For nearly three years after a miniature pinscher named Ditty was diagnosed with diabetes, his owner successfully managed his blood-sugar levels by giving him regular shots of insulin.

Then Ditty abruptly turned hypoglycemic. His owner brought the shaky, unsteady dog to his veterinary clinic in Poland, Maine.

Dr. Derralyn Rennix quizzed Ditty’s owner about what might have changed in the dog’s daily routine. Different food? More exercise? That’s when the owner remembered: A week or two earlier, the Wal-Mart pharmacy where she purchased Ditty’s insulin had switched his brand of medication because of changes in pricing.

“She was told by the pharmacist that they were the same,” Rennix told the VIN News Service. “...They switched — without calling us, without asking us, without telling us, they just told the owner it was the same.”

The idea that different brands of the same type of insulin are readily interchangeable isn’t unusual. It’s a common understanding in the medical community. But while it may be true for most human diabetics, switching brands seems to spell trouble for some veterinary patients.

On the Veterinary Information Network (VIN), an online community for the profession, numerous practitioners around the country have reported in recent months cases of dogs whose insulin brands were switched developing out-of-control blood glucose levels, a potentially life-threatening condition that can be expensive to remedy.

Dr. Sherri Wilson, an internal medicine consultant at VIN, called the information “an eye-opener.” On a message board discussion in which multiple colleagues described cases of dysregulation, Wilson commented, “It has really changed how I think about this brand change ...”

Asked about its policies and practices in substituting insulin brands, Wal-Mart acknowledged a recent switch but did not speak to whether or how its employees are supposed to inform customers of the change.

The insulins in question are NPH type, an intermediate-duration form of the hormone. (Insulins come in a variety of types, including rapid-acting, intermediate-acting and long-acting, of which different brands exist.) NPH insulin is characterized by its crystalline structure, which, when injected subcutaneously, is absorbed relatively slowly by the body, according to Gigi Davidson, director of clinical pharmacy services at North Carolina State University's Veterinary Teaching Hospital.

Two brands of NPH insulin are on the market: Humulin N, made by Eli Lilly and Co.; and Novolin N, made by Novo Nordisk Inc.

Spokespersons for the manufacturers say their brands are not identical. “Humulin and Novolin are made using different ingredients and manufacturing techniques, so they are not the same,” said Julie Williams, communications manager for Lilly Diabetes.

Ken Inchausti, director of media relations, communications and public affairs for Novo Nordisk, Inc., concurred. “There are going to be some distinctions,” he said. “... You can have variations in terms of, one NPH is constructed this way, one NPH is constructed another way.”

Inchausti advised: “I would say that any time you are switching medications in any situation, it does require delicate and close monitoring and care to make sure you will have a consistent outcome. ... Switching insulins is not like changing batteries!”

The patient information sheet for Humulin states in bold capital letters: “Any change in insulin should be made cautiously and only under medical supervision. Changes in strength, manufacturer, type (e.g., regular, NPH, analog), species or method of manufacture may result in the need for a change in dosage.”

Likewise, printed on the Novolin box is the admonition: “Any change in insulin should be made cautiously and only under medical supervision.”

The same warning appears on the website for ReliOn, Wal-Mart’s private label, less-expensive insulin offering. Wal-Mart recently switched its ReliOn NPH insulin from Humulin N to Novolin N.

Despite the warning on the company website, at least some Wal-Mart pharmacy employees treat Humulin N and Novolin N as interchangeable.

A VIN News Service reporter who asked for Humulin N at a Wal-Mart in Washington state was given ReliOn Novolin N by an employee who slipped the product into a bag and stapled it shut, saying nothing about the substitution.

NPH insulin is sold over-the-counter (OTC) for human use. However, for veterinary patients, the hormone is an extra-label drug so technically does require a prescription, according to Davidson. “By federal law, OTC drugs for humans are prescription drugs if used in animals (even if the human owner buys them without a prescription),” she said by email.

Wal-Mart, in a brief statement to the VIN News Service provided 12 days after first being asked for comment, confirmed that the company recently switched the brand it uses for ReliOn products. "If an individual (human or animal) had a prescription for ReliOn insulin, the pharmacist is instructed to contact the prescribing doctor or veterinarian to receive a new prescription," said the statement provided by company spokeswoman Molly Philhours. She did not elaborate or respond to follow-up questions.

