Side Effects May Include: Sudden Death

Oct 11, 2019 - 8:00 AM

It was just another afternoon at the barn for assistant trainer Sara Greene.* The head trainer was out of town, and Greene was following her normal routine, which included administering medroxyprogesterone acetate, the compounded form of Depo-Provera, to several horses. She injected the last horse on her list and then left his stall to put away the bottle.

“I gave him a shot, and by the time I walked around the corner to the feed room, I heard [someone] scream,” she said. “He had collapsed. He was in shock. His legs were straight out. I guess at that point he was unaware of what was happening to him. He proceeded to canter on his side for 10 minutes, whinnying. I don’t know if he was hallucinating, but it was like he saw his friend across the field and was cantering to his friends. It was horrific.”

The horse died shortly thereafter. A necropsy at a top veterinary hospital revealed that the shot had been administered correctly, and the horse had died of anaphylaxis, an allergic reaction, caused by the medroxyprogesterone acetate.

“Our vet hadn’t heard of this until she started talking to others,” said Greene. “Until she started talking to other vets and asking about it, she didn’t realize this was a possibility.”

Ten years ago Ilene Gudelsky suffered a similar tragedy. She was on her way to the barn for a lesson when she got a phone call that her horse Fig Newton had collapsed following an injection of medroxyprogesterone acetate. By the time she got to the barn, Fig Newton was dead.

“He didn’t do anything wrong; he didn’t deserve that,” she said. “I know they didn’t try to kill him.”

Is It Safe?

Medroxyprogesterone acetate, also known as medroxy or MPA, is a compounded drug rather than one approved by the U.S. Food and Drug Administration for use in animals. Compounding is the manipulation of an existing drug to make a different drug or dosage to meet the needs of a particular patient by a compounding pharmacist. In this case, they’re taking a medication approved as a contraceptive for humans and reformulating it for horses.

Medroxy bottles
Many horsemen administer compounded medroxyprogesterone acetate to help regulate their horses’ behavior. Alison Thayer Photo

The medication was long believed to suppress estrus in mares, but a study by Dr. Patrick McCue, DVM, DACT, and a professor in the clinical sciences department and the equine reproduction laboratory at Colorado State University, showed that unlike altrenogest (brand name Regu-Mate), medroxyprogesterone acetate was not effective at suppressing estrus. Many horsemen report that medroxy does diminish inappropriate behavior in mares, geldings and stallions to make them more rideable and relaxed. Research in rats indicates that medroxyprogesterone acetate may work on the GABA receptors in the brain, much like benzodiazepines such as Valium or Xanax.

Another draw to medroxy is that, unlike Regu-Mate, it’s safe for women to touch. The drug is most often given to hunters, and it’s also commonly used for jumpers.

If medroxyprogesterone acetate is accidentally administered intravenously instead of intramuscularly there’s a big risk of an immediate adverse reaction and death as the medication rushes to the brain. Similar reactions can occur with other suspension drugs like procaine penicillin when they’re administered intravenously.

But even if the drug is administered correctly there’s a risk of anaphylaxis—a life-threatening allergic reaction—which generally sets in a few minutes after injection, and subsequent death.

Dr. Joe Davis, DVM, has twice seen anaphylactic reactions from medroxyprogesterone acetate at Piedmont Equine Practice in The Plains, Virginia. In both cases a veterinarian correctly administered the medication, and the horses died. Both horses had received the drug before without incident.

“The presumption is it takes one [administration] to prime the immune system for anaphylactic response from the second shot,” Davis explained.

Dr. Mark Baus, DVM, founder of Grand Prix Equine in Hawleyville, Connecticut, also had a client’s horse die from an anaphylactic reaction following a correctly administered injection of medroxyprogesterone acetate. This was confirmed by a post-mortem. He hadn’t heard of the reaction before.

“It’s funny, afterward in casual conversation with my colleagues it starts to come out of the woodwork,” said Baus. “ ‘Oh yeah, I heard of that.’ You wouldn’t say this is a pandemic. It’s not a common reaction.”

Death by anaphylaxis following injections of medroxy is uncommon enough that there have been no official warnings, and it hasn’t been studied. And some top veterinarians haven’t had any negative experiences with it.

Co-founder of Fairfield Equine and U.S. Equestrian Team veterinarian Dr. Richard Mitchell, DVM, DACVSMR, has never had a patient in his care have an anaphylactic reaction following the injection of medroxyprogesterone acetate. He considers the medication to be a “very safe drug.” He pointed out that when he was riding ponies in the 1960s the two mares he rode were on medroxy, and he’s never had a problem with it.

That said, Mitchell does recommend a veterinarian give the injection because of the possibility of a bad reaction if it’s inadvertently administered intravenously.

