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Update: ProHeart6, removed from the market in 2004, is back. No formula revision but only an extensive label change as well as the Client Information Sheet.

Advisory Committee Meeting
VeterinaryMedicineAdvisoryCommittee/ucm208439.htm

http://forum.dog.com/forums/p/80885/631178.aspx

Website to post your experience with ProHeart6:
http://bewareofproheart6.freecyberzone.com/

ProHeart6 Heartworm Preventative Recalled 

Amidst Veterinary Confusion, Contradictory Research, Passionate Pet Owners Pleas to Discontinue Product…Expert Panel to Decide Outcome by Steve Dale

 ProHeart 6 is the first ever pharmaceutical for pets to be recalled by the United States Food and Drug Administration. The recall of this preventative for canine heartworm disease came at the FDA’s request, announced September 3. Unlike other heartworm preventatives, (which are monthly chewables or pills) this one is an injectable given by a veterinarian, and it has a six month duration.

In other ways, the FDA recall is also unique. Dr. Thomas Nelson, president of the American Heartworm Society seems to represent the feeling of many veterinarians, “I have not seen the science to substantiate the need for a recall,” he says.

The professionals who treat the pets suggest the FDA has been pushed to take their position by watchdog groups of ordinary consumers who have organized on the Internet.

According to both the manufacturer of ProHeart 6, Overland, KS-based Fort Dodge Animal Health and the FDA, there have been 5,552 report adverse events (side effects) reported since the product’s release in the summer of 2001, and 500 deaths. 

Fort Dodge and the FDA agree the majority of those side effects have been minor in nature such as irritation or swelling at the site of the injection. At a recent telephone press conference, even Dr. Stephen Sundloff, director for veterinary medicine at the FDA indicated not all deaths may be directly attributed to ProHeart 6. He explained that the FDA assigns a causality score on each report of death, from a very remote association with the drug to a highly likely link to the drug. He said that most deaths were in the low range of probability of association with ProHeart 6.

“It’s clear too many dogs are dying and there is a direct link to ProHeart 6,” says Meri Christensen of Watertown, WI. In April of 2003, her dogs were given the injection. “It seemed like a good idea at the time,” she says. “One injection and then I don’t have to worry about remembering the monthly heartworm pills for six months. I just wasn’t feeling well that day and didn’t think to ask the vet about side-effects. You’d think the vet might offer that information, but that didn’t happen.”

One of her dogs suffered no ill effects, but the other, Augie, her champion dog in Flyball (a canine sport) began to act lethargic. Augie was soon diagnosed by a second vet with an autoimmune disease. That second vet believed the disease was a direct result of the ProHeart injection.

When asked at the teleconference what type of side-effects pet owners should be most watchful for, Sundloff mentioned lethargy, vomiting, bleeding and other generalized symptoms. However, more problematic are anecdotal reports of fatal autoimmune issues and seizures being consistent as a reaction.

Christensen fought valiantly to save her dog. “But when lesions began to appear on Augie’s tongue, and then all over his body,” she pauses. “I can still barely talk about it. There was no reason this wonderful dog had to die, but he did and on my birthday (in August, 2003).”

Christensen joined a previously organized effort on the Internet to warn consumers, alert the media (stories on ProHeart 6 made the rounds on many TV and radio stations, and in newspapers several months back) and ultimately get the product banned. “We feel it’s unsafe, and someone has to speak up for dogs,” she says.

“I understand the emotional impact these pet owners feel,” says Dr. Rami Cobb, vice president of Pharmaceutical Research & Development at Fort Dodge, who doesn’t deny that some deaths are attributed to ProHeart 6. “After all, it is a drug – the reality is that all drugs can result in a potentially a severe reaction. But we’ve had (administered) 18 million doses of it. Even at the reported numbers (including those that the FDA concedes may not be linked to ProHeart 6 with certainty) we are still within WHO (World Health Organization) guidelines.”

Cobb says she’s mystified about why the same drug has been prescribed as the most often used heartworm preventative in Australia (since 2000) and in Italy, and their regulatory agencies don’t have an issue.

“You’d figure the American Heartworm Society would be hearing from veterinarians from all over America who are having problems with ProHeart, but we’re not,” Nelson adds.

There’s clearly a breach between what veterinarians are reporting and what groups on the Internet contend. Dr. Larry Glickman, professor of epidemiology and environmental medicine at Purdue University School of Veterinary Medicine – West Lafayette, IN says he just wants to learn the truth. Like Nelson, he has no special interest in Ft. Dodge.

Glickman revealed for this column his findings (which have also been reported to both the FDA and Ft. Dodge, but until now not to the media), looking at the pure data of over 400 veterinary clinics all operated by Banfield. It’s rare to find one source for data in the human or animal health field, and Glickman, has access to the data in the computer system for all Banfield clinics. He researched dogs given ProHeart 6 from February of 2003 through January of 2004.

The data did not fully jive with the FDA or Fort Dodge accounts based on previous complaints. Glickman’s data indicates not a single death was associated with ProHeart 6. Also, 4.4 of each 10,000 dogs dosed with ProHeart 6 alone (not given in conjunction with another vaccine) had a reported a side effect or adverse response; of those 0.8 in 10,000 were considered serious or life threatening. What’s more, anecdotal (unverified) reports had suggested that ProHeart 6 was more likely to create a side effect when given in conjunction with vaccines (which it often was)Glickman’s research showed this was not true.