But judging from posts on VIN and an interview with an affected pet owner, the pharmacies do not consistently contact prescribing veterinarians.

Owners report being pressed to switch

A common perception is that Wal-Mart pharmacies aggressively push customers to take the less-expensive NPH insulin option. Rennix, owner of Poland Animal Hospital in Maine, said that happened repeatedly in Ditty’s case.

The miniature pinscher’s dysregulation surfaced in December 2010. He had been on Novolin N, and the pharmacy switched him to Humulin N. “We ended up having to decrease the insulin,” Rennix recalled. “It took us a couple of months to re-regulate this dog. We ended up with about half the original dose.”

Re-regulation is a laborious process that generally entails drawing blood every two hours over a period of 12 hours to measure glucose levels. To avoid having to re-regulate Ditty, his owner decided to keep him on Humulin N, even if it meant having to pay more for the drug.

The owner asked Wal-Mart to put a note in the patient record specifying that Ditty was to remain on Humulin N. Rennix’s clinic contacted the pharmacist, as well, to alert him to the potential for problems when switching insulin brands.

But last October, the pharmacy tried to switch Ditty again, impressing upon his owner the price difference — about $80 for Humulin, versus about $25 for Novolin, Rennix said. It happened again to the owner on a subsequent visit.

Another client of Poland Animal Hospital related a similar frustrating experience. Georgia Harris said her husky-wolf hybrid, Tucker, has been on Humulin N for slightly more than a year. When Wal-Mart’s ReliOn was Humulin N, the medicine cost her $24.88 for a 10 ml vial.

One day last fall, the pharmacy switched to Novolin N — a switch Harris said she did not realize had been made until she got home and opened the bag. Harris called the veterinary clinic to ask whether the substitution was OK. By then, Poland Animal Hospital was aware of the potential for trouble and warned her of the possibility.

Harris said she took the insulin back to the store, telling the pharmacist that her veterinarian advised her not to switch. The pharmacist asked, with what Harris perceived as irritation, for the name of her veterinarian. “He gave me the impression he was going to make a phone call and have a discussion,” she said. “I don’t know if he ever did.”

Harris noted that Tucker had a prescription for insulin when he was first diagnosed with diabetes, but when she inquired about it at Wal-Mart later, the pharmacy had no record of it.

Since the switch, Harris said, she’s had to call in advance to order Humulin, and even still, pharmacy employees have tried several times to give her Novolin instead. When she refuses the substitution, explaining that they are not the same drug, she said, “The girls look so dumbfounded.”

Rennix said clients who wish to switch to the less-expensive alternative may opt to monitor their pets’ blood-sugar levels and adjust dosage if necessary. However, that process could cost upwards of $100 — negating the insulin price savings. Plus, there’s the chance that the pharmacy will switch brands again in the future.

Patients' insulin responses show no apparent pattern

How individual patients respond to insulin appears to be confoundingly unique. Rennix has a second patient who, after being switched from Novolin to Humulin, became hyperglycemic — a state of having abnormally high blood-sugar levels. Ditty had had the opposite reaction: His blood-sugar levels fell.

Dr. Erica Row, a practitioner in Findlay, Ohio, also has a pair of diabetic patients whose experiences with insulin-switching are inconsistent. Both had been stable on Humulin. They became hyperglycemic within weeks of one another last fall.

Their respective owners had obtained the dogs’ insulin from a Wal-Mart pharmacy, which had switched to Novolin. “Neither owner noticed it was different and they weren’t told, or they didn’t remember (being told), and didn’t tell me,” Row said.

In the case of one patient, an American Eskimo, increasing the dosage resolved his clinical signs of excessive urination.

The second patient, a terrier, has proved to be a tougher case. Adjusting his dosage didn’t seem to work — he shot from too-high to too-low glycemic levels — so Row put him back on Humulin. He’s still not stable.

“His (situation), I think, is less of a brand issue, unless it was a triggering factor,” said Row.

