02 |     |
| lus | rantel |        | immitis*) for a month (30 days) |    |     |
|     | P      |        | after infection and for the     |    |     |
|     | amoate |        | treatment and control of        |    |     |
|     |        |        | ascarids (*Toxocara canis,      |    |     |
|     |        |        | Toxascaris* leonina) and        |    |     |
|     |        |        | hookworms (*Ancylostoma         |    |     |
|     |        |        | caninum, Uncinaria stenocephala |    |     |
|     |        |        | Ancylostoma braziliense*).      |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Tri | Iver   | Oral   | For use in dogs to prevent      | 2  | 8/1 |
| -He | mectin |        | canine heartworm diseases by    | 00 | 3/2 |
| art | and    |        | eliminating the tissue stage of | -3 | 003 |
| P   | Py     |        | heartworm larvae (*Dirofilaria  | 38 |     |
| lus | rantel |        | immitis*) for a month (30 days) |    |     |
|     | P      |        | after infection and for the     |    |     |
|     | amoate |        | treatment and control of        |    |     |
|     |        |        | ascarids (*Toxocara canis,      |    |     |
|     |        |        | Toxascaris* leonine) and        |    |     |
|     |        |        | hookworms (*Ancylostoma         |    |     |
|     |        |        | caninum, Uncinaria              |    |     |
|     |        |        | stenocephala, Ancylostoma       |    |     |
|     |        |        | brazilense*).                   |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| In  | Milb   | Oral   | INTERCEPTOR Flavor Tabs are     | 1  | 6/1 |
| ter | emycin |        | indicated for use in the        | 40 | 4/1 |
| cep |        |        | prevention of heartworm disease | -9 | 990 |
| tor | Oxime  |        | caused by *Dirofilaria          | 15 |     |
|     |        |        | immitis*, the control of adult  |    |     |
|     |        |        | *Ancylostoma caninum            |    |     |
|     |        |        | (hookworm)*, and the removal    |    |     |
|     |        |        | and control of adult *Toxocara  |    |     |
|     |        |        | canis* and *Toxascaris leonina* |    |     |
|     |        |        | (roundworms) and *Trichuris     |    |     |
|     |        |        | vulpis* (whilpworm) infections  |    |     |
|     |        |        | in dogs and puppies four weeks  |    |     |
|     |        |        | of age or greater and two       |    |     |
|     |        |        | pounds of body weight or        |    |     |
|     |        |        | greater.                        |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Se  | Milb   | Oral   | SENTINEL Flavor Tabs are        | 1  | 4/1 |
| nti | emycin |        | indicated for use in dogs and   | 41 | 0/1 |
| nel | Oxime  |        | puppies, four weeks of age or   | -0 | 997 |
|     | and    |        | older, and two pounds of body   | 84 |     |
|     | Luf    |        | weight or greater for the       |    |     |
|     | enuron |        | prevention of heartworm disease |    |     |
|     |        |        | caused by *Dirofilaria          |    |     |
|     |        |        | immitis*, for the prevention    |    |     |
|     |        |        | and control of flea             |    |     |
|     |        |        | populations, the control of     |    |     |
|     |        |        | adult *Ancylostoma caninum*     |    |     |
|     |        |        | (hookworm), and the removal and |    |     |
|     |        |        | control of adult *Toxocara      |    |     |
|     |        |        | canis*, and *Toxascaris         |    |     |
|     |        |        | leonina* (roundworm) and        |    |     |
|     |        |        | *Trichuris vulpis* (whipworm)   |    |     |
|     |        |        | infections. Lufenuron controls  |    |     |
|     |        |        | flea populations by preventing  |    |     |
|     |        |        | the development of flea eggs    |    |     |
|     |        |        | and does not kill adult fleas.  |    |     |
|     |        |        | Concurrent use of insecticides  |    |     |
|     |        |        | may be necessary for adequate   |    |     |
|     |        |        | control of adult fleas.         |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| **P | **     | *      | **Indications for Dogs**        | ** | *   |
| rod | Active | *Route |                                 | NA | *Ap |
| uct | Ing    | of     |                                 | DA | pro |
| Nam | redien | Admi   |                                 | /A | val |
| e** | t(s)** | nistra |                                 | NA | Dat |
|     |        | tion** |                                 | DA | e** |
|     |        |        |                                 | ** |     |
+-----+--------+--------+---------------------------------+----+-----+
| Pr  | Moxi   | Oral   | ProHeart (moxidectin) heartworm | 1  | 5/2 |
| oHe | dectin |        | prevention tablets are          | 41 | 7/1 |
| art | (Ta    |        | indicated for once-a-month use  | -0 | 997 |
|     | blets) |        | in dogs to prevent infections   | 51 |     |
|     |        |        | by the canine heartworm,        |    |     |
|     |        |        | *Dirofilaria immitis,* and the  |    |     |
|     |        |        | subsequent development of       |    |     |
|     |        |        | canine heartworm disease.       |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| Pr  | Moxi   | Subcut | ProHeart 6 is indicated for use | 1  | 6/  |
| oHe | dectin | aneous | in dogs six months of age and   | 41 | 6/2 |
| art | (Sus   | Inj    | olderfor the prevention of      | -1 | 001 |
| 6   | tained | ection | heartworm disease caused by     | 89 |     |
|     | Re     |        | *Dirofilaria immitis*. ProHeart |    |     |
|     | lease) |        | 6 is indicated for the          |    |     |
|     |        |        | treatment of existing larval    |    |     |
|     |        |        | and adult hookworm              |    |     |
|     |        |        | (*Ancylostoma caninum* and      |    |     |
|     |        |        | *Unicinaria stenocephala*)      |    |     |
|     |        |        | infections.                     |    |     |
+-----+--------+--------+---------------------------------+----+-----+
| R   | Sela   | T      | Revolution is recommended for   | 1  | 5/2 |
| evo | mectin | opical | use in dogs six weeks of age or | 41 | 6/1 |
| lut |        |        | older for the following         | -1 | 999 |
| ion |        |        | parasites and indications:      | 52 |     |
|     |        |        | Revolution kills adult fleas    |    |     |
|     |        |        | and prevents flea eggs from     |    |     |
|     |        |        | hatching for one month and is   |    |     |
|     |        |        | indicated for the prevention    |    |     |
|     |        |        | and control of flea             |    |     |
|     |        |        | infestations (*Ctenocephalides  |    |     |
|     |        |        | felis*), prevention of          |    |     |
|     |        |        | heartworm disease caused by     |    |     |
|     |        |        | *Dirofilaria immitis*, and the  |    |     |
|     |        |        | treatment and control of ear    |    |     |
|     |        |        | mite (*Otodectes cynotis*)      |    |     |
|     |        |        | infestations. Revolution is     |    |     |
|     |        |        | also indicated for the          |    |     |
|     |        |        | treatment and control of        |    |     |
|     |        |        | sarcoptic mange (*Sarcoptes     |    |     |
|     |        |        | scabiei*) and for the control   |    |     |
|     |        |        | of tick infestations due to     |    |     |
|     |        |        | *Dermacentor variabilis*.       |    |     |
+-----+--------+--------+---------------------------------+----+-----+

