Avanafil, sildenafil, tadalafil, and vardenafil are PDE-5 inhibitors available in the USA and indicated for erectile dysfunction.  PDE-5 inhibitors prevent the breakdown of cGMP and it is also one of the drug classes that interacts with nitrates. Nitrates are one of the important medications to manage angina and other cardiovascular diseases.  Nitrates increase cGMP which will contribute to vasodilation. Concomitant use of PDE-5 inhibitors and nitrates is contraindicated because of the high risk of severe hypotension due to increased levels of cGMP. In this article, we will discuss the recommended separation for nitrates and PDE-5 inhibitors.

Then, what should we do if nitrate administration is deemed medically necessary and the patient is taking PDE-5 inhibitors? How long should we wait between the last dose of PDE-5 inhibitors and nitrates to avoid drug interactions? 

The study called “Overview of Cardiovascular Effects of Tadalafil” evaluated nitroglycerin administration 1 day after sildenafil, tadalafil, or placebo. This study shows that there is lack of interactions between PDE-5 inhibitors and Nitrates after approximately 6 half-lives of sildenafil. The half-life of both sildenafil and vardenafil is 4 hours. The American College of Cardiology and American Heart Association recommends that nitrates can be administered at least 24 hours (6 half-lives) after last dose of sildenafil. The package insert of Vardenafil recommends at least 24 hours after last dose of vardenafil. 

The half-life of tadalafil is 17.5 hours. However, the study called Time Course of the Interaction Between Tadalafil and Nitrates shows that there is no significant differences were observed between the tadalafil and placebo groups at 48, 72, or 96 hours after the last tadalafil intake.  Therefore, it is recommended that nitrates can be administered at least 48 hours after the last dose of tadalafil.

Drug Name (Brand)	Half-life (hours)	Recommended time to avoid nitrates (hours)
Sildenafil (Viagra)	4	24
Vardenafil (Levitra and Staxyn ODT)	4	24
Tadalafil (Cialis)	17.5	48
Avanafil (Stendra)	5	12

The half-life of avanafil is 5 hours. However, the package insert and the study “Phosphodiesterase-5 (PDE₅) Inhibitors in the Management of Erectile Dysfunction” recommends at least 12 hours between nitrates and last dose of avanafil. 

In circumstances where nitrates need to be given to a person who is using the PDE-5 Inhibitors, administration of nitrates should be done under medical supervision with appropriate hemodynamic monitoring.

Article written by Su Myat, PharmD Candidate in collaboration with Eric Christianson, PharmD, BCPS, BCGP

We have discussed management strategies of the nitrate PDE-5 interaction; you can find that article here.

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Sources:

Emmick JT, Stuewe SR, Mitchell M. Overview of the cardiovascular effects of tadalafil. Eur Heart J Suppl. 2002; 4: H32–H47.

Bayer Health Care Pharmaceuticals. Product monograph for LEVITRA (vardenafil HCL). Available at: http://www.univgraph.com/bayer/inserts/levitra.pdf. Accessed March 29, 2010.

 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.

Huang, S. A., & Lie, J. D. (2013). Phosphodiesterase-5 (PDE5) Inhibitors In the Management of Erectile Dysfunction. P & T : a peer-reviewed journal for formulary management, 38(7), 407–419.VIVUS Inc. Product monograph for STENDRA (Avanafil). Available at: https://www.accessdata.fda.gov/drugsatfda_docs/label/2012/202276s000lbl.pdf