Q & A: Caninsulin Shortage & Insulin Alternatives

I practice in Canada and we have just learned that Intervet's Caninsulin insulin (Porcine insulin 40 IU/ml for those not familiar with it) is on backorder. Our clinic is rather small, and we will likely run short on stock before we will be able to purchase more of the insulin.

Is there suitable insulin alternatives that have been used in the USA (after the withdrawal of Vetsulin)? Any problems or complications that were run into when switching insulin preparations?

My Response:

The only Lente insulin preparation still on the market, at least up until this time, has been Caninsulin (1). This is a 40 U/ml porcine insulin zinc suspension specifically registered for veterinary use and manufactured by Intervet Schering-Plough. Caninsulin is the trade-name for this intermediate-acting insulin preparation (1). It is identical to Vetsulin, the porcine lente insulin that was withdrawn from the US market in early 2010 (2).

On the human market, lente insulin preparations are no longer available. What that means is once your supply of Caninsulin is gone, a totally different insulin preparation will have to be used to control the diabetes. And no, you can't change to a new insulin and administer the same dose that you'd used for the Caninsulin. You will need to again start from scratch to regulate the dog's diabetes with the new insulin preparation.

So what insulin should you switch to? Without porcine lente insulin (Caninsulin or Vetsulin), we have four choices for a insulin substitute in dogs with diabetes.

NPH Insulin
The NPH insulin family is a genetically-engineered version of the human insulin molecule. It is an intermediate acting insulin that uses protamine to delay the absorption of the insulin so that one injection can have a measured effect on blood glucose over 8-12 hours in dogs (3,4). Like lente insulins, NPH is generally given twice a day —an injection with a meal every 12 hours— and provides control of the dog’s blood glucose level for about 8-14 hours.

It is a very popular insulin for treating diabetic dogs, and it has a very good track record of providing good glycemic control, is less expensive than newer insulin analog formulations, and can be purchased without a prescription. At least in the USA, Walmart sells this insulin as ReliOn Humulin N for significantly less than most pharmacies do, only about $25 per vial (5).

NPH/Regular Insulin Mixtures
Humulin 70/30 (Eli Lilly) may be a good choice in dogs previously well controlled on lente insulin. This is a 100 U/ml pre-mixed combination of 30% short-acting (regular insulin) and 70% intermediate-acting insulin (NPH).

Remember that lente insulin (Caninsulin or Vetsulin) is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente, respectively) (6,7). Because it has a similar duration/action curve to lente insulin, Humulin 70/30 insulin is well suited to a twice-daily dosing regimen in diabetic dogs where meals are fed at the same time as the insulin injections (8).

Again, Walmart sells this insulin as ReliOn Humulin 70/30 for significantly less than most pharmacies do, only about $25 per vial (5).

Insulin Analogue Mixtures with an Intermediate Duration of Action
Another insulin choice similar to Humulin 70/30, are pre-mixed combinations of a short-acting synthetic insulin analogue (ie, Lispro or Aspart insulin) with a longer-acting insulin analogue (ie. Lispro or Aspart Protamine Insulin) (9).

Examples of these synthetic insulin combinations include Humalog Mix 75/25 (Eli Lilly) or NovoLog Mix 70/30 (Novo Nordisk). Both of these insulin analogue mixtures are given twice daily with meals.

All of these insulin analogue mixtures are 3 to 4 times more costly than human NPH or NPH 70/30 insulins.

Insulin Analogues with a Longer Duration of Action
Finally, my fourth choice is detemir insulin (Levemir, Novo Nordisk). This is another insulin analogue with a long duration of action with a similar action profile to glargine (Lantus), but detemir appears to be more potent and work better in dogs than than glargine does (10,11).

Detemir is the most potent of these insulin choices and is dosed initially at 0.1 U/kg BID, again generally administered at time of feeding. Again, this insulin analogue is 3-4 times more costly than human NPH or NPH 70/30 insulins.

The Bottom Line (for veterinarians in the USA, too)
The fact that Caninsulin is on backorder is worrisome. This sounds very similar to the situation we in the United States had with Vetsulin before it was recalled — and I really doubt if we are every going to get Vetsulin back on the market!

The good news is that we do have alternatives that work in the diabetic dog. We generally start with human NPH insulin, but the NPH-regular insulin mixtures result in better glycemic control in most dogs. And when Humulin 70/30 mixtures fail to regulate the diabetes satisfactorily, we can move on to the newer insulin analogue products.  These include the Humolog or Novolog analogue mixtures, which will be more effective in some dogs, and Levemir (detemir), the most potent insulin preparation that we currently have at our disposal to use in dogs with diabetes.

References

1. Caninsulin website. http://www.caninsulin.com
2. Vetsulin website. http://www.vetsulin.com
3. Goeders LA, Esposito LA, Peterson ME.  Absorption kinetics of regular and isophane (NPH) insulin in the normal dog. Domestic Animal Endocrinology 1987;4:43-50.
4. Palm CA, Boston RC, Refsal KR, et al. An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus. J Vet Intern Med 2009;23:50-55. 
5. ReliOn Insulins. http://relion.com/diabetes/insulin
6. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Veterinary Record 2009;164:232-237.
7. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. Journal of Veterinary Internal Medicine 2005;19:675-82.
8. Fleeman LM. The recent developments in the management of diabetes mellitus in dogs. 2010 ACVIM Forum Proceedings 2010.
9. Garber AJ. Premixed insulin analogues for the treatment of diabetes mellitus. Drugs 2006;66:31-49. 
10. Sako T, Mori A, Lee P, et al. Time-action profiles of insulin detemir in normal and diabetic dogs. Research in Veterinary Science 2011;90:396-403. 
11. Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Veterinary Clinics of North America Small Animal Practice 2010;40:297-307. 