# 

# **Appendix C. ProHeart 6 Label, May 2003**

(note, if difficulty viewing click "view" on the tools menu and then
click "print layout".

![](media/image3.png){width="5.483333333333333in"
height="8.991666666666667in"}

![](media/image4.png){width="5.823611111111111in"
height="8.991666666666667in"}

# **Appendix D. Case Studies**

## [Anaphylaxis/Anaphylactoid Reactions]{.underline} 

The following examples represent dogs with anaphylaxis or anaphylactoid
reactions that are possibly or probably associated with ProHeart 6.

1\. [**Case
200202319**](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200202319CVM_REPORT.pdf)\
Signalment:

-   Age: 8 months

-   Breed: Mexican Hairless

-   Gender: Neutered male

-   Weight: 21 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: Neutered on 4/16/02

-   Date of Injection: 4/17/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: ketamine, Valium, isoflurane

-   Outcome: **Euthanasia**

-   Necropsy: Not performed

Causality Assessment Category: Probably drug-related

The dog recovered from surgery and received a ProHeart® 6 injection the
next day in the hospital. He collapsed within 20 minutes and was
transferred to an emergency clinic. Radiographs revealed no significant
findings. He was treated supportively with intravenous fluids. The
attending veterinarian was unable to stabilize his blood pressure, and
the owners elected euthanasia.

2\. [**Case
200306896**](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200306896CVM_REPORT.pdf)

Signalment:

-   Age: 3 years

-   Breed: Schnauzer

-   Gender: Spayed female

-   Weight: 12.5 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 12/17/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Not performed

Causality Assessment Category: Probably drug-related

The dog began to vomit within 20 minutes of the injection. She became
depressed and collapsed shortly after injection. She was treated with
epinephrine, Benadryl, dexamethasone, and intravenous fluids. She
recovered initially, but died during the night.

