Report on New Patented Drugs - Integrilin

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: Integrilin

Generic Name: eptifibatide

DIN: 02240351 0.75 mg/mL
DIN: 02240352 2 mg/mL
Patentee: Key Pharmaceuticals/Schering Canada Inc.

Indication - as per product monograph:

For the treatment of patients presenting with symptoms of unstable angina (UA)/non-Q-wave myocardial infarction (NQMI), including those patients who may subsequently undergo percutaneous transluminal coronary angioplasty (PTCA) as well as those who will be managed medically.

For the treatment of patients undergoing percutanerous transluminal coronary angioplasty (PTCA).

Notice of Compliance: June 11, 1999

Date of First Sale: June 23, 1999

In most cases, patents are issued before the drugs come to market. In this case, the first patent pertaining to Integrilin was issued in August 2002 and it came under the PMPRB's jurisdiction at that time.

ATC Class: B01AC16
Antithrombotic agents: Platelet aggregation inhibitors excluding heparin

Application of the Guidelines

Summary:

The introductory prices of Integrilin at the date of first sale were found to be within the PMPRB's Guidelines because the cost of therapy did not exceed the cost of therapy of existing drugs in the therapeutic class comparison and the prices did not exceed the range of prices in other comparator countries where Integrilin was sold. These prices continued to be within the Guidelines when Integrilin came under the PMPRB's jurisdiction, and this continued to be the case in 2004.

Scientific Review:

Integrilin (eptifibatide) is a new active substance. The Guidelines provide that new DINs with multiple approved indications will be categorized based on the approved indication for which the medicine offers the greatest therapeutic advantage in relation to alternative therapies for the same indication in a significant population. Where there is no apparent single approved indication for which the medicine offers the greatest therapeutic advantage, the approved indication representing, potentially, the greatest proportion of sales will be the basis for categorization and selection of comparable medicines. The HDAP recommended that patients presenting with NQMI who will subsequently undergo PTCA be considered as the primary indication. On this basis, the PMPRB's Human Drug Advisory Panel (HDAP) recommended that Integrilin be reviewed as a category 3 new medicine (provides moderate, little or no therapeutic advantage over comparable medicines).

The Therapeutic Class Comparison (TCC) test of the Guidelines provides that the price of a category 3 new drug product cannot exceed the prices of other drugs that treat the same disease or condition. Comparators are generally selected from among existing drug products in the same 4th level of the Anatomical, Therapeutic, Chemical (ATC) System that are clinically equivalent in addressing the approved indication. See the PMPRB's Compendium of Guidelines, Policies and Procedures for a more complete description of the Guidelines and the policies on TCCs.

There are numerous agents in the same 4th level ATC class available on the Canadian market. Only Aggrastat (tirofiban) and Reopro (abciximab) share similar approved indications as Integrilin and both are available in comparable dosage forms to Integrilin.

Reopro was available at the date of first sale of Integrilin in 1999; Aggrastat was not available in Canada at that time. The HDAP recommended Reopro as the most appropriate comparator at the date of first sale.

The 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 Integrilin and the comparators are based on the respective product monographs and supported by clinical literature.

Price Review:

Under the Guidelines, the introductory price for 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 TCC test, or if it exceeds the prices of the same medicine in the seven countries listed in the Patented Medicines Regulations.

The prices of Integrilin were within the Guidelines as the cost of treatment did not exceed the cost of treatment with the comparator medicine.

1 PPS, January 2004

At the time of introduction, both strengths of Integrilin were also being sold in Germany, Italy and the United States. In compliance with the Guidelines, the prices in Canada did not exceed the range of prices in these countries; the price of Integrilin 0.75 mg/mL was the lowest, and the price of Integrilin 2 mg/mL was the 2nd lowest of these countries. In 2003, both strengths of Integrilin were sold in all seven countries and remained within the Guidelines.

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.