While this system of gathering data is not perfect, it’s arguably the closest thing to methodically going through real life records. Had Glickman been given more time to accumulate data, he says he certainly would have learned more. “This is actually a wonderful opportunity to objectively look at a product retrospectively and learn,” he says. “Certainly, the clinical trials required for approval for any drug going to market isn’t the same as real world experience.”

The FDA and Ft. Dodge have agreed to create an independent advisory panel to review real world safety data concerning ProHeart 6. “We don’t really understand why we are seeing the problems we are seeing,” Sundloff said at the teleconference.

Glickman says, “The first goal should be to determine to what extent those problems actually do exist in the first place, then describe what those specific problems are, and go from there.”

Nelson adds, he wishes there was a way to include the number of animals whose lives have been saved because they’ve used ProHeart 6 into the data. “For people who might otherwise forget to dose dogs with a heartworm preventative, ProHeart 6 has been literally a lifesaver (since heartworm disease is often fatal). I just hope people understand they need to protect their pets from heartworm.”

"It’s all about the truth, Christensen says. “Consumers just want the truth.” Meanwhile, ProHeart 6 will remain unavailable. The FDA wouldn’t make additional veterinary personnel available to comment by this story’s deadline. 

Pro Heart 6

The following is listed for clinical field trials for NADA 141-189:

"Adverse Reactions:   The following potential adverse drug reactions (number of cases) were observed in the moxidectin injectable treatment group: vomiting (3), diarrhea (2), weight loss (2), listlessness (1), seizures (1), injection site pruritus (3), elevated body temperature (1). Injection site evaluations of the ProHeart 6 treated dogs revealed no abnormalities.

Two geriatric dogs with a history of weight loss after the initial ProHeart® 6 injection died within a month of the second 6-month injection.   A third dog who was underweight for its age and breed and who had a history of congenital problems experienced lethargy following the initial injection of ProHeart® 6.   The dog never recovered and died 3 months later.   Treatment with ProHeart® 6 could not be ruled out as contributing to these observations."

Fort Dodge Animal Health, Division of Wyeth
9401 Indian Creek Parkway, Suite 1000, Overland Park, KS 66210 
Steve Connell, DVM , Director Professional Services, (800) 533-8536 

July 22, 2002

Dear Doctor: Thank you for purchasing ProHeart 6 (moxidectin), Fort Dodge Animal Health's innovative product for six-month protection against heartworm infection in dogs.   The purpose of this letter is to provide you with some new information regarding a recently approved label indication for ProHeart 6, as well as a review of the adverse events that have been reported for the product during its introduction into the marketplace.   This update on the performance of ProHeart 6 reflects our desire to share information that has been learned about the product after its first year on the market.

Along with the new indication, a second label change will appear in the "Adverse Reactions" section of the product labeling, and is based on the reporting patterns received from the field.   With over six million doses of ProHeart 6 (moxidectin) sold during the first year, we have seen a number of reported reactions that were not seen in pre-approval clinical studies.   This is typical in cases of a new product after introduction to a wide population base.   Through our work with CVM, a new label statement has been approved for ProHeart 6 describing our post-approval experience.   The new statement being added is as follows: 

Post-Approval Experience: although not all adverse reactions are reported, the following reactions are based on voluntary post-approval drug experience reporting:

  • anaphylaxis/toid reactions

  • depression/lethargy

  •  urticaria

  • head/facial edema

As with anaphylaxis/toid reactions resulting from the use of other injectable products, standard therapeutic intervention should be initiated immediately.

Since introduction, we have received and tracked reports from practicing veterinarians regarding adverse events subsequent to the clinical use of Proheart 6. A review of these reports is presented below and includes events observed when ProHeart 6 was administered alone, as well as those observed when given with concurrent medications.   The numbers presented are unfiltered, as reported to CVM, which include observations subsequently determined to be unrelated to product administration.

During the first twelve months of product use, 105 reports of site reactions post administration (.0016% of doses sold into veterinary clinics) have been received.   These events are predominantly swelling, pain, and/or pruritos that are observed post administration.   The vast majority are self-limiting in nature, though selected cases have been treated with anti-inflammatories, and in some cases, antibiotics.

A total of 946 reports of allergic responses post administration (.015%) have been received.   As with vaccines, this category represents the most frequently reported event.   Most of these reactions are mild and have responded to standard medical intervention.   Some, however, have been more severe, including a small percentage of anaphylaxis cases. The most frequently reported effects have been vomiting and diarrhea, followed by angioedema and/or facial swelling, urticaria and gastrointestinal symptoms.   Other less common events include ataxia, weakness, dyspnea, pale mucous membranes, lethargy and fever.

A total of 685 reports of illness post administration (.011%) have also been received.   This category encompasses a wide variety of reports that are received in a broad timeframe  (from one day to several months)  post administration. There is overlap with the allergic events where both allergy and additional symptoms were recorded.   The most frequently reported signs have been vomiting and diarrhea at variable time frames post administration, seizures or other neurological signs and lethargy.   Other rare, but more serious reports, include erythema multiforme in 3 cases and autoimmune hemolytic anemia in a low number of patients, most of whom had received vaccines concurrently.

Full updated letter available here   As is the case when prescribing any medication, careful examination of the dog prior to administration, consideration of appropriate laboratory tests in dogs that may have chronic conditions, and advice to the owner to watch for signs of drug intolerance is good medical practice.   If a drug reaction or intolerance is suspected, examine the patient, provide the necessary supportive therapy, and contact Fort Dodge.  Animal Health Professional Services veterinarians at 1-800-533-8536. Additional information including a copy of the product labeling