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Questions and Answers regarding the FDA Recall of ProHeart®6

From a Pet Owners Perspective:

Q: Why did CVM ask Fort Dodge Animal Health to recall ProHeart®6?
 
A: Since the product was approved in June 2001, we have received reports of nearly 5,500 serious adverse drug reactions attributed to ProHeart® 6.  After evaluating these reports, the Center for Veterinary Medicine (CVM) determined that at least 1,900 of those were unrelated to the concurrent administration of other drugs or vaccines.  The clinical signs contained in those reports were possibly or probably associated with the ProHeart®6 injection. Many of the adverse events were severe, including more than 600 reports of death.
 
The actual incidence of adverse events is likely to be even higher than reported, because studies show that only a fraction of actual adverse reactions are reported.  Based on its experience with adverse drug reactions attributed to animal drugs over the years, CVM considers the number and severity of those attributed to ProHeart®6 to be unacceptable, even when considering the number of doses of the drug that have been administered.
 
FDA's concern is based on voluntary self-reporting to FDA by veterinarians and owners whose dogs have suffered adverse drug experiences (ADEs) to ProHeart®6 (which contains the drug moxidectin) as well as the mandatory reporting of adverse events by the product’s sponsor, Fort Dodge Animal Health (FDAH).
 
CVM has worked with Fort Dodge to investigate numerous adverse event reports to try to determine the cause of the problem. At FDA’s request, the product sponsor has also made three revisions to the label to include post approval safety information including rare reports of death and a caution to practitioners that dogs should have a negative test for heartworm before administration of ProHeart®6.  The firm has also added a Client Information Sheet and issued two “Dear Doctor” letters to advise veterinarians and pet owners of the risks associated with use of the product.  Despite these label changes and educational efforts, FDA is still receiving an unacceptable number of reports of unexplained and severe adverse events.

Because the cause of the problems associated with ProHeart®6 have not been identified or remedied, and because veterinarians and dog owners have effective alternative heartworm products available to them, CVM believes that removing the product from the market is in the best interest of the dogs and their owners. 
As of September 10, 2004, Fort Dodge submitted the more than 5,500 adverse event reports in compliance with federal regulations (21 CFR §514.80) that require sponsors to submit serious and unexpected adverse drug events within 15 working days of first receiving the information.  
 
Q: Had CVM made Fort Dodge aware of the problem before asking for the product recall?
 
A: CVM has been working with Fort Dodge Animal Health to investigate the numerous adverse event reports to determine the cause of the problem. At FDA’s request, the product sponsor has also made three revisions to the label to include post approval safety information including rare reports of death and a caution to practitioners that dogs should test negative for heartworms before administration of ProHeart®6.  The firm has also added a Client Information Sheet, and issued two “Dear Doctor” letters to advise veterinarians and pet owners of the risks associated with use of the product.  Discussions with Fort Dodge have been ongoing.  CVM has requested that the firm continue to conduct research to determine the cause of related adverse reactions and develop a strategy to help prevent such problems in the future before the product is marketed again.
 
Q: What are Adverse Drug Experience reports? How does the system work?
 
A: Adverse Drug Experience (ADE) reports are voluntary descriptions of side effects that appear to be caused by a drug. Approximately 99% of the ADE reports are filed by veterinarians with the remaining 1% or so coming from consumers. Typically, the reports are filed with the drug sponsor, who is required to send them all to CVM for review and analysis.
 
Q: How are ADE reports analyzed?
 
A: CVM adverse drug experience reviewers, who are experienced veterinarians, use a standardized method to determine whether the side effects are caused by the drug. The multi-part system used by reviewers evaluates the following criteria: previous experience with the drug (the reviewers determine if the side effects have already been predicted), the timing of the reaction, whether the dog was overdosed, whether other disease factors are present, and what happened if the drug was withdrawn or reintroduced. The reports are given a causality score, and only the reports that show the possibility that side effects are associated with the use of the drug are considered when CVM is determining the safety of a product. Those reports that indicate only a remote likelihood that the drug caused the reaction are not considered when determining whether a drug is safe.
 
Q: Do you get ADE reports on other animal drugs?
 
A: Yes, in fact we typically receive many ADE reports following a drug’s approval, and the Center’s experts are constantly reviewing them to identify specific problems and determine the severity or frequency of problems. When problems are detected through this analysis, CVM begins working with the company to determine the cause and potential remedies. The remedies can include label or even dosage changes. In the case of ProHeart®6, the root cause of the severe side effects has not been found, and none of the steps the company has taken, including label changes, has reduced the problem. Therefore, CVM requested that Fort Dodge Animal Health remove the product from the market to protect the health of the dogs.
 
Q: When will the product be allowed back on the market?
 
A: There is no way to predict that. FDA is requesting that the firm continue to conduct research to determine the cause of related adverse reactions and develop a strategy to help prevent such problems in the future before the product is marketed again. The FDA will convene an independent scientific advisory committee to thoroughly evaluate all available data.
 
Q: Has Fort Dodge cooperated with CVM in the review of this product?
 
A: Yes.  As of September 10, 2004, Fort Dodge submitted the more than 5,500 adverse event reports in compliance with federal regulations (21 CFR §514.80) that require sponsors to submit serious and unexpected adverse drug events within 15 working days of first receiving the information.  Fort Dodge has worked with CVM to make label revisions to include post approval safety information including rare reports of death and a caution to practitioners that dogs should have a negative test for heartworm before administration.  The firm has also added a Client Information Sheet, and issued two “Dear Doctor” letters to advise veterinarians and pet owners of the risks associated with use of the product.  Also, after consultations with CVM, the company agreed to recall the product.
 