3**. [Case
200400552](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200400552CVM_REPORT.pdf)**

Signalment:

-   Age: 7 years

-   Breed: Wire Haired Fox Terrier

-   Gender: Spayed female

-   Weight: 24.6 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 1/22/04

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Progressed to severe condition, survived**

-   Necropsy: Not applicable

Causality Assessment Category: Probably drug-related

The dog was depressed and lethargic for 48 hours after the injection and
was taken to Tufts University Teaching Hospital. The attending
veterinarian at Tufts found facial edema and swollen lymph nodes and
diagnosed a delayed hypersensitivity adverse event to ProHeart® 6. The
dog's condition progressed in 12 days to a more generalized adverse
event including thrombocytopenia, prolonged partial thromboplastin time
(PTT), painful abdomen, and elevated bilirubin. She was treated with
tapering doses of Benadryl. The dog was discharged on 2/10/04.

4\. [Case
200403348](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200403348CVM_REPORT.pdf)

Signalment:

-   Age: 8.5 years

-   Breed: Alaskan Malamute

-   Gender: Spayed female

-   Weight: 104 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 5/29/04

-   Dose: Underdosed by 0.16 mL

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Acute death**

-   Necropsy: Acute anaphylactic shock

Causality Assessment Category: Possibly drug-relatedThe dog was found
dead 12 hours post-injection. A post-mortem revealed venous congestion
of the lungs and liver consistent with acute anaphylactic shock.

5\. [Case
200403885](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200403885CVM_REPORT.pdf)

Signalment:

-   Age: 3 years

-   Breed: Staffordshire Bull Terrier

-   Gender: Female

-   Weight: 62 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 6/18/04

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Probably drug-related

The dog began vomiting within 30 minutes of the injection. She became
recumbent with pale membranes within 1 hour. She was given Benadryl and
dexamethasone and recovered.

CVM also had concern about anaphylaxis/toid events reported among dogs
that received ProHeart® 6 concurrently with a vaccine or another drug.
The following examples represent a sample of cases with causality
assessment scores of zero or above for anaphylaxis/anaphylactoid
reactions in the concomitant drug and vaccine subgroup.

6\. [**Case
200200791**](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200200791CVM_REPORT.pdf)

Signalment:

-   Age: 4 years

-   Breed: Miniature Schnauzer

-   Gender: Female spayed

-   Weight: 19 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 2/11/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Distemper vaccination

-   Outcome: **Progressed with multiple clinical signs, recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog collapsed within 2 hours of injection, was treated with fluids,
steroids and diphenhydramine, and released. She presented later that
evening to the emergency clinic at Michigan State University (MSU) with
a seizure. She recovered, but presented to her regular veterinarian the
next day with a papular skin eruption on the neck and back and wheals on
the head. She was referred to MSU for a skin biopsy. No biopsy results
were submitted to CVM, but the dog was progressing well clinically on
4/16/02 re-evaluation.

7\. [**Case
200203569**](../../../../../../../../D:/cases%20for%20narrative/anaphylaxis_%20individual%20case%20reports/200203569%20CVM_REPORT.pdf)

Signalment:

-   Age: 3 years

-   Breed: Pug

-   Gender: Neutered male

-   Weight: 25.6 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: Overweight, arthritis

-   Date of Injection: 6/5/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Carprofen

-   Outcome: **Acute death**

-   Necropsy: Acute anaphylaxis

Causality Assessment Category: Possibly drug relatedThe dog became
agitated during a nail trim following the injection. He vomited,
collapsed, arrested and died within 25 minutes. His body was transported
to the University of Minnesota Veterinary Teaching Hospital for a post
mortem examination; findings were consistent with acute anaphylaxis. The
nail trim may have exacerbated the anaphylactic response due to
endogenous epinephrine release.

## [Convulsions]{.underline}

The following examples represent cases involving convulsions that are
possibly related to ProHeart® 6 injections in the absence of concomitant
vaccinations or drugs.