Q & A: Vetsulin Insulin Discontinued, Now What Insulin?

I have a 10-year-old male neutered diabetic chihuahua that was diagnosed after Vetsulin went off the market.  We tried for several months to regulate him on Humulin N, but we never could get him controlled.  

We finally got him enrolled in the Vetsulin Critical Need Program.  He is doing great on Vetsulin given twice daily, but now we're unable to get any more of the Vetsulin.  As you know, the Vetsulin Critical Need's Program has been discontinued!

Now that that honeymoon is over, what insulin can I try on this problem diabetic?

My Response:

Vetsulin (Lente insulin) is actually a mixture of rapid-acting and long-acting insulins (Semi-lente and Ultralente). So knowing that your patient responded better to the Vetsulin, you have 3 'general' choices for selecting the next insulin preparations in this dog. I do not believe that Vetsulin will be returning to the market anytime soon. You also know from past experience that human NPH isn't a good choice for this diabetic patient.

Humulin 70/30 (Eli Lilly) may be a good choice in this dog. This is a 100 U/ml pre-mixed combination of 30% short-acting and 70% intermediate-acting insulin. Because it has a similar duration/action curve to Vetsulin, Humulin 70/30 insulin is well suited to a twice-daily dosing regimen in diabetic dogs where meals are fed at the same time as the insulin injections.

Another insulin choice similar to Humulin 70/30, is a pre-mixed combination of a short-acting synthetic insulin analogue (ie, Lispro or Aspart insulin) with a longer-acting insulin analogue (ie. Lispro or Aspart Protamine Insulin). Examples of these synthetic insulin combinations include Humalog Mix 75/25 (Eli Lilly) or NovoLog 70/30 (Novo Nordisk).  Both of these insulin analogue mixtures are given twice daily with meals.

Finally, my third choice is detemir insulin (Levemir, Novo Nordisk). This is another insulin analogue with a long duration of action with a similar action profile to glargine (Lantus), but detemir appears to be more potent and work better in dogs than than glargine does.   Detemir is the most potent of these insulin choices and is dosed initially at  0.1 U/kg BID, again generally administered at time of feeding.

More Information on the Discontinuation of the Vetsulin® Critical-Need Program (CNP)

Intervet/Schering-Plough Animal Health has announced it is discontinuing the VETSULIN® Critical-Need Program (CNP) effective immediately and will no longer provide VETSULIN® after the current supply is exhausted, which is expected to be the end of this month (February 2011).

Quality tests showed that the sterility of the most recent batch of VETSULIN® manufactured for the Critical-Need Program may be compromised by bacterial contamination.  This batch of VETSULIN® has not been released.  We therefore cannot supply the program and it is being discontinued.

See attached letters for more information (click on each letter to enlarge):

No Resolution to Problems in Shortage of Vetsulin

A new development in the ongoing Vetsulin recall situation. From the FDA website: http://www.fda.gov/AnimalVeterinary/NewsEvents/CVMUpdates/ucm242368.htm

FDA Announces Upcoming Shortage of Vetsulin for Dogs and Cats in the Critical Need Program

February 4, 2011

The Food and Drug Administration (FDA) announced today an anticipated shortage of Vetsulin (porcine insulin zinc suspension), a product used to treat diabetes mellitus in dogs and cats. Vetsulin is manufactured by Intervet/Schering-Plough Animal Health and is only available to animals currently enrolled in the Vetsulin Critical Need Program.

In November 2009, FDA announced its concerns about the stability of Vetsulin, which may cause the product to have unpredictable onset and duration of action in dogs and cats treated with Vetsulin. At that time, FDA recommended that diabetic dogs and cats currently receiving Vetsulin be switched to other insulin products. In May 2010, Intervet/Schering-Plough Animal Health initiated the Vetsulin Critical Need Program, intended for a critical need dog or cat that, in the medical judgment of the pet’s veterinarian, could not be effectively managed on another insulin product.

In November 2010, Vetsulin intended for use in the Critical Need Program, failed critical manufacturing tests which are routinely conducted to assure consistency and quality of the drug. The tests showed that the sterility of the most recently manufactured batches of Vetsulin may be compromised by bacterial contamination. This batch of Vetsulin has not been released.

FDA has no evidence that Vetsulin currently on the market and being used under the Critical Need Program is affected. No adverse events consistent with bacterial infection in cats and dogs receiving Vetsulin have been reported to CVM under the current program.

Intervet/Schering-Plough Animal Health has indicated that it will be sending letters to owners of the pets enrolled in the Vetsulin Critical Need Program and their veterinarians. In those letters, the firm will be notifying veterinarians and pet owners of the upcoming shortage of Vetsulin and consequent discontinuation of the Vetsulin Critical Need Program. Owners of diabetic cats and dogs are encouraged to consult their veterinarian as soon as possible about transitioning their pets to other insulin products. Intervet/Schering-Plough Animal Health is planning to provide detailed instructions to veterinarians on how to manage the transition.