Report on New Patented Drugs – Lantus

Under its transparency initiative, the PMPRB publishes the results of the reviews of new patented drugs by Board Staff, for purposes of applying the PMPRB's Price Guidelines, for all new active substances introduced after January 1, 2002.

Brand Name: Lantus

Generic Name: insulin glargine

DIN: 02245689 100 units per mL (10 mL per vial)

Patentee: Sanofi-Aventis

Indication - as per product monograph: For once daily subcutaneous administration in the treatment of patients over 17 years of age with Type 1 or Type 2 diabetes mellitus who require basal (long-acting) insulin for the control of hyperglycemia.

Notice of Compliance: April 3, 2002

Date of First Sale: November 28, 2004

ATC Class: A10AE04
Drugs used in Diabetes, Insulins and analogues, Insulins and analogues, long-acting, insulin glargine

Application of the Guidelines

Summary:

The introductory price of Lantus was found to be within the PMPRB's Guidelines because the price in Canada did not exceed the median of the prices of the same drug product in those countries listed in the Patented Medicines Regulations (Regulations) in which it was sold.

Scientific Review:

Lantus is a new active substance and the PMPRB's Human Drug Advisory Panel (HDAP) recommended that Lantus be reviewed as a category 3 new medicine (provides moderate, little or no therapeutic advantage over comparable medicines).

The HDAP identified Novolin GE NPH, Humulin N (insulin NPH), Novolin GE Lente, Humulin L (insulin lente), Novolin GE Ultralente, Humulin U (insulin ultralente), and continuous subcutaneous insulin infusion (CSII) using Humalog (insulin lispro). All of these drug products are indicated and used in the treatment of diabetes.

The PMPRB's Guidelines provide that the dosage recommended for comparison purposes will normally not be higher than the maximum of the usual recommended dosage. The recommended comparable dosage regimens for Lantus and the comparators are based on their respective product monographs and supported by clinical literature.

Price Review:

Under the Guidelines, the introductory price of a new category 3 drug product will be presumed to be excessive if it exceeds the price of all of the comparable drug products in the Therapeutic Class Comparison (TCC) test, or if it exceeds the prices of the same medicine in the seven countries listed in the Regulations. The Guidelines further state that when it is inappropriate or impossible to conduct a TCC test, Board Staff will give primary weight to the median of the international prices identified in an International Price Comparison (IPC) test. See the PMPRB's Compendium of Guidelines, Policies and Procedures for a more complete description of the Guidelines.

There are costs associated with CSII in addition to the cost of the medicine, in this case Humalog: pump, cannulas, tubing, batteries, pump cartridges, etc. As this raises a number of issues regarding the conduct of a TCC test, in accordance with the Guidelines in this case it was determined that it was appropriate to give primary weight to the median of the international prices.

At introduction, Lantus was also sold in France, Germany, Italy, Sweden, United Kingdom and United States. The price of Lantus was within the Guidelines as it did not exceed the median of the international prices identified in the IPC test, in fact the price of Lantus in Canada was the lowest.

Canada: Publicly available price as per the Patented Medicines Regulations
France: Sempex, November 2004*
Germany: Rote Liste, July 2004*
Italy: Informatore Farmaceutico, December 2004*
Sweden: Prislista, November 2004*
United Kingdom: MIMS, December 2004*
United States: Average of Thomson Micromedex Wholesale Acquisition Cost (WAC) and Federal Supply Schedule (FSS)

*Derived from publicly available formulary price using regulated wholesale mark-ups set out in PMPRB Study Series S-0215

Where comparators and dosage regimens are referred to in the Summary Reports, they have been selected by the PMPRB Staff and the HDAP for the purpose of carrying out the PMPRB's regulatory mandate, which is to review the prices of patented medicines sold in Canada to ensure that such prices are not excessive. The publication of these reports is also part of the PMPRB's commitment to make its price review process more transparent.

The information contained in the PMPRB's Summary Reports should not be relied upon for any purpose other than its stated purpose and is not to be interpreted as an endorsement, recommendation or approval of any drug nor is it intended to be relied upon as a substitute for seeking appropriate advice from a qualified health care practitioner.

