cal equivalence among a number of im-
portant cardiovascular drugs, even in
higher-risk contexts such as the NTI drug
warfarin. These findings also support the
use of formulary designs aimed at stimu-
lating appropriate generic drug use. To
limit unfounded distrust of generic medi-
cations, popular media and scientific
journals could choose to be more selec-
tive about publishing perspective pieces
based on anecdotal evidence of dimin-
ished clinical efficacy or greater risk of
adverse effects with generic medica-
tions. Such publications may enhance
barriers to appropriate generic drug use
that increase unnecessary spending with-
out improving clinical outcomes.
Author Contributions: Dr Kesselheim had full access to
all of the data in the study and takes responsibility for the
integrity of the data and the accuracy of the data analysis.
Study concept and design: Kesselheim, Misono, Shrank.
Acquisition of data: Kesselheim, Misono, Lee, Shrank.
Analysis and interpretation of data: Kesselheim,
Misono, Stedman, Brookhart, Choudhry, Shrank.
Drafting of the manuscript: Kesselheim, Misono, Lee,
Critical revision of the manuscript for important in-
tellectual content: Kesselheim, Misono, Stedman,
Brookhart, Choudhry, Shrank.
Statistical analysis: Stedman, Brookhart, Choudhry.
Obtained funding: Kesselheim, Shrank.
Administrative, technical, or material support:
Kesselheim, Misono, Lee, Shrank.
Study supervision: Kesselheim, Shrank.
Financial Disclosures: None reported.
Funding/Support: The study was supported in part by
a grant from the Attorney General Prescriber and Con-
sumer Education Grant Program. Dr Kesselheim’s work
was supported by an Agency for Healthcare Re-
search and Quality Post-Doctoral Fellowship in Health
Services Research at the Harvard School of Public
Health. Dr Brookhart is supported by a career devel-
opment award from the National Institute on Aging
(AG027400). Dr Shrank is supported by a career de-
velopment award from the National Heart, Lung, and
Blood Institute (K23HL090505-01).
Role of the Sponsor: These funding organizations had
no role in the design and conduct of the study; in the
collection, management, analysis, and interpretation
of the data; or in the preparation, review, or ap-
proval of the manuscript.
Additional Contributions: Paul Shekelle, MD, PhD (Vet-
erans Affairs Greater Los Angeles Health Care System
and RAND Corp), provided comments on an earlier ver-
sion of the manuscript. Jerry Avorn, MD (Brigham and
Women’s Hospital and Harvard Medical School), helped
conceive the study and provided comments on the de-
sign and manuscript. Neither received compensation.
1. Fischer MA, Avorn J. Potential savings from in-
creased use of generic drugs in the elderly. Pharma-
coepidemiol Drug Saf. 2004;13(4):207-214.
2. Shrank W, Hoang T, Ettner S, et al. The implica-
tions of choice. Arch Intern Med. 2006;166(3):
3. Goldman DP, Joyce GF, Zheng Y. Prescription drug
cost sharing. JAMA. 2007;298(1):61-69.
4. Kesselheim AS, Fischer M, Avorn J. Extensions of
intellectual property rights and delayed adoption of
generic drugs. Health Aff (Millwood). 2006;25
5. Fischer MA, Avorn J. Economic implications of evi-
dence-based prescribing for hypertension. JAMA. 2004;
6. Strom BL. Generic drug substitution revisited. N Engl
J Med. 1987;316(23):1456-1462.
7. 21 CFR §320.1, 2000.
8. Shrank W, Cox E, Fischer MA, Mehta J, Choudhry
NK. Patient perceptions of generic medications. Health
Aff. In press.
9. Banahan BF, Bonnarens JK, Bentley JP. Generic sub-
stitution of NTI drugs. Formulary. 1998;33(11):
10. Gaither C, Kirking D, Ascione F, Welage L. Con-
sumers’ views on generic medications. J Am Pharm
11. Saul S, Berenson A. Maker of Lipitor digs in to fight
generic rival. New York Times. Nov 3, 2007:A1.
12. Beck M. Inexact copies: how generics differ from
brand names. Wall Street Journal. Apr 22, 2008:D1.
13. Rockoff J. Cost of medicine could increase. Bal-
timore Sun. Jun 17, 2008:1A.
14. Stagnitti M. The top five therapeutic classes of out-
patient prescription drugs ranked by total expense for
adults age 18 and over in the US civilian noninstitu-
tionalized population, 2004. http://www.meps.ahrq
.pdf. Accessed June 23, 2008.
15. Jadad AR, Moore RA, Carroll D, et al. Assessing
the quality of reports of randomized clinical trials. Con-
trol Clin Trials. 1996;17(1):1-12.
16. Deeks JJ, Dinnes J, D’Amico R, et al. Evaluating
non-randomised intervention studies. Health Tech-
nol Assess. 2003;7(27):iii-x, 1-173.
17. 21 CFR 320.33(c), 2000.
18. Guidance for industry: immediate release and solid
oral dosage forms [Nov 1995]. http://www.fda.gov
/cder/guidance/cmc5.pdf. Accessed November 7, 2008.
19. Cohen J. Statistical Power Analysis for the Be-
havioral Sciences. New York: Lawrence Erlbaum;
20. Dunlap WP, Cortina JM, Vaslow JB, Burke MJ.
Meta-analysis of experiments with matched groups
or repeated measures designs. Psychol Methods. 1996;
21. Hedges LV, Olkin I. Statistical Methods for
Meta-Analysis. San Diego: Academic Press; 1985.
