Photo by Carly Taft
Nine out of 10 brands of levothyroxine sodium used to treat hypothyroidism in dogs no longer may be manufactured or distributed due to a federal initiative to cut the number of unapproved animal drugs on the market. However, practitioners with existing stocks of the drugs, such as these products at a veterinary clinic in Ohio, may continue to prescribe what they have on hand, FDA officials say.
The number of medicines available to veterinarians for treating hypothyroidism in dogs is dropping from 10 to one, following a U.S. Food and Drug Administration warning to multiple manufacturers of levothyroxine sodium that they no longer may sell their unapproved products.
The warnings came shortly after Thyro-Tabs Canine made by Lloyd Inc. became the first — and so far only — brand of veterinary levothyroxine sodium to receive FDA approval.
Levothyroxine products have been used with apparent safety for decades in dogs and people alike to treat hypothyroidism, a condition in which the thyroid gland produces abnormally low levels of hormones that control metabolism.
The FDA warnings aren’t based on findings that the prohibited levothyroxine products are dangerous or ineffective. Rather, they stem from the agency’s strategy to prod makers of established but unapproved drugs to achieve FDA approval, according to Dr. Martine Hartogensis, deputy director of the FDA Center for Veterinary Medicine Office of Surveillance and Compliance.
Hartogensis said that although manufacturers must stop making unapproved levothyroxine products and distributors must stop selling them, the agency is not asking veterinarians to stop prescribing from their remaining stock.
"This action certainly is not meant to put panic in veterinarians and have them go to drastic measures," Hartogensis told the VIN News Service. "This is really all about supporting our approval process and also helping educate veterinarians about the benefits of using approved products. We’re really focused on working with the manufacturers. ... "
She added: "For veterinarians, my best advice would be that they should take steps to transition their patients to the approved product."
The FDA announced on Jan. 29 that it sent warning letters to Merck Animal Health, Neogen Corporation, Virbac Animal Health, Quality Animal Care Manufacturing, Dechra Veterinary Products and Diamond Animal Health, notifying the companies that their levothyroxine products are not in compliance with the Federal Food, Drug, and Cosmetic Act of 1938 and "are not generally recognized among experts qualified by scientific training and experience to evaluate the safety and effectiveness of animal drugs, as safe and effective for use under the conditions prescribed, recommended, or suggested in the labeling."
The affected products are Leventa, Levocrine, Soloxine, Thyroid Chewable Tablets, Thyrokare, Thyromed, Thyrosyn, ThyroVet and Thyroxine L.
The move took many in the veterinary community by surprise. Levothyroxine has been used for so long to treat canine hypothyroidism that some veterinarians weren't aware that the drugs were not FDA-approved.
"I was always under the assumption that Soloxine was the brand name [for levothyroxine] and everything else was generic," said Dr. Jeffrey Horn, founder of the Orange County Veterinary Medical Center in Southern California.
Horn estimates that he has about 100 canine patients with hypothyroidism. "You’re always taught in school that Soloxine is the gold standard of thyroid medication," he said. "So when I came to find out that was one of the ones on the list [of unapproved drugs], I was really surprised that there was no FDA-approved [version] that we were using. … It makes me very worried about what other drugs we’re using that are not FDA-approved."
Dr. Dawn Boothe, who directs the clinical pharmacology laboratory at Auburn University College of Veterinary Medicine, also was taken aback.
"I was surprised [to learn] that there was no approved thyroid supplementation in dogs, because we’ve been using it forever," she said.
What’s more, it’s not easy to tell by looking at a drug’s label whether it is approved.
"To know if a drug is approved or not is really difficult," Boothe said. "Today, [when] an animal drug is approved, there will be an ‘NADA’ number on the label that’s on the actual product in hand; that’s a New Animal Drug Approval number. But for older drugs, that NADA number might not be on there, and you can’t say that if it’s not on there, it’s not an approved drug."
The FDA keeps a listing, updated monthly, of all approved animal drugs in a publication known as the Green Book. However, the Green Book is not a perfect reference, either.
As Siobhan DeLancey, a spokeswoman in the FDA Office of Foods and Veterinary Medicine, noted, “Its utility for veterinarians looking to see if a particular animal drug is or is not FDA-approved is somewhat limited, as it doesn’t necessarily list approved products sold under all the different distributor trade names, nor does it include information on unapproved products.”
