LETTER TO THE EDITOR
Reply
Robert A. Kloner, MD, PhD
Good Samaritan Hospital, Cardiovascular Division, 1225 Wilshire Boulevard, Los Angeles, California 90017, USA
Adolph M. Hutter, MD,
Jeffrey T. Emmick, MD, PhD,
Malcolm I. Mitchell, MBBS, MFPM,
Jonathan Denne, PhD and
Graham Jackson, MD
rkloner{at}goodsam.org
We would like to thank Dr. Abrams for his questions regarding our study on the time course of the interaction between tadalafil and sublingual nitroglycerin (SL-NTG) (1). In response to question 1 regarding the duration of efficacy: Since the publication of the article (1), tadalafil, a phosphodiesterase 5 (PDE5) inhibitor, has been approved by the Food and Drug Administration for the treatment of erectile dysfunction (ED) (2). Tadalafil improves erectile function in men with ED for up to 36 h after dosing (2,3). Therefore, the duration of efficacy of tadalafil for the treatment of ED for up to 36 h is similar to the time course of the interaction of tadalafil with nitrates (i.e., the hemodynamic interaction between tadalafil and SL-NTG lasted 24 h but was not seen at 48 h and beyond).
In response to question 2 regarding study design: Our study was a randomized, placebo-controlled, double-blind, two-period, cross-over, multicenter study (n = 150). During treatment period 1, subjects received seven consecutive daily doses of either tadalafil (20 mg) or placebo before SL-NTG administration. After a 10- to 21-day washout period, subjects were crossed over to the opposite treatment (treatment period 2) and received seven consecutive daily doses of either tadalafil or placebo before SL-NTG administration.
In response to question 3 regarding the recommendation to withhold nitrates for 48 h: In our study, SL-NTG (0.4 mg) was administered at 2, 4, 8, 24, 48, 72, and 96 h after the last dose of tadalafil 20 mg or placebo. Tadalafil augmented the blood pressure-lowering effects of SL-NTG from 2 to 24 h post-dosing compared with placebo, with no significant differences at 48, 72, or 96 h. Our study did not examine the time points between 24 and 48 h to assess when the hemodynamic interaction between tadalafil and SL-NTG was no longer detectable. Therefore, if deemed medically necessary, nitrates should be administered only under close medical supervision with hemodynamic monitoring at 48 h and beyond the last dose of tadalafil.
In response to question 4 regarding the half-life of sildenafil: The half-life of sildenafil is 4 h (4). Several studies have demonstrated the interaction between sildenafil and organic nitrates (5–7). Recently, a preliminary study (7) performed in 33 healthy men showed that SL-NTG, administered at multiple time points up to 48 h post-sildenafil 100 mg or placebo dosing, produced decreases in mean sitting blood pressure that were significantly different (sildenafil minus placebo) only at 1 h post-sildenafil or placebo dosing. Although the experimental design was similar to our clinical trial (1), the sildenafil study only reported mean blood pressures. Because interactions may be missed by only analyzing mean changes in blood pressure, the number of patients with potentially clinically significant blood pressure changes (i.e., ‘outliers’) should also be used to detect hemodynamic interactions (1,8,9). This preliminary sildenafil study (7) was also much smaller than our study and was performed in healthy men only. Because of the potential for clinically relevant hypotension, the American College of Cardiology/American Heart Association Consensus Committee recommends that nitrates not be given until 24 h (5 to 6 half-lives) after taking sildenafil (4).
In response to question 5 regarding the non–steady-state dosing of tadalafil: We examined the hemodynamic effects of SL-NTG administered after single doses of tadalafil (5 mg and 10 mg) compared with placebo (8–10). These studies examined both mean maximal changes in blood pressure as well as blood pressure outlier data. Although not performed within the same study, the hemodynamic interactions with nitrates after a single dose of tadalafil were comparable to those after steady-state dosing of tadalafil (1,8–10). Studies have not been done to examine the development of tolerance to the hemodynamic effects of nitrates in the presence of PDE5 inhibitors. Importantly, nitrates are contraindicated whether a patient has been taking daily or intermittent doses of any PDE5 inhibitor (e.g., tadalafil, sildenafil, or vardenafil).
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References
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1. Kloner RA, Hutter AM, Emmick JT, Mitchell MI, Denne J, Jackson G. Time course of the interaction between tadalafil and nitrates. J Am Coll Cardiol. 2003;42:1855–1860[Abstract/Free Full Text]
2. Tadalafil [package insert]. Indianapolis, IN, and Bothell, WA: Lilly ICOS LLC, 2003
3. Porst H, Padma-Nathan H, Giuliano F, Anglin G, Varanese L, Rosen R. Efficacy of tadalafil for the treatment of erectile dysfunction at 24 and 36 hours after dosing: a randomized controlled trial. Urology. 2003;62:121–126[CrossRef][Medline]
4. Cheitlin MD, Hutter AM Jr., Brindis RG, et al. ACC/AHA expert consensus document. Use of sildenafil (Viagra) in patients with cardiovascular disease. J Am Coll Cardiol. 1999;33:273–282[Free Full Text]
5. Webb DJ, Freestone S, Allen MJ, Muirhead GJ. Sildenafil citrate and blood pressure lowering drugs: results of drug interaction studies with an organic nitrate and calcium antagonist. Am J Cardiol. 1999;83:21C–28C[Medline]
6. Webb DJ, Muirhcad GJ, Wulff M, Sutton JA, Levi R, Dinsmore WW. Sildenafil citrate potentiates the hypotensive effects of nitric oxide donor drugs in male patients with stable angina. J Am Coll Cardiol. 2000;36:25–31[Abstract/Free Full Text]
7. Oliver JJ, Bell K, Leckie SM, Webb DJ. Interaction between glyceryl trinitrate and sildenafil citrate (Viagra) may last less than four hours. Int J Impot Res. 2002;14(Suppl 3):522
8. Emmick JT, Stuewe SR, Mitchell M. Overview of the cardiovascular effects of tadalafil. Eur Heart J. 2002;4(Suppl):H32–47
9. Kloner RA, Mitchell MI, Emmick JT. Cardiovascular effects of tadalafil. Am J Cardiol. 2003;92(Suppl):37M–46M[CrossRef][Medline]
10. Kloner RA, Emmick JT, Bedding A, Humen D. Pharmacodynamic interaction between tadalafil and nitrates. (abstr)J Am Coll Cardiol. 2002;39:291A
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