A grassroots petition to make pergolide mesylate available for the treatment of horses with Cushing’s disease proves the squeaky wheel gets the grease.

It’s been conservatively estimated that 75,000 U.S. horses suffer from Cushing’s Syndrome, also known as pituitary pars intermedia dysfunction. A hormonal imbalance that usually hits horses in their teens or 20s (though there have been instances of much earlier onset), Cushing’s in-creases a horse’s thirst and urination, triggers the growth of an abnormally heavy, often curly winter coat year-round, causes immunosuppression and significantly increases the risk of laminitis. Eventually, it is fatal.

For at least the past decade, the treatment of choice for Cushing’s horses has been a drug called pergolide mesylate (brand name Permax). At very low doses—averaging 1 mg a day—pergolide, a dopamine agonist, reverses many of the symptoms of Cushing’s for the vast majority of affected horses. While it’s not a cure, it often provides years of improved quality of life for older horses and their devoted owners.

But pergolide, originally developed as a drug for the treatment of Parkinson’s Disease, was recently implicated in a handful of cases of cardiac valve dysfunction in human patients. Between that, and the fact that newer and safer drugs had become available for Parkinson’s sufferers, the U.S. Food and Drug Administration issued a warning, which prompted a voluntary withdrawal of the drug from the market on March 29.

Horses are very sensitive to the drug, so they need only miniscule doses, and no cardiac side effects similar to those in humans have ever been reported. Pergolide is also vastly more effective than the second-choice drug, cyproheptadine. The FDA announcement, which prompted the three U.S. drug companies manufacturing pergolide to cease doing so, threw the veterinary community into a crisis, when suddenly the supply threatened to dry up.

Find Me A Source

Like many drugs produced and intended for humans, pergolide was being used “off-label” by veterinarians to treat equine Cushing’s patients. Veterinarians have been prescribing the drug under the provisions of the Animal Medicinal Drug Use Clarification Act.

Veterinarians ordinarily source drugs like pergolide (which are not specifically labeled for equine use) in one of two ways: either by prescribing the human form at an appropriate dosage for the equine patient, or by getting it from a compounding pharmacy, which makes up prescriptions with generic forms of the drugs, or their ingredients, on a case-by-case basis.

With the production of pergolide pills halted, compounders were forced to rely on bulk ingredients, imported from Canada or overseas, to create the drug. But bulk compounding (making up large batches of a drug and then selling based on demand) is considered a violation of FDA guidelines, though it has issued exemptions for certain substances in the past.

“It was concerning,” said Melinda Freckleton, DVM, of Haymarket Veterinary Services in Haymarket, Va. “Over 1 percent of the horses in our practice are on pergolide, including a beloved horse of my own who I’ve had for 20 years. And there are many more clients out there with Cushing’s horses who aren’t on the drug but probably should be.”

She noted that while Cushing’s is generally considered a geriatric disease, every few years the endrocrinologists drop the age at which they expect to first see Cushing’s symptoms in horses and encourage veterinarians to watch closely for the symptoms.

“No other drug can substitute for pergolide,” she added. “Horses tolerate it very, very well, and there are no side-effects. Cyprohep-tadine doesn’t do the same job, and it’s actually more expensive. I consider it a distant second-choice drug.”

Grassroots Action

Members of an online discussion group for owners of Cushing’s and insulin-resistant horses didn’t waste time spreading the word that pergolide was about to become unobtainable in the United States. Within a week, a petition had been launched to ask the FDA to publish a specific exemption for the importation of pergolide for veterinary use, as well as a specific exemption to the prohibition of the use of the drug in bulk veterinary compounding.

Addressed to Stephen Sundlof, DVM, Ph.D., the Director of the Center for Veterinary Medicine within the FDA, Dr. Marcia Larkins, Ombudsman for the CVM, Andrew von Eschenbach, FDA Commissioner, and Virginia Behr, FDA Ombudsman, the petition pointed out that pergolide had a crucial role to play in the management of Cushing’s horses.

Eleanor Kellon, VMD, co-owner and veterinary advisor to the Cushing’s/IR discussion group, led the charge, encouraging members to write personalized letters to the FDA as well as their congressional representatives and to lobby the media for coverage of the impending veterinary crisis.

Many of the pleas were poignant: “I have a 36-year-old gelding who would not be alive without pergolide!” read one. “We still ride trails, chase cows and do many things I know we would never be doing without that medication.”

Another said: “My daughter’s 12-year-old pony has recently been diagnosed with Cushing’s. He has suffered laminitis for the past four months but is making a dramatic recovery thanks to pergolide. Please help him and the thousands of others like him. He’s too young to die. Let him have a chance of a long and happy life.”

