Practitioners confused, asking questions about stability concerns following FDA's warning
When Dr. Kathryn Trenholm opened her e-mail earlier this month, a Veterinary Information Network (VIN) newsletter caught her eye. The banner headline read “FDA notice: Vetsulin manufacturing problems.”
With half a dozen diabetic patients on the drug, Trenholm poured over the Food and Drug Administration’s (FDA) warning that some batches of Vetsulin could have varying amounts of crystalline zinc insulin in the formulation. Intervet/Schering-Plough Animal Health, maker of Vetsulin, apparently could not guarantee the stability of the drug, which could result in unpredictable fluctuations in the glucose levels of diabetic patients.
FDA asks that veterinarians closely monitor their diabetic patients on Vetsulin for signs of hyperglycemia or hypoglycemia and consider changing them to other insulin products. If the rumors are correct, they might have to. While Intervet/Schering-Plough admits that production might slow, insider reports are that the company has ceased, for now, to manufacture a drug that FDA warns
could cause a delay in insulin action and an overall longer duration of insulin activity.
Also plaguing the company is growing frustration from veterinarians who complain that a lack of official information from Intervet/Schering-Plough leaves them with little insight into how serious the issue with Vetsulin is and what do to with their remaining product, let alone patients. While Trenholm, practicing in Ayer, Mass., has contacted the owners of her Vetsulin patients by phone to eventually make a switch to another drug, she’s fuming. Armed with bevy of questions, she says: “I have not heard one word from Intervet at all. That infuriates me.
“I was flabbergasted that this is the way I found out about it,” Trenholm adds. “What about the thousands of vets in this country who don’t have VIN? At some point, all this is going to hit the lay press. What are we going to tell our clients then?”
(The American Veterinary Medical Association also published an alert
to its veterinary membership based on the Nov. 2 FDA statement.)
Trenholm refers to questions concerning how Vetsulin stability concerns might translate to the health of clients' pets, whether or not there’s a buy-back policy for the drug or if Intervet/Schering-Plough plans to compensate owners and practitioners for costs tied to transferring pets to new medications. Veterinarians wonder whether the warning applies to the Canadian and European version of Vetsulin, marketed as Caninsulin (it does), how many batches are affected and how the stability issue was detected.
Contacted numerous times by the VIN News Service and VIN’s veterinary consultants, representatives with Intervet/Schering-Plough Animal Health have responded only with an official media statement revealing that the company knows of no data showing that there are efficacy or safety problems with Vetsulin. Still, supplies of the drug might be limited.
According to company spokeswoman Sharon Dilling and Dr. Chris Pappas, director of Companion Animal Technical Services, open discussion or speculation by them about the issue is being discouraged at this time; higher ups within the pharmaceutical company must first approve all Vetsulin statements.
Yet a source within the company who spoke on condition of anonymity shed light on details of what's been dubbed by some as a “big fiasco.” FDA’s warning, according to the source, was prompted when several stability tests, part of the company’s stringent quality control processes, proved to be outside the company’s specifications on three batches, some of which entered the United States.
The clinical impact to patients is thought to be limited and possibly non-existent, the source contends. Additionally, a crossover study was performed on four male and four female non-diabetic, healthy dogs and no difference between affected and unaffected batches was noted. Studies were not performed in diabetic animals due to licensing restrictions.
If Intervet/Schering-Plough cannot find the underlying cause for the variability in the stability test, one solution might be to change its specification guidelines, which the company sets with regulatory agencies.
The issue with Vetsulin could be clinically irrelevant and purely a technical one, the source says. “However, the missing piece of data is the behavior of the affected insulin batches in a large group of diabetic animals.”
To glean that kind of information, FDA has asked veterinarians to report adverse events associated with Intervet/Schering-Plough Animal Health’s Vetsulin to the pharmaceutical company through its Technical Services Department at (800) 224-5318.