1.  [Case
    200103398](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200103398CVM_REPORT.PDF)

Signalment:

-   Age: 2 years

-   Breed: Yorkshire Terrier

-   Gender: Male

-   Weight: 3.2 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 7/21/01

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: Progressive neurological signs

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related (convulsion)

Remotely drug-related (encephalitis)

The dog developed convulsions and periorbital pruritus within 2 hours of
ProHeart 6 injection. He was diagnosed with encephalitis of unknown
origin. The cause of small dog encephalitis is not known; drugs are one
etiologic explanation. ^34^

2\. [Case
200104935](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200104935CVM_REPORT.pdf)\
Signalment:

-   Age: 7 years

-   Breed: German Shepherd Mix

-   Gender: male

-   Weight: 100 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 10/15/01

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome**: Recovered, ongoing treatment**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog presented with seizures 30 hours after injection. He was treated
with phenobarbital and Valium. The dose of phenobarbital was decreased
in late October. As of late November, no additional seizures were
reported. The veterinarian listed differential diagnoses of
idiosyncratic drug reaction or epilepsy.

3\. [Case
200202452](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200202452CVM_REPORT.pdf)\
Signalment:

-   Age: 18 months

-   Breed: Pit Bull Terrier

-   Gender: Neutered male

-   Weight: 47.5 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 4/19/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered, ongoing treatment**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

Vomiting, diarrhea, and inappetence began an hour after the injection
and were ongoing for 3 days. He was examined on 4/22/02 and treated with
Baytril, dexamethasone, and cimetidine. The dog began having seizures 9
days after injection. Blood tests showed elevated liver enzymes. He was
treated with Valium and phenobarbital. On 5/5/02 (14 days after
injection) the dog was trembling and had severe pain when he opened his
mouth. A magnetic resonance imaging (MRI) test and a cerebrospinal fluid
(CSF) tap identified no cause for the seizures.

4\. [Case
200207752](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200207752CVM_REPORT.pdf)

Signalment:

-   Age: 3 years

-   Breed: Golden Retriever

-   Gender: Male

-   Weight: 107 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 12/27/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered, onging treatment**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog had a seizure 10 hours after injection. He had two more seizures
over the next 24 hours and was treated with phenobarbital and Valium. He
developed bloody diarrhea and vomiting at 2 weeks post injection and
lost 5 pounds. The veterinarian tried to discontinue phenobarbital in
February 2003, but the dog had another seizure and was started on the
phenobarbital again. No additional seizures were noted at a 2 month
follow-up visit.

5\. [Case
200301322](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200301322CVM_REPORT.pdf)

Signalment:

-   Age: 10 years

-   Breed: Miniature Schnauzer

-   Gender: Spayed female

-   Weight: 30 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 3/1/03 (3^rd^ dose)

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Euthanasia**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

The dog had a seizure 4 days after she was given her third dose of
ProHeart® 6 and developed elevated liver enzymes 7 days later. A
veterinary neurologist developed a differential diagnosis that included
a forebrain lesion due to encephalitis, neoplasia, or a cerebral
vascular incident. The dog was euthanized without a necropsy 25 days
following her injection.

6\. [Case
200301797](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200301797%20ICVM_REPORT.pdf)

Signalment:

-   Age: 2.5 years

-   Breed: Weimaraner

-   Gender: Spayed female

-   Weight: Not provided

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 3/21/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Progressive neurological disease and visual impairment,
    survived**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

Twenty-four hours after injection, the dog developed bloody diarrhea,
vomiting, ataxia and a head tilt. She progressed to a prancing gait and
partial blindness and was referred to the Louisiana Statue University
(LSU) veterinary school. Fungal and tick titers were negative. MRI
revealed dilated optic vessels and subtle changes in the occipital area
of the cerebrum, thalamus, and optic radiation. CSF tap revealed mild
lymphocytic inflammation. Distemper titers were 1:80 indicating
vaccination, infection, or exposure. No diagnosis was made and the dog
was sent home on tapering doses of prednisone. When the owner tried to
wean her off her medication, clinical signs returned.

7\. [Case
200302409](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200302409CVM_REPORT.pdf)

Signalment:

-   Age: 18 months

-   Breed: Papillon

-   Gender: Neutered male

-   Weight: 6.7 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 4/14/03 (2^nd^ dose)

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Meningoencephalitis; cardiac lesions

Causality Assessment Category: Possibly drug-related (seizure)

Remotely drug-related (encephalitis, cardiac lesions)

This dog began to have seizures 48 hours after his second injection of
ProHeart 6. He had two seizures one hour apart. On 4/29/03 he was
started on phenobarbital. He had a seizure and died 16 days after the
ProHeart®6 injection. Necropsy revealed severe necrotizing granulomatous
and eosinophilic meningoencephalitis. Moxidectin levels in the brain
were run and were not found at the limits of detection. In the heart,
the right ventricle was dilated and flabby with dark red foci of the
epicardium. Turk's procedure (a special histopathology stain) indicated
right ventricular hypertrophy.