Evidence/References considered by the HDAP

1. Rossetti P, Pampanelli S, Fanelli C, Porcellati F, Costa E, Torlone E, Scionti L, Bolli GB. Intensive replacement of basal insulin in patients with type 1 diabetes given rapid-acting insulin analog at mealtime: a 3-month comparison between administration of NPH insulin four times daily and glargine insulin at dinner or bedtime. Diabetes Care 2003;26(5):1490-6.

2. Riddle MC, Rosenstock J, Gerich J; Insulin Glargine 4002 Study Investigators. The treat-to-target trial: randomized addition of glargine or human NPH insulin to oral therapy of type 2 diabetic patients. Diabetes Care. 2003 Nov;26(11):3080-6.

3. Canadian Diabetes Association 2003 clinical practice guidelines for the management of diabetes in Canada. Can J Diabetes 2003;27 (Suppl 2):S1-S152.

4. Murphy NP, Keane SM, et al. A randomized crossover trial comparing insulin glargine plus insulin lispro with NPH insulin plus soluble insulin in adolescents with type 1 diabetes. Diabetologia 2002;45 (Suppl 2):abstract 871.

5. Benedetti MM, Hamburg E, Dressler A, Zieman M. Lower incidence of nocturnal hypoglycaemia in patients with type 2 diabetes treated with insulin glargine compared with NPH insulin, given as a combination regimen with oral agents. Diabetologia 2002;45 (Suppl 2):abstract 804.

6. Yki-Jarvinen, et al. The relationship between HBA1c, fasting plasma glucose and hypoglycemia using insulin glargine versus NPH insulin: a meta-regression analysis in type 2 diabetes. Diabetes Metab 2003:29 (Spec No 2):Abstract 2216.

7. Rosenstock J, et al. Confirmed lower risk of hypoglycemia with insulin glargine versus NPH insulin: a meta-analysis of 2304 patients with type 2 diabetes. Diabetologia 2003;46 (Suppl 2):abstract 879.

8. Treatment to target study: timing and frequency of nocturnal hypoglycemia. The value of adding bedtime insulin glargine over NPH insulin in insulin-naïve patients with type 2 diabetes on oral agents. American Diabetes Association Diabetes Abstract Book 2002;51 (Supp2):A482.

9. Fritsche A, Schweitzer MA, Haring H. Improved glycemic control and reduced nocturnal hypoglycemia in patients with type 2 diabetes with morning administration of insulin glargine compared with NPH insulin. American Diabetes Association Diabetes Abstract Book 2002;51 (Supp2):A54.

10. Dailey G, et al. A meta-analysis of phase III/IIIB studies comparing insulin glargine with human NPH insulin in type 2 diabetes: severe hypoglycemia is less common with insulin glargine. Diabetologia 2003;46 (Suppl 2):abstract 880.

11. Lepore M, Pampanelli S, Fanelli C, Porcellati F, Bartocci L, Di Vincenzo A, Cordoni C, Costa E, Brunetti P, Bolli GB. Pharmacokinetics and pharmacodynamics of subcutaneous injection of long-acting human insulin analog glargine, NPH insulin, and ultralente human insulin and continuous subcutaneous infusion of insulin lispro. Diabetes 2000 Dec;49(12):2142-8.

12. Heinemann L, Linkeschova R, Rave K, Hompesch B, Sedlak M, Heise T. Time-action profile of the long-acting insulin analog insulin glargine (HOE901) in comparison with those of NPH insulin and placebo. Diabetes Care 2000;23(5):644-9.

13. Raskin P, Klaff L, Bergenstal R, Halle JP, Donley D, Mecca T. A 16-week comparison of the novel insulin analog insulin glargine (HOE 901) and NPH human insulin used with insulin lispro in patients with type 1 diabetes. Diabetes Care 2000;23(11):1666-71.

14. Pieber TR, Eugene-Jolchine I, Derobert E. Efficacy and safety of HOE 901 versus NPH insulin in patients with type 1 diabetes. The European Study Group of HOE 901 in type 1 diabetes. Diabetes Care 2000;23(2):157-62.