Reactions To The Reaction

So what’s a veterinarian to do?

Dr. Brendan Furlong, MVB, MRCVS, is the president and owner of B.W. Furlong & Associates in Califon, New Jersey, as well as the longtime veterinarian for the U.S. eventing team. When his practice saw four deaths in six years after the administration of medroxy he and his associates decided they wouldn’t recommend, carry or prescribe the drug.

“There’s been no pushback,” said Furlong. “I’m not open for discussion. It’s a very clear decision for me. I’m sure I’ve lost some business because of it, but I also have to be happy in my own mind that I’ve made the right decision. I believe if it was something I felt the cost/benefit analysis was a lot better I might feel differently, but I don’t feel like the potential cost/benefit ratio makes sense.”

Following the second anaphylaxis death at Piedmont Equine Practice, Davis, who is a senior partner in the business, had lawyers draw up a disclosure that is included with the medication whenever clients request medroxyprogesterone acetate.

After Baus’ patient died he started warning clients of the small chance of anaphylaxis, and he began distributing smaller bottles of the drug to lower the chance of contamination by being pierced repeatedly with needles.

“One of the hardest thing to discuss with clients is the small likelihood of a very bad outcome,” said Davis. “That’s one of the things we struggle with. One could argue that even if it killed one out of 900 horses that got it, for maybe 750 horses it makes them ridable for their current owners. That is a conundrum in the truest sense even if I said my only concern is horse welfare. If you can make the horse usable without being longed for four hours or receiving other illicit substances, it’s possible that that’s an acceptable product.

“We’re prescribing an unapproved med for an undefined problem—behavior—so the answer really should be we should never prescribe this,” he continued. “It doesn’t suppress estrus. I try to steer as many people as possible to Regu-Mate.”

What Are The Chances?

After the second horse at his clinic died, Davis attempted to quantify as best he could how common the anaphylactic reaction to medroxyprogesterone acetate really is.

“The problem is that the dose varies from horse to horse,” he said. “When you buy a bottle I can’t say exactly how many doses are in it. If I used a round figure, I came up with 18,000 doses [prescribed by Piedmont Equine], from 2007 to late 2018. So we had 18,000 doses, presumably, and had two horses die. That’s an incidence rate of 1 in 9,000 doses. However, if anaphylaxis occurs on shot No. 2, it’s not doses that are important, it’s horses. I don’t know that number so I have to guess. If we did 10 doses per horse we’re at 1,800 horses treated with an incidence rate of 1 in 900. That’s pretty high. It’s the sort of thing where 1 in 900 made sense in the incidence rate hearing people report it. It’s a guess.”

Vet DSC_6730 copy
Even some top veterinarians aren’t familiar with the dangers of medroxyprogesterone acetate. Mollie Bailey Photo

When horses have an adverse reaction to a compounded drug, the owner or veterinarian may report the issue to the pharmacy that prepared it. The Chronicle reached out to three compounding pharmacies for comment. Laura Riley, the pharmacist in charge at Hagyard Pharmacy in Lexington, Kentucky, said she isn’t aware of any deaths from anaphylaxis following administration of medroxyprogesterone acetate. Wickliffe Veterinary Pharmacy in Lexington, Kentucky, declined to respond. Wedgewood Pharmacy is a New Jersey compounding pharmacy licensed in 49 states that compounded the medroxyprogesterone acetate administered to several of the horses mentioned in this story that died. Wedgewood declined to give a raw number of reported deaths that had occurred from anaphylaxis following a medroxyprogesterone acetate injection.

“It wouldn’t be an accurate reflection of what happened to the horse,” said Nicole DeVirgiliis, quality director at Wedgewood. “Was the horse sick? Was the horse taking three other medications that would have contributed to the death? So a hard and fast number would just be a hard and fast number. It wouldn’t have any meaning behind it. Of the doses of medroxyprogesterone acetate that we’ve dispensed we have a death incident rate of .001 percent.”

DeVirgiliis said individual bottles of the drug do not list potential side effects.

“As a compounding pharmacy we rely on the vets to prescribe what they feel their patient needs, so they’re the learned person who should know those things, by referencing journals or Plumb’s [a veterinary drug guide] or things of that nature,” she said. “As a compounding pharmacy we’re not allowed to make any claims.”

Where’s The Proof?

In early 2017 the U.S. Equestrian Federation began looking into medroxyprogesterone acetate, which is show ring legal in the USA. USEF officials were primarily discussing the drug because of its effect on behavior, which goes against the spirit of the rules. Some equestrians, primarily from the show hunter world, strongly advocated for the medication, which they viewed as safe and a better alternative to excessive longeing or exercise. USEF officials convened the USEF MPA Panel to look into the medication and its use.