8\. [Case
200404520](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200404520CVM_REPORT.pdf)

Signalment:

-   Age: 4 years

-   Breed: Chihuahua

-   Gender: Spayed female

-   Weight: 7.4 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 5/14/04 (2^nd^ dose)

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

The dog had one previous ProHeart® 6 injection two years prior. Three
days after her second injection she presented for anorexia and lethargy.
Bloodwork was normal. She was treated with hydroxyzine and Pet-Tinic
vitamins. Four days after that (or 7 days post injection) she had a
seizure. She was treated with diazepam and phenobarbital. She had a
seizure and died two days later (9 days following injection).

The following examples represent cases involving convulsions that were
possibly related to ProHeart® 6 injections in dogs that had received
concomitant vaccines or drugs.

9\. [Case
200105179](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200105179%20CVM_REPORT.pdf)

Signalment:

-   Age: 6 years

-   Breed: Pug

-   Gender: Female

-   Weight: 25 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 10/29/01

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Distemper and rabies vaccinations

-   Outcome: **Died**

-   Necropsy: Inconclusive (body was frozen)

Causality Assessment Category: Possibly drug-related

This dog had a seizure within 10 minutes of the ProHeart® 6 injection
and vaccine administration. She was treated with fluids, Benadryl, and
steroids. She recovered and went home, but later that evening she
presented to an emergency clinic with difficulty breathing. She had
another seizure and died. At necropsy, chronic cardiac changes were
noted. Other organ changes were suggestive of shock but the necropsy was
inconclusive because the body had been frozen.

10\. [Case
200201651](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200201651%20ICVM_REPORT.pdf)

Signalment:

-   Age: 3 years

-   Breed: Mixed

-   Gender: Neutered male

-   Weight: Not recorded

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 3/11/02

-   Dose: Not provided

-   Concomitant Vaccinations or Drugs: Distemper, rabies, and Lyme
    vaccinations

-   Outcome: **Euthanasia**

-   Necropsy: Multifocal ischemia of the brain

Causality Assessment Category: Possibly drug-related

This dog had a seizure 6 days after the ProHeart® 6 and vaccine
administration. He was euthanized 11 days after the injections when he
failed to respond to treatment. A veterinary neurologist at Cornell
University examined the brain, noting multifocal ischemic lesions which
may have been secondary to the seizures. No evidence of inflammation was
found to support a diagnosis of infectious disease or a post-vaccinal
condition.

11\. [Case
200103297](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200103297CVM_REPORT.pdf)

Signalment:

-   Age: 1.5 years

-   Breed: Miniature Pinscher

-   Gender: Male

-   Weight: 13.5 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 6/27/01

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Monthly imidacloprid for fleas

-   Outcome: **Progressive neurological disease, survived**

-   Necropsy: Not provided

Causality Assessment Category: Possibly drug-related

The dog's signs started with ataxia and incoordination 12 hours after
ProHeart 6 injection and progressed to dysmetria, tremors, abnormal
reflexes, and stiffness by 18 days. He was treated successfully through
September and weaned off prednisone. A progress review in December 2001
indicated that he still had tremors when excited.

12\. [Case
200207622](../../../../../../../../D:/cases%20for%20narrative/Convulsion_%20individual%20case%20reports/200207622CVM_REPORT.pdf)

Signalment:

-   Age: 2 years

-   Breed: Pit Bull Terrier

-   Gender: Neutered male

-   Weight: 66.4 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 12/13/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Distemper, rabies, and Lyme
    vaccinations

-   Outcome: **Ongoing seizure disorder**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog started to vomit and have diarrhea within an hour of the
ProHeart® 6 injection and vaccination. He had a seizure 1 day post
--injections. The seizures returned in March and he has continued to see
a neurologist for repetitive seizures. At the last follow-up, he was on
potassium bromide, Valium, and phenobarbital and was having seizures
approximately every two weeks.

## [Liver Signs]{.underline}

The following examples represent cases involving liver lesions noted on
biopsy or necropsy (PR-Liver) or SGPT/ALT elevations that were possibly
related to ProHeart 6.

