Report on New Patented Drugs - TNKase

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 Excessive Price Guidelines (Guidelines) for all new active substances introduced after January 1, 2002.

Brand Name: TNKase

Generic Name: (tenecteplase recombinant)

DIN: 02244826 50 mg/vial

Patentee: Hoffmann-La Roche Limited, Canada

Indication - as per product monograph:
For IV use in adults for the lysis of suspected occlusive coronary artery thrombi associated with evolving transmural myocardial infarction to reduce the mortality associated with acute myocardial infarction

Date of Issuance of First Patent(s) Pertaining to the Medicine: June 17, 2003

Notice of Compliance: October 17, 2001

Date of First Sale: October 2001

ATC Class: J01FA15
Antiinfectives for Systemic Use, Antibacterials for Sytemic Use, Macrolides, Lincosamides and Streptogramins, Macrolides

APPLICATION OF THE GUIDELINES

Summary

The introductory price of TNKase was found to be within the Guidelines because the cost of therapy did not exceed the cost of therapy of existing drugs in the therapeutic class comparison and the price did not exceed the prices in the other comparator countries where TNKase was sold.

Scientific Review

The PMPRB's Human Drug Advisory Panel (HDAP) recommended that TNKase 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.

The HDAP recommended Streptase (streptokinase), Activase (alteplase) and Retavase (reteplase) as the most appropriate comparators for TNKase as the comparators are within the same 4th level ATC classification, share the same indication as TNKase and have comparable clinical efficacy rates.

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 TNKase and the comparators are based on their respective product monographs, clinical literature, current practice guidelines and clinical practice.

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 prices 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 price of TNKase was within the Guidelines as the cost per treatment did not exceed the cost per treatment with the comparator medicines.

Introductory Period (July to December 2003)
Name Strength Dosage Regimen Cost per Treatment
TNKase (tenecteplase recombinant) 50 mg/vial 0.8 vial $2,196.80001
Streptase (streptokinase) 1.5 MU/vial 1 vial $595.00002
Activase (alteplase) 100 mg/vial 1 vial $2,746.00001
Retavase (reteplase) 10.4U/vial 2 vials $1,900.00001

1. PPS Pharma, January 2003
2. Association québécoise des pharmaciens propriétaires (AQPP), October 2003

At introduction, TNKase 50 mg/vial was sold in all seven countries listed in the Regulations. In compliance with the Guidelines, the price in Canada did not exceed the range of prices in those countries; the price of TNKase in Canada was third highest of the seven countries, above the median international price.

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 - TNKase

  1. Gillis MC, ed. Compendium of Pharmaceuticals and Specialties. 32nd edition. Canadian Pharmacists Association. Ottawa, ON. 1997.

  2. Product Monograph of TNKase (tenecteplase, recombinant) Hoffmann-La Roche Limited. Mississauga, ON. October 17, 2001.

  3. Le May MR, Davies RF, Labinaz M, et al. Hospitalization costs of primary stenting versus thrombolysis in acute myocardial infarction. Circulation 2003;108:2624-30.

  4. Repchinsky C, ed. Compendium of Pharmaceuticals and Specialties. Canadian Pharmacists Association. Ottawa, ON. 2003.

  5. Health Canada Therapeutics Product Dictorate. Drug Product Database [index online]. Internet site: http://www.hc-sc.gc.ca/hpb/drugs-dpd/index.html (accessed 13 Jan 2003).

  6. Health Canada Therapeutics Product Dictorate. Notice of Compliance (NOC) Listings [index online]. Internet site: http://www.hc-sc.gc.ca/hpfb-dgpsa/tpd-dpt/index_drugs_noc_e.html (accessed 13 Jan 2003).

  7. WHO Collaborating Centre for Drug Statistics Methadology. ATC/DDD Index 2003 [index online]. Internet site: http://www.whocc.no/atcddd/ (accessed 13 Jan 2003).

  8. Heart and Stroke Foundation of Canada. Heart Attack - Causes & Symptoms & Statistics. 2001 Sept 9. Internet site: http://ww1.heartandstroke.ca/Page.asp?PageID=110&ArticleID=557&Src=heart (accessed 12 Jan 2003).

  9. Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction; results of the TIMI 10B trial. Circulation 1998;98:2805-14.

  10. ASSENT-2 Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomized trial. Lancet 1999;354:716-22. [electronic attached]

  11. ASSENT-3 Investigators. Efficacy and safety of tenecteplase in combination with enoxaparin, abciximab or unfractionated heparin: the ASSENT-3 randomized trial in acute myocardial infarction. Lancet 2001;358:605-13.

  12. Wallentin L, Goldstein P, Armstrong PW, et al. Efficacy and safety of tenecteplase in combination with the low-molecular-weight heparin enoxaparin or unfractionated heparin in the prehospital setting. Circulation 2003;108:135-42.

  13. Dubois CL, Belmans A, Granger CB, et al. Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab. J Am Coll Cardiol 2003;42(7):1178-85.

  14. Armstrong PW, Wagner G, Goodman SG, et al. ST segment resolution in ASSENT 3: insights into the role of three different treatment strategies for acute myocardial infarction Eur Heart J 2003;24(16):1515-22.

  15. Sinnaeve P, Alexander J, Belmans A, et al. One-year follow-up of the ASSENT-2 trial: A double-blind, randomized comparison of single-bolus tenecteplase and front-loaded alteplase in 16,949 patients with ST-elevation acute myocardial infarction. Am Heart J 2003;146:27-32.