Other diabetic dogs whose NPH insulin brand was swapped have tolerated the change without any problems, judging from posts on the VIN message board.

Wilson, the veterinary internal medicine specialist, described diabetes as a tricky disease. Changes in a patient’s diet, activity and stress levels can alter how much insulin he or she needs to stabilize blood glucose levels. Moreover, Wilson said, the blood-glucose curve, or pattern, of an individual can change regularly.

“Studies have shown it is a different curve every day,” she said.

Davidson, the North Carolina State veterinary pharmacist, isn’t convinced that manufacturing differences in Humulin and Novolin are significant enough to cause dysregulation. She suspects other factors are at play.

“I am hard-pressed to believe that there are differences in Novo Nordisk and Lilly NPH insulins on a molecular basis but ... any vial of insulin, depending on handling, storage and lifestyle circumstances of the individual patient, can cause changes in glycemic control,” she said.

In terms of handling and storage, Davidson said, differences in packaging and shelf-life of the brands could be a reason that a patient has a different response to each.

She noted that Humulin comes in 3 ml vials as well as 10 ml vials, whereas Novolin is sold only in 10 ml vials. Product housed in a larger container presumably will last longer and may be subject to more handling and potentially improper handling.

“Insulin ... is a fragile molecule and if handled too roughly, can be fractionated and lose activity,” Davidson said. “But by the same token, if caregivers do not mix insulin suspensions vigorously enough, the amount of insulin withdrawn can be either more or less concentrated over time. Crystalline insulin falls to the bottom of the vial over time. It must be assertively shaken to get the insulin into a uniform suspension.

“But owners are afraid to shake the insulin too vigorously,” she continued, “and with initial use, they are only drawing up the diluent off the top of the vial (getting less of a glycemic response).  By the end of the vial, the concentration of insulin crystals gets higher and higher and the glycemic response becomes more and more potent.”

Further, a vial of Novolin must be used within 42 days, and any remainder discarded after that time. Davidson speculated that pet owners would be disinclined to throw away unused product.

“For the folks that switch to the Novolin and had a perceived difference in effect, my first question would be, ‘How old was that bottle of Novolin?’ ” Davidson said. “There is a huge difference in terms of discard time.”

Advice from the U.S. Food and Drug Administration (FDA) for human patients supports Davidson’s view that the brands do not otherwise differ significantly. At the same time, it reinforces the caution that changing insulins is not a trivial matter.

On a webpage about storing and switching between insulin products in an emergency, the FDA states:

“Switching insulin should always be done in consultation with a physician and requires close medical supervision. If this is not possible under emergency conditions, the following recommendations may be considered. Make sure to closely monitor your blood glucose and seek medical attention as soon as possible.”

On intermediate-acting insulins such as NPH, the FDA recommendation is:

“One intermediate-acting insulin product ... may be substituted for another intermediate-acting insulin product on a unit-per-unit basis.”

Experts in human diabetes care say that changing brands of NPH insulin is not considered a problem for people, which raises the possibility that the issue is particular to species.

“In general, each type of insulin should work about the same regardless of manufacturer,” the American Diabetes Association told the VIN News Service, adding, “but there could be differences, and patients should always work closely with their health care team whenever a switch in brand or formulation is made.”

Wal-Mart is not the only pharmacy apt to change brands. The online pharmacy PetMed Express currently has this notice on its Humulin N insulin page: “In the future, we will not be carrying Humulin N, we will be carrying a very similar medication for your dog or cat called Novolin N.”

In light of the potential for problems with diabetic pets, Wilson, the veterinary internal medicine specialist, suggested that veterinarians with patients on NPH insulin alert owners to keep a close eye on brand.

“They may choose to pay more and stay on (the same brand), rather than risking dysregulation by changing,” Wilson said. And they should be made aware, she said, that “even if they are choosing to stay on (one brand), a substitution may be made by the pharmacist ... despite the request.”

Harris, the dog owner whose vigilance has prevented her pharmacy’s repeated attempts to switch the brand it sells to her, said, “I’m so tired of arguing with these people over this insulin; it’s crazy.”

But she’s determined not to acquiesce. “I’m not going to have my dog injured because of someone else’s inability to do the right thing,” she said.