Journal of Cardiovascular Pharmacology and Therapeutics http://cpt.sagepub.com/
Food and Drug Administration Regulation of Drugs That Raise Blood Pressure Robert P. Blankfield and Imran H. Iftikhar J CARDIOVASC PHARMACOL THER published online 6 May 2014 DOI: 10.1177/1074248414531852 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2014/05/06/1074248414531852
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Article
Food and Drug Administration Regulation of Drugs That Raise Blood Pressure
Journal of Cardiovascular Pharmacology and Therapeutics 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414531852 cpt.sagepub.com
Robert P. Blankfield, MD, MS1 and Imran H. Iftikhar, MD, FCCP2
Abstract Although it is recognized that a systolic blood pressure (SBP) increase 2 mm Hg or a diastolic blood pressure (DBP) increase 1 mm Hg increases the risk of heart attacks and strokes in middle-aged adults, the Food and Drug Administration (FDA) lacks an adequate policy for regulating medications that increase blood pressure (BP). Some FDA reviewers consider a clinically significant increase in BP to occur only if a drug raises SBP 20 mm Hg or if a drug raises DBP 10 to 15 mm Hg. In recent years, numerous drugs have been regulated or taken off the market due to cardiovascular safety concerns. The list includes rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine. It is probable that the hypertensive effect of these drugs explains why they increase the risk of adverse cardiovascular events. Other drugs, notably serotonin–norepinephrine reuptake inhibitors and drugs used to treat attention deficit hyperactivity disorder, were approved without cardiovascular safety data despite the fact that they raise BP comparable to valdecoxib and sibutramine. It is the responsibility of the FDA to ensure that drugs are properly labeled regarding risk. Even if a drug raises BP only modestly, FDA guidelines for new drug approvals should include a requirement for cardiovascular safety data. However, such guidelines will not address the problem of how to obtain cardiovascular safety data for the many already approved drugs that increase BP. The FDA should play a role in obtaining cardiovascular safety data for such drugs. Keywords Food and Drug Administration, hypertension, serotonin–norepinephrine reuptake inhibitors, amphetamine-salts combinations, attention deficit hyperactivity disorder medications
Rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine all have 3 things in common. First of all, they were all initially approved by the Food and Drug Administration (FDA) without any warnings about adverse cardiovascular outcomes. Second, all these drugs have been regulated or taken off the market in recent years after data demonstrated that they either increase the risk of heart attacks and strokes or are associated with an increased risk of heart attacks and strokes. Third, they all raise blood pressure (BP). It is likely that the reason these drugs increase the risk of serious adverse cardiovascular events is because of their hypertensive side effect, and the longer the duration of use, the greater the risk. A perusal of FDA medical reviews for new drug approvals reveals that different FDA reviewers have utilized different criteria to determine when medications raise BP to an extent that is clinically significant. In 1997, an FDA reviewer specified that in order to be considered clinically significant, the FDA Neuropharmacology guidelines require that a medication raises systolic BP (SBP) to a level 180 or raises the SBP from baseline 20 mm Hg, or else the medication raises diastolic BP (DBP) to a level 105 or raises the DBP 15 mm Hg.1
An FDA reviewer in 1999 wrote that a clinically significant increase in BP means that the drug raises the SBP to a level 140 mm Hg and increases the SBP 20 mm Hg. Correspondingly, a clinically significant increase in DBP means that the drug raises the DBP to a level 90 mm Hg and increases the DBP 10 mm Hg.2 The FDA reviewers also compare the difference in mean change in BP between drug and placebo. When there are small differences in the mean BP effect between drug and placebo (in the range of 1-4 mm Hg) that are not statistically significant, it is commonplace for FDA officials to comment that the differences are clinically irrelevant.3 1
Department of Family Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA 2 Department of Medicine, University of South Carolina School of Medicine, Columbia, SC, USA Manuscript submitted: January 15, 2014; accepted: March 21, 2014. Corresponding Author: Imran H. Iftikhar, Department of Medicine, University of South Carolina School of Medicine, Columbia, SC, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
2
Journal of Cardiovascular Pharmacology and Therapeutics
Table 1. Blood Pressure Effect of Valdecoxib and Sibutramine. Total Daily Dose, mg
Drug Valdecoxib
10
Sibutramine11
10-20 40 1 mm Hg, then there should be a requirement for cardiovascular safety data.
