Two years after Vetsulin was pulled from the U.S. market due to a problem with stability, the insulin product for diabetic dogs and cats has been re-approved by the U.S. Food and Drug Administration (FDA) and is back in circulation following manufacturing reforms.

Drug maker Merck Animal Health has instituted several label changes, although the product was not reformulated, company veterinarians said in an interview with the VIN News Service. The label changes involve instructions for use, product description and shelf life.

“The product itself has not changed,” said Dr. Linda Horspool, director of global scientific marketing affairs.

Consequently, patients whose blood sugar wasn’t regulated using Vetsulin before may have no better outcome with the rereleased product.

Any such difficulties likely would stem from variations in the way individuals respond to given insulin products rather than failings of the product, the Merck veterinarians indicated.

Noting that no single insulin product works well in every patient, Horspool said, “It’s about the individual and what works best for them, fitting that in with their owners, what they’re fed and their exercise. There’s no situation where there’s a magic bullet, if you like, that any insulin is the one.”

Dr. Christopher Pappas Jr., Merck director of U.S. scientific marketing affairs, said the company checked whether batches of Vetsulin that failed stability tests were associated with more reports to the Merck help line than batches of Vetsulin that did not have stability issues. “There was no significant difference,” he said.

Merck became aware of the stability problem not because of practitioner or pet owner complaints but through internal quality-control testing, Horspool said.

“We had product that was on the market, and once released, we continued testing,” she said. “There are about nine different parameters in the testing, including sterility, and also the amount of active insulin that’s in the vial.”

Horspool explained that the company tests samples of released product periodically for the duration of its shelf life to ensure stability. In one batch, the ratio of insulin components was found to be outside the limits of its specification.

Vetsulin, a porcine insulin zinc suspension, has two insulin components: an amorphous suspension, which acts immediately and for a short time; and a crystalline portion, which is slower to act and lasts longer. In November 2009, the FDA issued an alert that the crystalline zinc insulin component in Vetsulin was variable, which “could cause a delay in the insulin action and an overall longer duration of insulin activity.” The agency advised veterinarians to consider transitioning patients to a different insulin product. (The alert references Intervet/Schering-Plough Animal Health, which was in the process of being bought by Merck at the time.)

Now the label more accurately reflects the average ratio of crystalline to amorphous insulin, Horspool said: The previous label indicated a 70-percent-to-30 percent average ratio. The revision indicates an average 65-percent-to-35-percent ratio. The only change is in the label, not the product composition, she said.

“Product performance in patients will be unchanged,” Horspool said.

To address the stability problem, Merck reviewed its manufacturing process and tightened protocols to ensure that things are done exactly the same way every time. Using the analogy of baking cookies, Horspool said the ingredients in the recipe are the same but the process of combining them is more strictly prescribed.

For veterinarians and pet owners, the most notable change in Vetsulin’s label is guidance on what to do immediately before using the product. Insulin, a protein, long has been considered fragile, requiring careful handling. The previous Vetsulin label, similar to other insulins, instructed users to gently roll the vial to mix its components.

The new label reads: “Shake the vial thoroughly until a homogeneous, uniformly milky suspension is obtained.”

Dr. Madeleine Stahl, associate director of U.S. scientific marketing affairs for Merck, called the change “the one that is most significant that veterinarians will question.”

It certainly caught the eye of several veterinarians who posted on a message board of the Veterinary Information Network (VIN), an online community for the profession.

“Whatever happened to ‘roll insulin gently to mix it, so as not to destroy the insulin molecules’?" asked Dr. Jennifer Bouthilet, a practitioner in Maplewood, Minn.

“Is there something about Vetsulin that makes shaking it more vigorously than any other insulin all right?” wondered Dr. J. Keith Contarino, a practitioner in Marietta, Ga.

Whether Vetsulin is more robust than other insulin products, Pappas said Merck doesn’t know. “We don’t have data on other insulin,” he said. “We don’t want this to be a general statement (that) ‘Now you can shake insulin.’ ”

Merck tested Vetsulin’s ability to withstand vigorous manual shaking and found that the drug remained intact. Horspool said the new instruction to shake rather than roll the vial is unrelated to the stability problem.

“The shaking is something we had been thinking about for some time,” she said. “(The label change) was to address the fact that the product is two suspensions” that, after settling, she said, “can be quite difficult to be properly mixed again.”

Two other changes in Vetsulin relate to shelf life. Previously, the drug had a 24-month expiration date. The reintroduced product is labeled to expire in 12 months. Merck expects the shorter labeled shelf life to be temporary, continuing until the company completes required real-time studies to demonstrate stability for 24 months.

The new label also states that the product is usable for 42 days from the time the vial is first punctured. The previous label did not specify an in-use shelf life.

Finally, Vetsulin is being sold only in 10-ml vials. A 2.5-ml size offered before was discontinued because it did not sell well, Stahl said. The price has increased on the 10-ml vial by a “moderate” amount to keep pace with inflation, according to Merck spokeswoman Kelly Goss. She declined to specify the amount.

The changes in Vetsulin labeling are outlined in a video presentation posted on the product website.

Pappas said Merck received FDA approval on April 10 to return Vetsulin to the U.S. market. The product, made in Germany, is sold in Canada, Europe and Australia under the name Caninsulin; Horspool noted that the company was not required by regulatory agencies in those countries to suspend sales while it investigated the stability issue.

The FDA’s November 2009 alert about product instability was followed by an announcement in May 2010 that the agency would allow the drug company to make a limited supply of Vetsulin available for dogs or cats whose condition could not be effectively managed on another insulin product. Then in February 2011, the FDA warned of a pending shortage in Vetsulin even for those patients because batches of Vetsulin intended but not yet released for use in the critical-need program had failed sterility tests. At that point, Merck halted production for the U.S. market. Bringing it back required re-approval from the FDA.

The product’s troubled recent history makes some practitioners hesitant to rush back to Vetsulin.

Dr. Maria Deosdade Gonzales, a practitioner in San Antonio, reported, “We’ve had at least the same, if not better, success with NPH insulin,” referring to a human insulin product frequently prescribed for diabetic dogs in an extralabel use.

Gonzales added: “Having a veterinary-labeled product is certainly a consideration, though.”

In addition to NPH, some diabetic dogs were switched to another insulin product labeled for human use, insulin detemir.

Dr. Sherri Wilson, an internal medicine consultant at VIN and a practitioner in Seattle, said: “I think it’s great that Vetsulin is available again, as it gives us another choice for dogs, but I’d not switch them to it just because it’s labeled for animals. If they’re regulated on NPH or detemir, I really wouldn’t change, as you have to start over re-regulating them. But if they were previously regulated on Vetsulin before it went away and we haven’t been able to regulate them since, I’d change back to it. Or if they’ve never been on Vetsulin but I’m not having much luck with the NPH or detemir, I’d change them to Vetsulin.”

Merck veterinarian Pappas echoed that position. “If a cat or a dog has been switched to another insulin and it’s well-regulated, and the client and vet and pet are happy, we see no reason to switch back (to Vetsulin),” he said. “If they have a history of being better regulated on Vetsulin, then those would be the candidates to switch back. We don’t want to give a blanket statement. That would not be good medicine.”

For newly diagnosed diabetics, Dr. Mark Peterson, a veterinary endocrinologist, offers an opinion on his blog that Vetsulin is a good first choice for dogs but generally not for cats. An endocrinology consultant for VIN who also has consulted for Merck on Vetsulin, Peterson discusses the various insulin options and provides a cost comparison.