15. Ratner RE, Hirsch IB, Neifing JL, Garg SK, Mecca TE, Wilson CA. Less hypoglycemia with insulin glargine in intensive insulin therapy for type 1 diabetes. U.S. Study Group of Insulin Glargine in Type 1 Diabetes. Diabetes Care 2000;23(5):639-43.

16. Rosenstock J, Park G, Zimmerman J; U.S. Insulin Glargine (HOE 901) Type 1 Diabetes Investigator Group. Basal insulin glargine (HOE 901) versus NPH insulin in patients with type 1 diabetes on multiple daily insulin regimens. Diabetes Care 2000;23(8):1137-42.

17. Yki-Jarvinen H, Dressler A, Ziemen M. Less nocturnal hypoglycemia and better post-dinner glucose control with bedtime insulin glargine compared with bedtime NPH insulin during insulin combination therapy in type 2 diabetes. Diabetes Care 2000;23(8):1130-6.

18. Rosenstock J, Schwartz SL, Clark CM Jr, Park GD, Donley DW, Edwards MB. Basal insulin therapy in type 2 diabetes: 28-week comparison of insulin glargine (HOE 901) and NPH insulin. Diabetes Care 2001;24(4):631-6.

19. Pickup J, Keen H. Continuous subcutaneous insulin infusion at 25 years: evidence base for the expanding use of insulin pump therapy in type 1diabetes. Diabetes Care 2002;25(3):593-8.

20. Meltzer S, Leiter L, Daneman D, Gerstein HC, Lau D, Ludwig S, Yale JF, Zinman B, Lillie D. 1998 clinical practice guidelines for the management of diabetes in Canada. Canadian Diabetes Association. CMAJ 1998;159 Suppl 8:S1-29.

21. Rosenbloom AL, Young RS, Joe JR, Winter EW. Emerging epidemic of type 2 diabetes in youth. Diab Care 1999;22:345-54.

22. Meltzer S, et al. 1998 clinical practice guideline for the management of diabetes in Canada. CMAJ 1998; 159 (8 Suppl):S1-S29.

23. The diabetes control and complications trial research group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. NEJM 1993;329(14):977‑86.

24. UK prospective diabetes study group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk complications in patients with type 2 diabetes. Lancet 1998;352:837-53.

25. UK prospective diabetes study group. United Kingdom prospective diabetes study 24: a 6 - year randomized, controlled trial comparing sulphonylurea, insulin and metformin therapy in patients newly diagnosed type 2 diabetes that could not be controlled with diet therapy. Ann Inter Med 1998;1138(3):165-75.

26. Muggeo M, et al. Fasting plasma glucose variability predicts 10-tear survival of type 2 diabetic patients. Diab Care 2000;23:45-50.

27. European diabetes policy group 1999. S desktop guide to type 2 diabetes mellitus. Diab Med 1999;16:716-30.

28. Binder C, et al. Insulin pharmacokinetics. Diab Care 1984;7(2):188-99.

29. Hershon K, Blevins T, Donley D, Littlehorn C. Lower fasting blood glucose (FPG) and less symptomatic hypoglycemia with QD insulin glargine (Lantus) compared to BID NPH in subjects with type 1 diabetes (Abstract). ADA 61st Scientific Sessions.

30. Riddle M, Rosenstock J. Treatment to target study: insulin glargine vs. NPH insulin added to oral therapy of type 2 diabetes. Successful control with less nocturnal hypoglycemia (Abstract & Poster). ADA 62nd Scientific Sessions.

31. Rossetti P, et al. A three month comparison between multiple daily NPH and once daily glargine insulin administration in intensive replacement of basal insulin in Type 1 diabetes mellitus (Abstract 803 & Poster). Diabetologia 2002;45(supp 2).

32. Fanelli CG, Pampanelli S, Porcellati F, Rossetti P, Brunetti P, Bolli GB. Administration of neutral protamine Hagedorn insulin at bedtime versus with dinner in type 1 diabetes mellitus to avoid nocturnal hypoglycemia and improve control. A randomized, controlled trial. Ann Intern Med 2002;136(7):504-14.

33.Anon. Insulin glargine provides basal insulin requirements in the management of diabetes mellitus. Drugs and Therp Persp 2002;18(7):7-9.