References:

1. Integrilin product monograph, revised 2000.

2. Batchelor WB, Tolleson TR, Huang Y, et al. Randomized Comparison of platelet inhibition with abciximab, tirofiban and eptifibatide during percutaneous coronary intervention in acute coronary syndromes: the COMPARE trial. Circulation 2002;106(12):1470-6.

3. Braunwald, et al. ACC/AHA 2002 Guideline Update for the Management of Patients with Unstable Angina and Non-ST-Segment Elevation Myocardial Infarction. Internet address: www.acc.org. Accessed June 2002.

4. Brown DL, Fann CSJ, Chang CJ. Meta-analysis of effectiveness and safety of abciximab versus eptifibatide or tirofiban in percutaneous coronary intervention. Am J Cardiol 2001;87:537-41.

5. Cheng JWM. Efficacy of glycoprotein IIb/IIIa-receptor inhibitors during percutaneous coronary intervention. Am J Health-Syst Pharm 2002;59(Suppl 7):S5-14.

6. Kini AS, Richard M, Suleman J, et al. Effectiveness of tirofiban, eptifibatide, and abciximab in minimizing myocardial necrosis during percutaneous coronary intervention. Am J Cardiol 2002;90(5):526-9.

7. Lage MJ, Barber BL, McCollam PL, Bala M, Scherer J. Impact of abciximab versus eptifibatide on length of hospital stay for PCI patients. Cathet Cardiovasc Intervent 2001;53:296-303.

8. Marsh JD. Early use of glycoprotein IIb/IIIa-receptor inhibitors in non-ST-segment-elevation acute coronary syndromes. Am J Health-Syst Pharm 2002;59(Suppl 7):S15-26.

9. Neumann FJ, Hochholzer W, Pogatsa-Murray G, et al. Antiplatelet effects of abciximab, tirofiban and eptifibatide in patients undergoing coronary stenting. J Am Coll Cardiol 2001;37(5):1323-8.

10. Prescribing Information of Integrilin (eptifibatide). Key Pharmaceuticals/Schering Canada Inc. Pointe-Claire, PQ. July 2002.

11. PRICE Investigators. Comparative 30-day economic and clinical outcomes of platelet glycoprotein IIb/IIIa inhibitor use during elective percutaneous coronary intervention: Prairie ReoPro versus Integrilin Cost Evaluation (PRICE) Trial. Am Heart J 2001;141(3):402-9.

12. Product monograph of Aggrastat™ (tirofiban). Merck Frosst Canada & Co. Kirkland, PQ. July 16, 2001.

13. Racine E. Optimal utilization of glycoprotein IIb/IIIa-receptor inhibitors: Evolving considerations and evidence. Am J Health-Syst Pharm 2002;59 (Suppl 7):S3-4.

14. Repchinsky C, editor. Compendium of Pharmaceutical and Specialities, 38th ed. Canadian Pharmacists Association. 2003, Ottawa.

15. The Ottawa Hospital Physician's Orders. Standard Orders For Eptifibatide (Integrilin™) Use (in patients with acute coronary syndromes). SPO 38 (03/2002).

16. University of Ottawa Heart Institute. Cardiac Reference Center standard Orders for 11B3A inhibitors (Reopro & Integrilin) post P.T.C.A. HEA 15 (07/2000). Marsh JD. Early use of glycoprotein IIb/IIIa-receptor inhibitors in non-ST-segment-elevation acute coronary syndrome. Am J Health-Syst Pharm 2002;59(Suppl 7):S15-26.

17. University of Ottawa Heart Institute. Eptifibatide (Integrilin) for Acute Coronary Syndrome If Serum Creatinine < 180 mcmol/L. HEA 55 (07/2002)

18. Robinson M, Ginnelly L, et al. A systematic review update of the clinical effectiveness and cost-effectiveness of glycoprotein IIb/IIIa antagonists. HTA 2002;6(5).

19. NICE reports and Guidance on glycoprotein IIb/IIIa antagonists. http://www.nice.org.uk/cat.asp?c=10250