Still, a week after FDA issued its warning, Intervet/Schering-Plough’s slow response time and bureaucratic red tape has created an information vacuum that has veterinarians on VIN hungry for facts
Some veterinarians talk of having to alert panic-stricken clients about the potential Vetsulin problems. Others stress about having to switch their patients to new insulin drugs when they’ve experienced good success with Vetsulin. There are even reports of veterinarians buying mass quantities of Vetsulin that are still in stock with distributors, hoping to fend off a shortage, while a good number of VIN members are relaying third-party information to their colleagues who are starved for details about what to do and how to treat patients.
“The problem is a stability issue with the amorphous and crystalline form resulting in delayed onset and increased duration. Therefore BID patients are at highest risk of hypoglycemia,” states one VIN member whose practice manager reportedly spoke with technical services at Intervet/Schering-Plough. “They are recommending using glargine in new cats and NPH in new dogs until supply has been stabilized. It has only been noted in products over 18 months old. The expiration date is two years from the manufacture date, therefore do not use product that is within six months of expiration.”
More clinical recommendations come from VIN consultants like endocrinologist Dr. Sherri Wilson, who also recommends glargine, brand name Lantus, for cats.
“As a second choice, try detemir (Levemir),” she writes. “I would avoid PZI, as it is a compounded insulin, so it’s potency can vary from batch to batch.”
For dogs, Wilson’s first choice is NPH.
“If there is a problem with the NPH taking too long to start working after it is injected, try 70:30 insulin (a mixture of 30 percent regular insulin and 70 percent NPH),” she writes. “Note that this problem of delayed onset of insulin action can also be due to a post-prandial surge in the glucose levels; that can be addressed by giving insulin 30-45 minutes before the food is given (if the dog is a reliable eater).”
If there is a problem with too short of an insulin duration with NPH, then try glargine or detemir, Wilson adds. “But be aware that these sometimes cause no appreciable lowering of glucose levels in some dogs and will be very expensive in large dogs.”
Changing to Lantus (glargine), a human insulin, also can get pricey, with the drug running about $100 for a 10-ml. vial, compared to Vetsulin, which is around $20 for a vial of the same size. For the average cat, that means Lantus is five times as expensive.
Dr. Stijn Niessen, a VIN consultant and endocrinologist practicing in the United Kingdom, says that it seems sensible to not switch animals to new drugs if they are doing well on Vetsulin, but to notify owners of the potential problems and keep an eye on the patients. Regulatory agencies in European countries, so far, have not stopped distribution of the drug, he says. In the United States, however, supplies are likely to soon run short.
While the company works to fix Vetsulin's stability problem, Niessan notes that Intervet/Schering-Plough appears to be working closely with regulatory bodies and doesn't "seem to be hiding" anything.
"However, judging from the many messages we are getting from fellow VINners who have spoken to various company representatives who are telling them different stories, it would be helpful if we would be informed better and quicker by the company, specifically on the practical implications of this situation," he says. "Intervet/Schering-Plough is known to be a professional and client-friendly company, and I hope and expect that they will regain some of that reputation.
"(The company) has an enormous vested interest in promoting Vetsulin/Caninsulin's safety, so I'm pretty sure they will endeavor to solve this problem as soon as possible," Niessen adds.
Trenholm, the practice owner in Ayer, Mass., isn't holding her breath.
“If they were trying to corner the market on veterinary insulin, they’re losing it now,” she says. “I just wonder if the reason Intervet hasn’t done anything is because it’s going to be a pain in the neck and expensive.”
note: The VIN News Service elected to publish this story only to VIN
Members rather than to the general public to avoid causing any
widespread panic among pet owners. Intervet/Schering-Plough Animal
Health has invited VIN consultants to a Web-based meeting on Vetsulin,
scheduled for Nov. 10. We hope to have additional information for you
as a result of that meeting.
VIN News Service commentaries are opinion pieces presenting insights, personal experiences and/or perspectives on topical issues by members of the veterinary community. To submit a commentary for consideration, email firstname.lastname@example.org.