1\. [Case
200202432](../../../../../../../../D:/cases%20for%20narrative/Liver/200202432CVM_REPORT.PDF)

Signalment:

-   Age: 3 years

-   Breed: Labrador Retriever

-   Gender: Spayed female

-   Weight: 71 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: Mild atopy (skin allergies)

-   Date of Injection: 1/5/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Benadryl as needed for atopy

-   Outcome: **Recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog began vomiting and collapsed 3 days after the injection. She was
taken to an emergency clinic where she was found to be anemic and
tachycardic. She also had elevated liver enzymes. She was treated with
fluids and steroids. She improved and was re-examined the next day by
her regular veterinarian who ruled out toxins and Addison's disease. No
alternative etiologic candidate was found that explained her clinical
manifestations.

2\. [Case
200206333](../../../../../../../../D:/cases%20for%20narrative/Liver/200206333CVM_REPORT.PDF)

Signalment:

-   Age: 4 years

-   Breed: Pit Bull Terrier

-   Gender: Male

-   Weight: 58 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 10/8/02

-   Dose: Underdosed by 0.20 mL

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

The dog had bloody diarrhea and began vomiting within 10 minutes of the
injection. By 2 hours his condition had progressed to collapse,
cyanosis, and pulmonary congestion. He was sent to an emergency referral
clinic where he was treated with crystalloids, cefazolin, enrofloxacin,
famotidine, and sucralfate. He failed to improve, became oliguric, and
was referred to a specialist. His SGPT/ALT was as high as 20,773. He
died by day 3 following the injection. He was included in both the
anaphylaxis/anaphylactoid reaction category and the liver category.

3\. [Case
200303279](../../../../../../../../D:/cases%20for%20narrative/Liver/200303279CVM_REPORT.PDF)

Signalment:

-   Age: 10 years

-   Breed: Labrador Retriever

-   Gender: Spayed female

-   Weight: 72 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 5/20/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Survived**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog was lethargic and anorexic on the evening of her first
injection. By the third day following injection, she was jaundiced and
diagnosed with elevated liver enzymes. Liver biopsy revealed chronic
active hepatitis.

4\. [Case
200401208](../../../../../../../../D:/cases%20for%20narrative/Liver/200401208CVM_REPORT.PDF)

Signalment:

-   Age: 3 years

-   Breed: Jack Russell Terrier

-   Gender: Spayed female

-   Weight: 17 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 8/14/04

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered after several months**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

The dog presented 2 weeks after injection with vomiting, anorexia, and
depression. She was diagnosed at an emergency veterinary center with
elevated liver enzymes and a heart murmur. She was extensively evaluated
by two veterinarians and a specialist and her workups included
radiographs and ultrasound examination. No other cause for her condition
was found. She was treated supportively with fluids, amoxicillin, and
metronidazole and gradually improved over 60 days.

5\. [Case
200303623](../../../../../../../../D:/cases%20for%20narrative/Liver/200303623CVM_REPORT.PDF)\
Signalment:

-   Age: 11 years

-   Breed: Australian Cattle Dog

-   Gender: Neutered male

-   Weight: 32 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 6/3/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Euthanasia**

-   Necropsy: Multiple organ failure secondary to acute myocardial
    degeneration

Causality Assessment Category: Possibly drug-related

This dog showed signs of vomiting and lethargy 4 days after injection.
His blood work revealed elevated creatinine and elevated liver enzymes
and he was treated supportively with intravenous fluids and antibiotics.
He tested negative for antifreeze poisoning and leptospirosis. He failed
to improve and was euthanized at 2 weeks. At necropsy he was noted to
have myocarditis, pneumonia, kidney tubular mineralization, ulceration
of the stomach, endocardiosis, and mild multifocal hemorrhages of the
brain. A veterinary cardiac pathologist reviewed the cardiac slides and
diagnosed acute myocardial degeneration not thought to be related to
hypoxia or epinephrine. The cause of the acute myocarditis could not be
determined. Multiple organ failure was thought to be secondary to the
cardiac condition.

6\. [Case
200202608](../../../../../../../../D:/cases%20for%20narrative/Liver/200202608CVM_REPORT.PDF)

Signalment:

-   Age: 6 years

-   Breed: Maltese

-   Gender: Spayed female

-   Weight: 11.5 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Fair

-   Concomitant Medical Conditions: Mass in bladder, urinary tract
    infection

-   Date of Injection: 4/26/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Baytril