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
4
Journal of Cardiovascular Pharmacology and Therapeutics
In conclusion, it is unwise to allow drugs that predictably increase risk to be marketed without adequate safety data, regardless of when the drugs were approved. When drugs modestly increase BP, the FDA should require the collection of cardiovascular safety data for new drug approvals. In addition, the FDA should take a role in collecting cardiovascular safety data for already approved drugs that modestly increase BP. For drugs that increase risk, it is not necessary that they be taken off the market, but it is the duty of the FDA to ensure that drugs are properly labeled regarding risk. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RPB has a patent pending for the concept that one can use markers of fluid retention to gauge the cardiovascular risk of a drug. RPB and IHI have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020632a_apltr_thr_%20mor.pdf. Accessed November 25, 2013. 2. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P5.pdf. Accessed November 25, 2013. 3. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2004/021427_s000_Cymbalta_Medr_P2.pdf. Accessed November 25, 2013. 4. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P7.pdf. Accessed November 25, 2013. 5. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2001/21-341_Bextra_medr_P2.pdf. Accessed November 25, 2013. 6. Weber MA. The ALLHAT report: a case of information and misinformation. J Clin Hypertens (Greenwich). 2003;5(1):9-13. 7. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Agespecific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-1913. 8. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P36.pdf. Accessed November 25, 2013.
9. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8): 954-959. 10. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2001/21-341_Bextra_medr_P3.pdf. Accessed November 25, 2013. 11. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020632a_apltr_thr_%20mor.pdf. Accessed November 25, 2013. 12. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2004/021427_s000_Cymbalta_Medr_P1.pdf. Accessed November 25, 2013. 13. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2009/022256s000TOC.cfm. Accessed November 25, 2013. 14. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2013/204168s000lbl.pdf. Accessed November 25, 2013. 15. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2007/021977s000_MedR.pdf. Accessed November 25, 2013. 16. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020699ap_effexor_medrp2.pdf. Accessed November 25, 2013. 17. Thase ME. Effects of venlafaxine on blood pressure: a metaanalysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. 18. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005; 66(2):253-259. 19. Weisler RH, Biederman J, Spencer TJ, Wilens TE. Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(12 suppl 20):35-43. 20. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-904. 21. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683. 22. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2013/204447Orig1s000MedR.pdf. Accessed November 25, 2013. 23. US FDA http://www.fda.gov/downloads/Drugs/GuidanceCompli anceRegulatoryInformation/Guidances/ucm072974.pdf. Accessed November 25, 2013. 24. Sager P, Heilbraun J, Turner JR, et al. Assessment of druginduced increases in blood pressure during drug development: report from the cardiac safety research consortium. Am Heart J. 2013;165(4):477-488.
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
Food and Drug Administration Regulation of Drugs That Raise Blood Pressure Robert P. Blankfield and Imran H. Iftikhar J CARDIOVASC PHARMACOL THER published online 6 May 2014 DOI: 10.1177/1074248414531852 The online version of this article can be found at: http://cpt.sagepub.com/content/early/2014/05/06/1074248414531852
Published by: http://www.sagepublications.com
Additional services and information for Journal of Cardiovascular Pharmacology and Therapeutics can be found at: Email Alerts: http://cpt.sagepub.com/cgi/alerts Subscriptions: http://cpt.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - May 6, 2014 What is This?