DeLancey recommended instead consulting the National Library of Medicine's Daily Med website, which posts labels for all drugs. Using the search tool at the top of the page, users may look up any drug, approved or unapproved. Each drug listing includes its marketing status. The marketing status of unapproved drugs is “Unapproved Drug Other.”
The FDA in 2010 announced an initiative to reduce the number of unapproved animal drugs. "We realize that there are a lot of unapproved drugs out there," Hartogensis said, "and our goal is to increase compliance [by] increasing availability of safe and effective drugs and, in part, that means trying to shift the balance between the unapproved drugs to the approved drugs."
She continued: "In that process, we’ve also developed enforcement strategies to further support the approval process, sort of an incentive for manufacturers to get their drugs approved so that we can have the benefits of the approval process."
The benefits, Hartogensis said, are more predictability in manufacturing, including stability of the product; labeling consistent with FDA regulations; and government review of promotion and advertising materials to ensure they're not false or misleading.
In addition, Hartogensis said, with approved drugs, the agency receives ongoing information about safety because manufacturers are required to submit reports of adverse events. In the case of unapproved drugs, companies may voluntarily submit adverse event reports but they are not obligated to do so.
Consequently, the fact that unapproved levothyroxine products have triggered few reports of adverse events has an unclear meaning, Hartogensis said. "Is that because of under-reporting? Or is that because the product is safe and has [few] adverse events? We don't know," she said.
FDA urges manufacturers to apply for approval
Lloyd applied to the FDA for approval of Thyro-Tabs as a veterinary drug in 2005, three years after its Thyro-Tabs product for human patients received the agency's approval, according to Lloyd spokeswoman Dr. Carla Morrow.
She told the VIN News Service that the FDA prompted the company to seek approval for its canine product. "CVM approached Lloyd, and all other manufacturers of veterinary levothyroxine drugs, about having their products go through the FDA approval process," Morrow said by email.
She said that Lloyd tested a variety of canine levothyroxine tablet products and "noticed variability in the product quality. As we had recently received approval for our human product, our company founder, Dr. W. Eugene (Gene) Lloyd, realized the importance and value of obtaining approval for our veterinary product."
Levothyroxine sodium is prone to stability issues, according to the FDA. A presentation posted on the agency website states that the drug is "labile to ... heat, moisture, oxidative conditions [and] chemical reactions." Furthermore, it says, "Many levothyroxine drug products have exhibited ... significant loss of potency over shelf life [and] inconsistent stability profiles within an individual manufacturer's drug product line."
Morrow said Lloyd "spent millions of dollars in perfecting our formulation, [in] improving our manufacturing processes and in conducting the rigorous and largest clinical studies to date needed to prove the safety and efficacy of our product" as part of the FDA approval process.
The expense was worthwhile, Morrow noted, in part because FDA approval comes with five years of marketing exclusivity. That means generic competitors of Thyro-Tabs must wait five years to enter the market, according to Dr. Elizabeth Luddy, deputy director of the CVM Office of New Animal Drug Evaluation. (Makers of generic versions also would need FDA approval.) The marketing exclusivity doesn’t bar manufacturers of non-generic levothyroxine products from seeking FDA approval immediately.
"Any other drug company that markets levothyroxine that wants to get their drug approved through the standard approval process, not a generic copy, we could theoretically approve another levothyroxine tomorrow," Luddy said.
At least two other manufacturers of levothyroxine sodium for dogs are seeking or intend to seek approval for their products.
Michael Albo, vice president of communications and customer service at Virbac, maker of Soloxine, told the VIN News Service that Virbac has manufactured and sold the drug since 2004. "The FDA had used regulatory discretion to permit this, as no manufacturer had [at that point] received FDA approval for their levothyroxine sodium products," Albo said by email. Now, he said, "Virbac Corporation is working with the FDA to register Soloxine and resume manufacturing of the product."
(Before Virbac acquired Soloxine, the product was available under the ownership of other pharmaceutical companies. The now-defunct Daniels Pharmaceuticals Inc. created Soloxine in the early 1980s.)
Neogen Corp., maker of ThyroKare, began pursuing FDA approval in 2013, according to Terri Morrical, vice president of animal safety.