“My personal feeling is that no one has proven to me that the odds of [death by anaphylaxis] happening are higher than anything else,” said trainer Geoff Teall, who sits on the panel. “I’ve never personally had an episode of that, nor have I heard of it. I have had a horse one time have [a bad reaction] from antibiotics.

“I’m very interested in the research,” he continued. “If there’s proof that there’s something that is a bad thing for our horses, certainly I want to know about it. I’d be in favor of getting rid of it.”

Unfortunately that “proof” regarding medroxyprogesterone acetate is hard to come by.

DeVirgiliis said that while there’s an internal investigation any time a death related to a medication occurs, Wedgewood doesn’t report the death to the state licensing board, the FDA or anyone else. No one is collecting data on how many horses are dying by anaphylaxis following a medroxyprogesterone acetate injection.

Dr. Joseph Bertone, DVM, DACVIM, has studied drug compounding and speaks often on the issue. He’s a former employee of the FDA and a current professor at Western University of Health Sciences’ College of Veterinary Medicine (California). He explained that there’s not a great way to quantify how many drug problems occur due to compounded drugs, like compounded medroxy.

“Unfortunately, though the FDA has regulatory authority, they choose to apply little regulatory enforcement on these issues,” said Bertone. “Veterinarians and consumers should still report issues to the FDA, and if enough are collected, FDA may do something. It’s up to veterinarians to communicate these issues. We need to help regulate this ourselves by exposing these issues when they occur. If a horse has a serious problem when any drug, compounded or approved, is used, we need to share these instances with others so that we raise awareness. Animal drugs for horses and pets (non-food animals) are simply low priority to the FDA.”

The Canadian Example

Equestrian Canada officials banned medroxyprogesterone acetate this season after a two-year phase-in period, as they believe the medication alters behavior and is therefore contrary to the spirit of the EC rules, the same argument being made by some in the United States as well.

Dr. Yves Rossier, DVM, DACVIM and the chair of Equestrian Canada’s Equine Medication Control Committee, sits on the Fédération Equestre Internationale Veterinary Committee and serves as the national head veterinarian for the FEI for Canada. He said that the lack of studies on medroxy and understanding of how it works make the drug problematic, and it certainly doesn’t help that EC started hearing about horses dying from anaphylaxis when they looked into prohibiting the drug.

“There’s no science to describe potential side effects,” said Rossier, who’s also a professor at the University of Montreal Veterinary School in Saint-Hyacinthe, Quebec. “One difficult part is that people are using a compounded product, which adds another form of uncertainty.”

Rossier said that EC has seen one positive so far this year for medroxyprogesterone acetate.

“We’re quite proud in Canada that we took the lead on medroxyprogesterone,” said Dr. Geoff Vernon, DVM, who has served as a team veterinarian for the U.S. show jumping team and the Canadian dressage team. “It was difficult for us because we like to maintain a very good relationship with our American neighbors; our competitions thrive because of the participation of U.S. competitors. When you start making medication rules that don’t match and aren’t coherent that comes at a cost.”

The drug is also prohibited by the FEI, which considers it a controlled substance. That means that not only are U.S. riders who compete on both sides of the border and use medroxy at risk of a positive—the drug has an indeterminate withdrawal time and may take months to leave a horse’s system—but also riders who compete primarily in national competition and just occasionally in FEI, say the FEI North American Youth Championships.

“The conundrum is you have a drug with no therapeutic indication for use in the horse, and it is being used in sole purpose for affecting behavior and therefore altering performance,” said Vernon, Toronto. “It has the potential for sudden death from anaphylaxis from administration. I’ve yet to see a horse die from the administration of something like Dormosedan [detomidine hydrochloride] or Sedivet [romifidine hydrochloride] or acepromazine, so those are safe drugs that alter performance that have sedating, tranquilizing effects. So why are we permitting a dangerous drug to be used for the same purpose of more safe drugs?

“There seems to be a contradiction to me in the philosophy of what’s going on,” Vernon continued. “But in fairness to [Dr. Stephen Schumacher, DVM, the USEF chief administrator of the drugs and medication program] and the medication committee of U.S. Equestrian, this has been a big, big battle because the trainers really push back hard on any changes. The tail wags the dog. The perception is, mistakenly, two things: One that medroxyprogesterone suppresses estrus—which it doesn’t—and second that it’s a safe drug, which it isn’t. I think if people really knew what the risks were they’d go ‘Wow!’ ”

*This individual’s name has been changed.


This article appeared in the Oct. 7 & 14, 2019, issue of The Chronicle of the Horse as part of our Horse Care issue.

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