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
Article
Food and Drug Administration Regulation of Drugs That Raise Blood Pressure
Journal of Cardiovascular Pharmacology and Therapeutics 1-4 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1074248414531852 cpt.sagepub.com
Robert P. Blankfield, MD, MS1 and Imran H. Iftikhar, MD, FCCP2
Abstract Although it is recognized that a systolic blood pressure (SBP) increase 2 mm Hg or a diastolic blood pressure (DBP) increase 1 mm Hg increases the risk of heart attacks and strokes in middle-aged adults, the Food and Drug Administration (FDA) lacks an adequate policy for regulating medications that increase blood pressure (BP). Some FDA reviewers consider a clinically significant increase in BP to occur only if a drug raises SBP 20 mm Hg or if a drug raises DBP 10 to 15 mm Hg. In recent years, numerous drugs have been regulated or taken off the market due to cardiovascular safety concerns. The list includes rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine. It is probable that the hypertensive effect of these drugs explains why they increase the risk of adverse cardiovascular events. Other drugs, notably serotonin–norepinephrine reuptake inhibitors and drugs used to treat attention deficit hyperactivity disorder, were approved without cardiovascular safety data despite the fact that they raise BP comparable to valdecoxib and sibutramine. It is the responsibility of the FDA to ensure that drugs are properly labeled regarding risk. Even if a drug raises BP only modestly, FDA guidelines for new drug approvals should include a requirement for cardiovascular safety data. However, such guidelines will not address the problem of how to obtain cardiovascular safety data for the many already approved drugs that increase BP. The FDA should play a role in obtaining cardiovascular safety data for such drugs. Keywords Food and Drug Administration, hypertension, serotonin–norepinephrine reuptake inhibitors, amphetamine-salts combinations, attention deficit hyperactivity disorder medications
Rofecoxib (Vioxx), valdecoxib (Bextra), nonselective nonsteroidal anti-inflammatory drugs, sibutramine (Meridia), and phenylpropanolamine all have 3 things in common. First of all, they were all initially approved by the Food and Drug Administration (FDA) without any warnings about adverse cardiovascular outcomes. Second, all these drugs have been regulated or taken off the market in recent years after data demonstrated that they either increase the risk of heart attacks and strokes or are associated with an increased risk of heart attacks and strokes. Third, they all raise blood pressure (BP). It is likely that the reason these drugs increase the risk of serious adverse cardiovascular events is because of their hypertensive side effect, and the longer the duration of use, the greater the risk. A perusal of FDA medical reviews for new drug approvals reveals that different FDA reviewers have utilized different criteria to determine when medications raise BP to an extent that is clinically significant. In 1997, an FDA reviewer specified that in order to be considered clinically significant, the FDA Neuropharmacology guidelines require that a medication raises systolic BP (SBP) to a level 180 or raises the SBP from baseline 20 mm Hg, or else the medication raises diastolic BP (DBP) to a level 105 or raises the DBP 15 mm Hg.1
An FDA reviewer in 1999 wrote that a clinically significant increase in BP means that the drug raises the SBP to a level 140 mm Hg and increases the SBP 20 mm Hg. Correspondingly, a clinically significant increase in DBP means that the drug raises the DBP to a level 90 mm Hg and increases the DBP 10 mm Hg.2 The FDA reviewers also compare the difference in mean change in BP between drug and placebo. When there are small differences in the mean BP effect between drug and placebo (in the range of 1-4 mm Hg) that are not statistically significant, it is commonplace for FDA officials to comment that the differences are clinically irrelevant.3 1
Department of Family Medicine, Case Western Reserve University School of Medicine, Cleveland, OH, USA 2 Department of Medicine, University of South Carolina School of Medicine, Columbia, SC, USA Manuscript submitted: January 15, 2014; accepted: March 21, 2014. Corresponding Author: Imran H. Iftikhar, Department of Medicine, University of South Carolina School of Medicine, Columbia, SC, USA. Email: [email protected]
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
2
Journal of Cardiovascular Pharmacology and Therapeutics
Table 1. Blood Pressure Effect of Valdecoxib and Sibutramine. Total Daily Dose, mg
Drug Valdecoxib
10
Sibutramine11
10-20 40 1 mm Hg, then there should be a requirement for cardiovascular safety data.