22. Rosenthal R, Rubin DB. Comparing effect sizes
of independent studies. Psychol Bull. 1982;92:
23. Kripalani S, Yao X, Haynes B. Interventions to en-
hance medication adherence in chronic medical
conditions. Arch Intern Med. 2007;167(6):540-
24. Stelfox H, Chua G, O’Rourke K, Detsky A. Con-
flict of interest in the debate over calcium-channel
antagonists. N Engl J Med. 1998;338(2):101-106.
25. Ahrens W, Hagemeier C, Muhlbauer B, et al. Hos-
pitalization rates of generic metoprolol compared with
the original beta-blocker in an epidemiological data-
base study. Pharmacoepidemiol Drug Saf. 2007;
26. Portoles A, Filipe A, Almeida S, Terleira A, Vallee
F, Vargas E. Bioequivalence study of two different tab-
let formulations of carvedilol in healthy volunteers.
27. Mirfazaelian A, Tabatabaeifar M, Rezaee S,
Mahmoudian M. Bioequivalence study of atenolol.
Daru J Faculty Pharm. 2003;11(3):95-98.
28. Bongers V, Sabin GV. Comparison of the effect
of two metoprolol formulations on total ischaemic
burden. Clin Drug Invest. 1999;17:103-110.
29. Chiang HT, Hou ZY, Lee DK, Wu TL, Chen CY.
A comparison of antihypertensive effects between two
formulations of atenolol. Zhonghua Yi Xue Za Zhi
30. Sarkar MA, Noonan PK, Adams MJ, O’Donnell
JP. Pharmacodynamic and pharmacokinetic compari-
sons to evaluate bioequivalence of atenolol. Clin Res
Regul Aff. 1995;12(1):47-62.
31. Carter BL, Gersema LM, Williams GO, Schabold
K. Once-daily propranolol for hypertension.
32. el-Sayed MS, Davies B. Effect of two formula-
tions of a beta blocker on fibrinolytic response to maxi-
mum exercise. Med Sci Sports Exerc. 1989;21(4):
33. Sanderson JH, Lewis JA. Differences in side-
effect incidence in patients on proprietary and ge-
neric propranolol. Lancet. 1986;1(8487):967-968.
34. Murray MD, Haag KM, Black PK, Hall SD, Brater
DC. Variable furosemide absorption and poor pre-
dictability of response in elderly patients.
35. Awad R, Arafat T, Saket M, et al. A bioequivalence
study of two products of furosemide tablets. Int J Clin
Pharmacol Ther Toxicol. 1992;30(1):18-23.
36. Kaojarern S, Poobrasert O, Utiswannakul A,
Kositchaiwat U. Bioavailability and pharmacokinetics
of furosemide marketed in Thailand. J Med Assoc Thai.
37. Sharoky M, Perkal M, Tabatznik B, Cane RC Jr,
Costello K, Goodwin P. Comparative efficacy and bio-
equivalence of a brand-name and a generic triam-
terene-hydrochlorothiazide combination product. Clin
38. Singh A, Gupta U, Sagar S. Comparative bio-
equivalence study of furosemide in patients with edema
of renal origin. Int J Clin Pharmacol Ther Toxicol. 1987;
39. Meyer BH, Muller FO, Swart KJ, Luus HG,
Werkman IM. Comparative bio-availability of four for-
mulations of furosemide. S Afr Med J. 1985;68
40. Grahnen A, Hammarlund M, Lundqvist T. Impli-
cations of intraindividual variability in bioavailability
studies of furosemide. Eur J Clin Pharmacol. 1984;
41. Garg SK, Gupta U, Mathur VS. Comparative bio-
equivalence study for furosemide in human volunteers.
Int J Clin Pharmacol Ther Toxicol. 1984;22(11):
42. Pan HY, Wang RY, Chan TK. Efficacy of two pro-
prietary preparations of frusemide in patients with con-
gestive heart failure. Med J Aust. 1984;140(4):
43. Maitai CK, Ogeto JO, Munenge RW. Compara-
tive study of the efficacy of seven brands of fru-
semide tablets. East Afr Med J. 1984;61(1):6-10.
44. Martin BK, Uihlein M, Ings RM, Stevens LA,
McEwen J. Comparative bioavailability of two furo-
semide formulations in humans. J Pharm Sci. 1984;
45. Kim SH, Kim YD, Lim DS, et al. Results of a phase
III, 8-week, multicenter, prospective, randomized,
double-blind, parallel-group clinical trial to assess the
effects of amlodipine camsylate versus amlodipine be-
sylate in Korean adults with mild to moderate
hypertension. Clin Ther. 2007;29(9):1924-1936.
46. Mignini F, Tomassoni D, Traini E, Amenta F. Single-
dose, randomized, crossover bioequivalence study of
amlodipine maleate versus amlodipine besylate in
healthy volunteers. Clin Exp Hypertens. 2007;
47. Park JY, Kim KA, Lee GS, et al. Randomized, open-
label, two-period crossover comparison of the phar-
macokinetic and pharmacodynamic properties of two
amlodipine formulations in healthy adult male Ko-
rean subjects. Clin Ther. 2004;26(5):715-723.
48. Saseen JJ, Porter JA, Barnette DJ, Bauman JL, Zajac
EJ, Carter BL. Postabsorption concentration peaks with
brand-name and generic verapamil. J Clin Pharmacol.
49. Usha PR, Naidu MUR, Kumar TR, Shobha JC, Vijay
GENERIC DRUGS IN CARDIOVASCULAR MEDICINE
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