Q: ProHeart®6 is used in other countries. Are they experiencing problems?
 
A: We have only sketchy data from other countries, so we cannot answer that with any certainty. We want to point out, though, that ProHeart®6 adverse reactions, while many times severe, occur in only a small percentage of treated animals. Whether other countries see reactions may depend on the number of doses given.
 
Q: What more can you tell us about the advisory committee that will review the product?
 
A: The Veterinary Medicine Advisory Committee is made up of various independent scientists who will be asked to evaluate data about the product. No other details about the committee or the meeting dates are available. 
 
Q: My veterinarian just gave my dog a shot of ProHeart®6 before the recall. Why didn’t he know that the product was dangerous?
 
A: Although we have had concerns about ProHeart®6 for several months, it remains an approved product. Therefore, your veterinarian was acting in a completely legal manner when he treated your dog. And neither CVM nor ProHeart®6’s sponsor, Fort Dodge Animal Health, issued any statement saying that the drug was not safe prior to the voluntary recall.
 
The product has produced severe side effects in a limited number of dogs. So most dogs treated with it will not demonstrate any adverse reaction. Nonetheless, because the cause of the problems associated with ProHeart® 6 have not been identified or remedied, and because veterinarians and dog owners have effective alternative heartworm products available to them, CVM believes that removing the product from the market is in the best interest of the dogs and their owners. 
 
The drug manufacturer, Fort Dodge Animal Health, has agreed to voluntarily recall the product.
 
Q: My dog seems to be having or has had a reaction to ProHeart®6. Should I file a report with you about that?
 
A: First, return to your veterinarian and ask him or her to file a report for you. If he or she won’t, you can file a report by going to CVM’s website (<A href="[ioID]1FB93986303A443E810AF23E7CBE7C4A) and go to the Adverse Drug Experience page where you will find a form to use in reporting to FDA. Or you can call 1-888-FDA-VETS to file your report.
 
Q: When will I hear back from CVM about my report?
 
A: You will not hear back from CVM. The reports are analyzed by experts at the Center, and the results are entered into a database. You can view data generated from the database on CVM’s Website.
 
Q:  My dog has received an injection.  What side effects might occur from ProHeart®6, how soon will I see them and how long should I monitor my dog?
 
A: The side effects that are observable to dog owners that have been reported in association with ProHeart® 6 are anorexia (loss of appetite); lethargy; vomiting; neurologic signs, such as seizures, difficulty walking and reports of blindness; jaundice (a yellowish appearance); and bleeding disorders. Most of these observable clinical signs have occurred within one month of receiving the drug.
 
Q:   If my dog does have an abnormality (adverse reaction), how should he be treated?
 
A: A thorough veterinary examination including a routine complete blood count and serum chemistry should reveal most problems. There is no specific antidote for the adverse effects of ProHeart®6.  Supportive care according to the system and abnormality detected is indicated.  Your veterinarian is the best source of treatment advice.  Treatment will depend upon the organ system affected and the severity of the abnormality.
 
Q:  My dog got sick or died after an injection.  What should I do?
 
A: Have your veterinarian file an adverse drug experience report with the company or directly with the FDA. 
 
From a Veterinarian’s Perspective:
 
Q:  I have had more problems with vaccines.   I do not understand why ProHeart®6 is being singled out?
 
A:  CVM does not regulate vaccines.  The UDSA monitors adverse drug reactions in vaccines and it is a voluntary, not a mandatory manufacturer reporting process.   Vaccines do not receive the same scrutiny as drugs.  The testing requirements are different.  A more appropriate comparison would be ProHeart®6 and other heartworm preventatives that go through a pre-approval process at FDA.
 
Q:  Every drug has some side effect or reactions.  Why is ProHeart®6 any different?
 
A:  It is true that all drugs have some side effects.  Many of the adverse drug experiences associated with ProHeart®6 involve serious, life-threatening adverse events, such as anaphylaxis, convulsions, hematopoetic disorders and heptopathies followed, in some instances, by death.  CVM has also evaluated reports that include neurologic problems and, unusual cardiac signs.  If the adverse drug events ended at transient anaphylaxis or other mild sign, CVM would not have requested FDAH to initiate a recall. Second, ProHeart®6 is a sustained release product which, if dosed according to the label, is never withdrawn from the system.
 
Q: Was the recall of ProHeart®6 the result of media hype and done at the spur of the moment?
 
A:  No, CVM has evaluated the adverse drug events over the past several years, worked very hard at obtaining accurate follow up information, and all of this information has originated in veterinary hospitals and been reported through the manufacturer to FDA.  CVM was concerned about this product before the media became aware of the concerns and had already required three label changes and informed the company that they were concerned about the liver and autoimmune signs and were watching those reports carefully.  All of this occurred before March of 2003 when the media became aware them. 

Q:  I have not had any more problems with ProHeart®6 than other heartworm preventatives in my clinic.  How do you explain this fact?
 
A:  There are over 5000 reports of veterinarians who have had a problem with ProHeart®6. 
 
Q: Why were veterinarians not consulted in the decision to remove this product from the market?
 
A: The decision to remove a product from the market is between FDA and the manufacturer.  FDA made the recommendation based on veterinary reporting to the manufacturer in at least 5000 instances.

OVERLAND PARK, Kan. (January 31, 2005) – Fort Dodge Animal Health, a division of Wyeth

(NYSE: WYE), announced today that the Veterinary Medicine Advisory Committee (VMAC) did not reach a consensus regarding its review of safety data for ProHeart® 6. The committee commented on the breadth and complexity of the data presented today and difficulty in drawing firm conclusions. The VMAC is the advisory committee to the Food and Drug Administration’s Center for Veterinary Medicine (CVM).