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
4
Journal of Cardiovascular Pharmacology and Therapeutics
In conclusion, it is unwise to allow drugs that predictably increase risk to be marketed without adequate safety data, regardless of when the drugs were approved. When drugs modestly increase BP, the FDA should require the collection of cardiovascular safety data for new drug approvals. In addition, the FDA should take a role in collecting cardiovascular safety data for already approved drugs that modestly increase BP. For drugs that increase risk, it is not necessary that they be taken off the market, but it is the duty of the FDA to ensure that drugs are properly labeled regarding risk. Declaration of Conflicting Interests The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: RPB has a patent pending for the concept that one can use markers of fluid retention to gauge the cardiovascular risk of a drug. RPB and IHI have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed.
Funding The author(s) received no financial support for the research, authorship, and/or publication of this article.
References 1. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020632a_apltr_thr_%20mor.pdf. Accessed November 25, 2013. 2. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P5.pdf. Accessed November 25, 2013. 3. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2004/021427_s000_Cymbalta_Medr_P2.pdf. Accessed November 25, 2013. 4. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P7.pdf. Accessed November 25, 2013. 5. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2001/21-341_Bextra_medr_P2.pdf. Accessed November 25, 2013. 6. Weber MA. The ALLHAT report: a case of information and misinformation. J Clin Hypertens (Greenwich). 2003;5(1):9-13. 7. Lewington S, Clarke R, Qizilbash N, Peto R, Collins R. Agespecific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. 2002;360(9349):1903-1913. 8. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/ 021042_52_vioxx_medr_P36.pdf. Accessed November 25, 2013.
9. Mukherjee D, Nissen SE, Topol EJ. Risk of cardiovascular events associated with selective COX-2 inhibitors. JAMA. 2001;286(8): 954-959. 10. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2001/21-341_Bextra_medr_P3.pdf. Accessed November 25, 2013. 11. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020632a_apltr_thr_%20mor.pdf. Accessed November 25, 2013. 12. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2004/021427_s000_Cymbalta_Medr_P1.pdf. Accessed November 25, 2013. 13. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2009/022256s000TOC.cfm. Accessed November 25, 2013. 14. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/label/ 2013/204168s000lbl.pdf. Accessed November 25, 2013. 15. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2007/021977s000_MedR.pdf. Accessed November 25, 2013. 16. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/ 020699ap_effexor_medrp2.pdf. Accessed November 25, 2013. 17. Thase ME. Effects of venlafaxine on blood pressure: a metaanalysis of original data from 3744 depressed patients. J Clin Psychiatry. 1998;59(10):502-508. 18. Wilens TE, Hammerness PG, Biederman J, et al. Blood pressure changes associated with medication treatment of adults with attention-deficit/hyperactivity disorder. J Clin Psychiatry. 2005; 66(2):253-259. 19. Weisler RH, Biederman J, Spencer TJ, Wilens TE. Long-term cardiovascular effects of mixed amphetamine salts extended release in adults with ADHD. CNS Spectr. 2005;10(12 suppl 20):35-43. 20. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious cardiovascular events in children and young adults. N Engl J Med. 2011;365(20):1896-904. 21. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and risk of serious cardiovascular events in young and middle-aged adults. JAMA. 2011;306(24):2673-2683. 22. US FDA. http://www.accessdata.fda.gov/drugsatfda_docs/nda/ 2013/204447Orig1s000MedR.pdf. Accessed November 25, 2013. 23. US FDA http://www.fda.gov/downloads/Drugs/GuidanceCompli anceRegulatoryInformation/Guidances/ucm072974.pdf. Accessed November 25, 2013. 24. Sager P, Heilbraun J, Turner JR, et al. Assessment of druginduced increases in blood pressure during drug development: report from the cardiac safety research consortium. Am Heart J. 2013;165(4):477-488.
Downloaded from cpt.sagepub.com at PENNSYLVANIA STATE UNIV on May 27, 2014