Not every maker of levothyroxine will fall in line.
Merck told the VIN News Service by email that it does not have plans to seek FDA approval for its product, Leventa. Merck did not explain why.
Luddy at the FDA said the agency is amenable to finding ways to expedite the process for unapproved animal drugs that long have been in use.
"There are flexibilities for a drug company to show that they have the data to show that their drug is safe, effective, quality-manufactured, and properly labeled," she said. "The classic standby for years and years has always been a prospective, double-blind clinical trial. That’s one way, and a lot of times for a lot of drugs, that’s the easiest way or the best way. But it’s not the only way. One of the things we’re really excited about with some of these products that have been marketed in an unapproved status for many years is to have the company look to see if there is available evidence of safety and/or effectiveness through studies that are reported in the published literature."
Luddy pointed to the 2014 approval of Folltropin, an injectable follicle-stimulating hormone for cattle derived from pigs’ pituitary glands, as a recent example. Manufacturer Bioniche Animal Health USA was able to provide much of its safety and efficacy data from a systematic review of existing Folltropin studies in cattle, she said.
"The other thing we’re encouraging folks to look at, particularly for the unapproved drugs, is ... use data out there [from] the clinics," Luddy continued. "By using some of the epidemiologic tools such as observational studies and case-controlled studies, there are ways to collect data on the effectiveness, specifically. So instead of doing a prospective study, you’re doing a retrospective study following epidemiological principles. That’s an option for companies, too."
Meanwhile, the American Health Institute, a trade group representing veterinary pharmaceutical companies, has expressed to the FDA dismay with what it perceives as the agency's abrupt adoption of a hard line on unapproved levothyroxine products.
“We ... basically voiced a concern that the approach that they took was overly breathless and punitive,” said Ron Phillips, the group’s vice president of legislative and public affairs. “… There has been an unnecessary uproar and questions about safety created in the marketplace because of the tone and severity of the [warning] letters [sent to manufacturers], which is not necessary in light of a product — albeit an unapproved product — that has been on the market for years without safety concerns.”
Phillips added that his organization supports the shift to approved drugs but it believes “there could have been a more orderly transition, rather than the hammer coming down.”
Will price rise and supply fall?
Some veterinarians express concern that the absence of other levothyroxine products on the market, even if only temporarily, will drive up the price of Thyro-Tabs. Another worry is whether Lloyd will be able to meet demand after stocks of other products are depleted.
Lloyd representative Morrow said the company is prepared. "We had several meetings with CVM on market supply prior to approval and have been ramping up production for several months to ensure we could supply the market without any shortage," she said. "We can assure all veterinarians and practices that ample supplies of Thyro-Tabs Canine are widely available at veterinary distributors..."
Morrow also said Lloyd is not planning any "major price increases" for Thyro-Tabs.
Horn, the veterinarian in Orange County, nonetheless is bracing for higher costs because the other products were less expensive, he said. He stocked up on Thyro-Tabs immediately after hearing about the FDA warning letters.
Horn said he’s concerned that the FDA push on manufacturers to register older, unapproved drugs will lead to shortages and higher drug prices in general. "How many other companies are going to say, ‘If we just get approval we get a five-year [marketing exclusivity], and research is going to be pretty minimal because the drugs are already made’?
"There’s going to be a scramble to patent everything, and what that’s going to do is drive up costs for clients and drive down competition, especially with all the mergers of the big pharmaceutical companies that are out there," he said. "It will be the patients who suffer or the clients having to pay for it who suffer."
As far as transitioning patients to Thyro-Tabs from other products, some veterinarians say it will be inconvenient.
"Any change requires monitoring, as the bioavailability has the potential to vary between products," said Dr. Kristie Ponce, owner of the Animal Medical and Surgical Clinic of Wisconsin Rapids in Wisconsin. "Since that is an added expense, I expect that it will both irritate and inconvenience clients. I know it irritates and inconveniences me!"
While acknowledging the disruption to practitioners and affected pet owners, Auburn’s Boothe said a strong drug-approval process benefits everyone in the long run. The process, she said, is intended "to assure efficacy of the product for the stated claim, and then, of course, to assure a reasonable level of safety."
Edie Lau contributed to this report.