Kellon also lobbied drug wholesalers to make them aware of the veterinary use for pergolide and asked for guarantees that they would continue to stock the drug, even as horse owners started to report supplies were drying up, or that pharmacies were price-gouging on what small stock they had left.

And she urged other veterinarians to make their voices heard with the CVM, the American Association of Equine Practitioners, and its state chapters. Letters and background information on the need for pergolide were also sent to the Boards of Pharmacy in each of the 50 states, in the hope that might open the door for exemptions on a state-by-state basis.

Freckleton became involved in the campaign as liaison for the Virginia Association of Equine Practitioners.

“The pharmacies would have run out [of pergolide] by late summer or early fall, which is just about the most dangerous time of year for Cushing’s horses,” she said. “That’s when there’s a surge of sugars in pasture grass, at the same time that ACTH [andrenocorticotropic hormone, produced by the pituitary gland that, in Cushing’s horses, triggers overproduction of cortisol from the adrenal gland] surges in horses as they prepare for winter.”

As the petition swelled to more than 4,800 signatures, it got the attention of FDA officials, and replies started trickling back to those who’d written letters and e-mails, saying the agency was looking into the matter. Kellon described the FDA as “responsive,”

but after the agency promised a response or solution to the pergolide crisis would be published by April 20, and none appeared, veterinarians and horse owners stepped up the pressure.

Kellon even prepared what she called “The Surprise.” “We were going to have between 35 and 40 express mail boxes (not envelopes) delivered to David Horowitz’s [Division of Compliance at the FDA] office at the same time. Inside each box would be 10 or more printed pages of petition signatures and a ‘pointed’ cover letter. On that same day we were set up to tie up his fax machine, faxing each and every signature. Local news and TV were to have been tipped off, and a letter to the editor would have been sent to every newspaper in the Baltimore/D.C. area starting something like, ‘The office of David Horowitz will be a hectic place today…’ ”

Victory Is Sweet

“What a relief to not have to do it,” Kellon wrote on the Cushing’s/IR chatlist. On May 11, the Center for Veterinary Medicine, a division of the FDA, issued a statement, which said, in part: “CVM recognizes that veterinarians are prescribing pergolide for the treatment of Cushing’s Syndrome in horses. Veterinarians have been prescribing the drug under the provisions of the Animal Medicinal Drug Use Clarification Act, which allows veterinary practitioners to prescribe approved human drugs for ‘extralabel’ use in animals.

“FDA is working with the [manufacturers] of the approved products and all other interested parties to ensure that pergolide remains available to treat Cushing’s Syndrome in horses until a new animal drug application is approved for that use. This includes trying to make the approved product available through veterinary distribution channels and exercising enforcement discretion as appropriate over the pharmacy compounding of pergolide. Bulk substance used for pharmacy compounding should be labeled for ‘animal use only.’ All pharmacy compounding must be done under a valid veterinary prescription to treat an affected horse.”

Translation: The FDA did not issue the exemption for bulk compounding that veter-inarians and horse owners had been lobbying for, but they agreed to a compromise solution. It would exercise enforcement discretion as appropriate over the pharmacy compounding of pergolide, so long as certain criteria are met—for example the drug can be made only with a valid prescription for an individual animal, and bulk ingredients must be clearly marked “for veterinary use only.”

In other words, said Kellon, “The exemption would have been a statement that they are allowing it, not considering it illegal. The regulatory discretion basically means they’ll look the other way but technically they still consider it illegal.

“Either one works for us; either one keeps the flow of drug to the compounders. [The] only difference is the FDA saves face a bit more with regulatory discretion,” she noted.

From the FDA’s point of view, she added, the ideal solution would be for one of the three U.S. drug companies who previously manufactured pergolide for human use, to volunteer to do so again for the veterinary market. So far, that hasn’t happened, despite Kellon having calculated that U.S. horse owners go through an estimated 2,250 kilograms of the drug per month, a sizeable quantity by anyone’s standards.

Should it transpire, horse owners and veterinarians will only be able to source pergolide through that route, but for the moment drug compounders (which can usually produce the drug more cheaply) are the sole source of pergolide for equine use.

Freckleton said, “The FDA has addressed the crisis adequately and in time. My concern now is whether the cost of the drug will increase. It has never been inexpensive, and if the price goes up significantly we’ll have even more Cushing’s horses left untreated.”

For now, though, veterinarians and owners of Cushing’s horses are savoring their victory. “A lot of hard work by a large number of people went into getting this resolution,” Kellon said. “We’ve been working on it since the week after the announcement of the drug’s withdrawal. It’s been a long six weeks, but we’re all pleased that the FDA acted in time to prevent any horses having to go without treatment.

“The FDA’s action has averted a crisis in health care,” she concluded.