-   Outcome: **Euthanasia**

-   Necropsy: Hepatocellular degeneration, encephalomalacia

Causality Assessment Category: Possibly drug-related

This dog presented for a urinary tract infection. The attending
veterinarian diagnosed a bladder mass by palpation and ultrasound and
prescribed Baytril. It is not clear exactly when the Baytril was
started, but two hours after the ProHeart 6 injection, she was noted to
be lethargic. Forty-eight hours later she had a seizure. She was treated
with Valium and phenobarbital and the seizures stopped. She was
transferred the next day to her regular veterinarian who noted elevated
bile acids and elevated bilirubin. An MRI indicated diffuse infiltrative
disease of the cerebral cortex. The dog was euthanized. A necropsy
indicated a leiomyoma of the bladder which was pre-existing according to
the history. The liver lesion was described as hepatocellular
degeneration. The brain lesion was described as laminar cortical
necrosis of the grey matter; most likely due to hypoxia. This dog had
strong temporal drug association for neurologic and hepatic signs as
well as neurologic signs that were consistent with what has been
observed in other small breeds such as Yorkshire Terriers and Pugs
(discussed previously under convulsions).

## [Hematologic Signs]{.underline}

The following examples represent cases of immune-mediated hemolytic
anemia (IMHA) and/or thrombocytopenia possibly related to ProHeart 6.

1\. [Case
200103479](../../../../../../../../D:/cases%20for%20narrative/AIHA/200103479CVM_REPORT.PDF)

Signalment:

-   Age: 5 years

-   Breed: Australian/Border Collie Mix

-   Gender: Neutered male

-   Weight: 52 lb

History:

-   Heartworm Status: Negative

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 7/5/01

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Euthanasia**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

This dog presented for lethargy and depression 14 days post-injection
and was diagnosed with immune-mediated hemolytic anemia the next day. He
was treated with Oxyglobin® (artificial hemoglobin), steroids, and
antibiotics but did not respond. He was euthanized 12 weeks after his
ProHeart 6 injection.

2\. [Case
200200772I](../../../../../../../../D:/cases%20for%20narrative/AIHA/200200772.PDF)

Signalment:

-   Age: 12 years

-   Breed: Yorkshire Terrier

-   Gender: Spayed female

-   Weight: 12 lb

History:

-   Heartworm Status: Not mentioned

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 1/11/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

This dog was diagnosed with immune-mediated hemolytic anemia 27 days
after injection. She had a packed cell volume of 10% and died overnight
at the local veterinary emergency clinic.

3\. [Case
200201234](../../../../../../../../D:/cases%20for%20narrative/AIHA/200201234CVM_REPORT.PDF)

Signalment:

-   Age: 1 year

-   Breed: Labrador Retriever Mix

-   Gender: Neutered male

-   Weight: 67 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 2/26/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

This dog vomited and was depressed 6 hours after injection and was
treated with dexamethasone, Benadryl, and fluids. Eight days later, he
was diagnosed with immune-mediated hemolytic anemia. He tested negative
for Lyme and Ehrlichia. He was treated with prednisone and Immuran and
recovered.

4\. [Case
200203935I](../../../../../../../../D:/cases%20for%20narrative/AIHA/All%20%20AIHA%20cases.PDF)

Signalment:

-   Age: 5 year

-   Breed: Golden Retriever

-   Gender: Neutered male

-   Weight: 77 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 4/13/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Unknown**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related (IMHA and low
platelets)

This dog presented with exercise intolerance 5 weeks after ProHeart 6
injection. Blood tests showed a Coombs' Positive hemolytic anemia and
thrombocytopenia. He was treated with cyclosporine and prednisone. The
outcome of the case was not provided.

5[. Case
200303433](../../../../../../../../D:/cases%20for%20narrative/AIHA/200303433CVM_REPORT.PDF)

Signalment:

-   Age: 2 years

-   Breed: Dachshund

-   Gender: Neutered male

-   Weight: 40 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: Obesity; narcolepsy

-   Date of Injection: 5/26/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Died**

-   Necropsy: Centrilobular hepatic necrosis; pulmonary vascular
    thrombosis

Causality Assessment Category: Possibly drug-related

This dog presented 34 days after his ProHeart 6 injection with anorexia
and lethargy. His hematocrit on presentation was 11%. He had a positive
slide agglutination test and elevated serum bilirubin. He was treated
with prednisone, but died two days later. Necropsy revealed
centrilobular hepatic necrosis due to severe anemia. He also had
cholestasis, hemosiderosis of the spleen, and pulmonary vascular
thrombosis.