  16. Serebruany VL, Malinin AI, Callahan KP, et al. Effect of tenecteplase versus alteplase on platelets during the first 3 hours of treatment for acute myocardial infarction: the assessment of the safety and efficacy of a new thrombolytic agent (ASSENT-2) platelet substudy. Am Heart J 2003;145(4):636-42.

  17. Guigliano RP, Roe MT, Harrington RA, et al. Combination reperfusion therapy with epitfibatide and reduced dose tenecteplase for ST-elevation myocardial infarction: results of the integrilin and tenecteplase in acute myocardial infraction (INTEGRITI) phase II angiographic trial. J Am Coll Cardiol 2003;41(8):1251-60.

  18. Al-Shwafi KA, de Meester A, Pirenne, et al. Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus mutants tenecteplase and lanoteplase during treatment of acute myocardial infarction. Am Heart J 2003;145(2):217-25.

  19. Antman EM, Louwerenburg HW, Baas HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction; Results of the ENTIRE-thrombolysis in myocardial infarction (TIMI) 23 trial. Circulation 2002;105:1642-9.

  20. Gibson CM, Cannon CP, Murphy SA, et al. Relationship of the TIMI myocardial perfusion grades, flow grades, frame count, and percutaneous coronary intervention of long-term outcomes after thrombolytic administration in acute myocardial infarction. Circulation 2002;105(16):1909-13.

  21. Van de Werf F, Barron HV, Armstrong PW, et al. Incidence and predictors of bleeding events after fibrinolytic therapy with fibrin-specific agents: a comparison of TNK-tPA and rt-PA. Eur Heart J 2001;22(24):2253-61.

  22. Angija BG, Alexander JH, Chin R, et al. Safety of the weight-adjusted dosing regimen of tenecteplase in the ASSENT-trial. Am J Cardiol 2001;88:1240-5.

  23. Fu Y, Goodman S, Chang WC, et al. Time to treatment influences the impact of ST-segment resolution on one-year prognosis: insights form the assessment of the safety and efficacy of a new thrombolytic (ASSENT-2) trial. Circulation 2001;104(22):2653-9.

  24. Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue -plasminogen activator in acute myocardial infarction: The ASSENT-1 trial. Am Heart J 1999;137:786-91.

  25. Dubois CL, Belmans A, Granger CB, et al. Outcome of urgent and elective percutaneous coronary interventions after pharmacologic reperfusion with tenecteplase combined with unfractionated heparin, enoxaparin, or abciximab. J Am Coll Cardiol 2003;42:1178-85.

  26. Lesaffre E, Bluhmki E, Wang-Clow F, et al. The general concepts of an equivalence trial, applied to ASSENT-2, a large-scale mortality study comparing two fibrinolytic agents in acute myocardial infarction Eur Heart J 2001;22:898-902.

  27. Szabo S, Letsch R, Ehlers R, et al. Absence of paradoxical thrombin activation by fibrin-specific thrombolytics in acute myocardial infarction. Comparison of single-bolus tenecteplase and front-loaded alteplase. Thromb Res 2002;106:113-9.

  28. ACC/AHA Practice Guidelines. 1999 Update: ACC/AHA Guidelines for the Management of Patients with Acute Myocardial Infarction. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [electronic document] Available from: http://www.acc.org/clinical/guidelines/nov96/1999/amipdf99.pdf (Accessed 28 Jan 04).

  29. Van de Werf FV, Ardissino D, Betriu AM et al. Management of acute myocardial infarction in patients presenting with ST-segment elevation. Eur Heart J 2003;24:28-66. [electronic attached]

  30. Tu JV, Austin PC, Filate WA, et al. Outcomes of acute myocardial infarction in Canada. Can J Cardiol 2003;19(8):893-901.

  31. Ohman EM, Harrington RA, Cannon CP, et al. Intravenous thrombolysis in acute myocardial infarction. CHEST 2001;119:253S-77S.

  32. The Ottawa Hospital. Physician's Orders. TNKase (tenecteplase). April 2002. [copy attached]

  33. Graham M. Acute Coronary Syndromes. Chapter 26. In: Gray J, ed. Therapeutic Choices. 4th ed. Canadian Pharmacists Association. Ottawa, On. 2003. P. 284-301.

  34. Dundar Y, Hill R, Dickson R, Walley T. Comparative efficacy of thrombolytics in acute myocardial infarction: a systematic review. Q J Med 2003;96:103-13. [electronic attached]

  35. Wally T, Dundar Y, Hill R, Dickson R. Superiority and equivalence in thrombolytic drugs: an interpretation. Q J Med 2003;96:155-60.

  36. Vermeer R. Thrombolytic therapy in patients of female gender. Thromb Res 2001;103:S101-4.

  37. Cannon CP, McCabe CH, Givson CM, et al. TNK-tissue plasminogen activator in acute myocardial infarction. Results of the thrombolysis in myocardial infarction (TIMI) 10A dose-ranging study. Circulation 1997;95:351-6.

  38. Murphy SA, Gibson CM, Van de Werf F, et al. Comparison of errors in estimating weight and in dosing of single-bolus tenecteplase with tissue plasminogen activator (TIMI 10B and ASSENT I). Am J Cardiol 2002;90(1):51-4.

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