6\. [Case
200305624](../../../../../../../../D:/cases%20for%20narrative/AIHA/200305624CVM_REPORT.PDF)

Signalment:

-   Age: 3 years

-   Breed: Poodle

-   Gender: Spayed female

-   Weight: 15 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 5/22/03

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome: **Recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

This dog was diagnosed with immune-mediated hemolytic anemia 7 days
after ProHeart 6 injection. Her tick panel was negative. She was treated
with azathiaprine, prednisone, doxycycline, and cyclosporine and two
whole blood transfusions. She gradually improved and by six months
post-injection, was off all medications.

7\. [Case 200200725
I](../../../../../../../../D:/cases%20for%20narrative/AIHA/200200725%20ICVM_REPORT.PDF)

Signalment:

-   Age: 11 years

-   Breed: Pit Bull

-   Gender: Spayed female

-   Weight: 21 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: Grade 3 heart murmur

-   Date of Injection: 1/29/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Distemper Vaccination

-   Outcome: **Euthanasia**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related

This dog presented to an emergency clinic 8 days after her injections
with pale mucous membranes. Her packed cell volume was 8.5%, and she was
diagnosed with immune-mediated hemolytic anemia. She was Coombs', Lyme,
and Ehrlichia negative and was treated with a blood transfusion and
prednisone. She was euthanized at day 33 post-injection.

8.      [Case
200307034](../../../../../../../../D:/cases%20for%20narrative/AIHA/All%20%20AIHA%20cases.PDF)

Signalment:

-   Age:  6 years

-   Breed:  Beagle mix

-   Gender:  Neutered male

-   Weight:  50 lb

History:

-   Heartworm Status:  Negative

-   Health Status:  Good

-   Concomitant Medical Conditions: None

-   Date of Injection:  9/27/03 (4^th^ dose)

-   Dose:  Labeled

-   Concomitant Vaccinations or Drugs:  None

-   Outcome:  **Recovered**

-   Necropsy: Not applicable

Causality Assessment Category:  Possibly drug-related

The dog developed a hot spot (pyoderma of the skin) at the tail base 2
hrs after his fourth ProHeart 6 injection and was treated successfully
with gentamycin spray.  He returned to the veterinarian 7 weeks later
with a history of anorexia which started an unknown number of days
prior. He was febrile and weak and was diagnosed with immune-mediated
hemolytic anemia (IMHA). Coombs test and tick panels were negative.  His
chemical profile was normal.  He began a course of doxycycline,
metronidazole, and increasing doses of prednisone. By 4 months, signs
progressed to include elevated liver enzymes, bloody diarrhea, and
vomiting.   This dog was transferred to Purdue University and was
further treated for blood in the stool.  An endoscopic exam revealed
ulceration of the gastrointestinal tract.  Biopsy indicated mild
suppurative inflammation of the gastric mucosa.  No further follow-up
information was provided. 

9[. Case 200202652
I](../../../../../../../../D:/cases%20for%20narrative/AIHA/200202652CVM_REPORT.PDF)

Signalment:

-   Age: 3 years

-   Breed: Rottweiler

-   Gender: Spayed female

-   Weight: 85 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 4/1/02

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: Distemper-Corona and Rabies
    Vaccinations

-   Outcome**: Recovered**

-   Necropsy: Not applicable

Causality Assessment Category: Possibly drug-related

This dog presented 26 days after ProHeart 6 injection and vaccination to
a local emergency clinic for lethargy and depression of unknown
duration. On physical examination, she was icteric. Her packed cell
volume was 8%, and she had a positive slide agglutination test. She was
treated with a blood transfusion, prednisone, and antibiotics.

10\. [Case
200205461](../../../../../../../../D:/cases%20for%20narrative/AIHA/All%20%20AIHA%20cases.PDF)

Signalment:

-   Age: 8 years

-   Breed: Keeshond

-   Gender: Neutered male

-   Weight: 45 lb

History:

-   Heartworm Status: Not provided

-   Health Status: Good

-   Concomitant Medical Conditions: None

-   Date of Injection: 5/9/02 (2^nd^ dose)

-   Dose: Labeled

-   Concomitant Vaccinations or Drugs: None

-   Outcome**: Died**

-   Necropsy: Not performed

Causality Assessment Category: Possibly drug-related (IMHA and low
platelets)

There were no reported problems after the initial dose of ProHeart 6 on
11/2/01. This dog presented with depression and lethargy 14 weeks after
the second injection. His PCV was 11% with agglutinating red cells.
Platelets were estimated at 22,000. He was treated with two blood
transfusions, prednisone, and cytoxin but died in 3 days.

[^1]: Seizures are coded as "convulsions" in the CVM database.