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Safety of Sildenafil Citrate: Review of 67 Double-BlindPlacebo-Controlled Trials and the Postmarketing Safety Database

F. Giuliano, G. Jackson, F. Montorsi, A. Martin-Morales, and P. Raillard

Eduardo Bertero, MD* and Francesco Montorsi, MD†

*Hospital do Servidor Publico Estadual, Sao Paulo, Brazil; †Università Vita Salute San Raffaele, Milan, Italy

“S afety of sildenafil citrate: review of 67double-blind placebo-controlled trials and

the postmarketing safety database” was publishedin the International Journal of Clinical Practice in2010. The following are comments regarding thispublication discussing the relevance at the time ofpublication as well as in 2013.1

This paper of Giuliano et al. [1] is a landmarkstudy on the polemic issue of tolerability andadverse events of sildenafil used to treat the malepopulation with erectile dysfunction (ED). Usinga large database of 67 double-blind, placebo-controlled (DBPC) trials conducted by themanufacturer and using the manufacturer’spostmarketing safety database, the authorsreviewed special safety topics and, for the mostfrequently prescribed doses (50 and 100 mg), con-ducted a comprehensive assessment of the toler-ability of sildenafil overall and by age. The DBPCdatabase contains all routine safety data and seriousevent data from the 67 DBPC sildenafil trials,which were completed by June 1, 2007. Thisdatabase included more than 14,000 men. Thepostmarketing safety database contains all cases ofadverse events that were reported spontaneously toPfizer by healthcare professionals, persons otherthan healthcare professionals, national or local reg-istries, and health authorities, or that are systemati-cally identified from the medical literature. Itexcludes cases from the sildenafil clinical trialsprogram and cases of sildenafil usage other than for

ED. The total number of patients identified was39,277, with the vast majority reported spontane-ously by health or nonhealth professionals (40.5%and 57%, respectively).

The safety profile of sildenafil 50 and 100 mg ofboth databases remained consistent with that pre-sented in the original regulatory submissions frommore than a decade ago. Very rare were the cases ofpriapism, nonarteritic anterior ischemic optic neu-ropathy, and hearing loss. Priapism was more fre-quently reported when used in association withanother ED drug, such as alprostadil and withconcomitant medications such as alpha-adrenergicantagonists (phentolamine), amphetamine, andcocaine. Common adverse events in men treatedwith sildenafil were those related to the pharmacol-ogy of phosphodiesterase type 5 (PDE5) inhibition,such as headache, vasodilation, and facial flushing.Interestingly, the safety profiles of sildenafil 50 and100 mg in the DBPC trials were comparable, andthe only exception to this was a known increasedincidence of men with transient-altered colorvision at doses of 100 mg. This review shows thatsildenafil was not associated with increased risk ofcardiovascular disease events. The overall fre-quency of death was low in the DBPC database andwas comparable between men using sildenafil (13/8,691, 0.15%) and placebo (7/6,602, 0.11%). In thepostmarketing database, 20% (7,683/39,277) ofadverse events were considered serious, and 3.3%(1,310/39,277) of patients died. These differencesin the findings of the two databases studied here arebecause of vastly different natures of the metricsbetween them according to the authors. However,it should be noted that the deaths reported were not

1Correction added on 07 April 2014, after first online pub-lication: The last statement of the first paragraph has beendeleted.

© 2014 International Society for Sexual Medicine

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attributed to sildenafil but explained given theknown association between ED and cardiovasculardisease (endothelial dysfunction).

This paper is really a breakthrough and sum-marizes the safety data on all the clinical trialscontaining sildenafil. By far, this molecule is prob-ably the most studied in well-designed trials onthe planet. Like many other physicians over theworld, I have been designated as a principal inves-tigator on several trials including phase 3 studies[2]. We all know that there is a difference betweenseeing a man in a clinical trial and one in a regularoffice visit (real life). We all have gained experi-ence in prescribing sildenafil to thousands ofpatients with ED in different selected populations.The differences between real life and clinical trialsare very difficult to describe and to compare clini-cally; therefore, there is a lack of data in the lit-erature. Many men do not report side effects totheir referral physicians nor to local healthauthorities. In fact, many ED patients do not evenreport using PDE5 inhibitors to their partnersbecause of embarrassment. In Brazil, one of thebiggest markets for ED medications worldwide,many men get the drug without a prescription.Furthermore, recreational use is a fact, and thereare many young men using the drug to improvetheir ability to have “better” sex [3]. We allacknowledge that, often, men get Viagra on web-sites on the Internet, and as shown previously, themajority are counterfeit [4]. This means thatreports of adverse events related to a nongenuineproduct could be entered wrongly onto a database.Another point is that many couples use alcoholbefore having sex, and we have limited data onthat as well [5]. Aforementioned are some reasonsto believe that the postmarketing database shownin this study might not reflect real-world use.Despite the differences among data collected inclinical trials, the postmarketing database, andreal-life experience, it can be assumed thatsildenafil is a very efficacious medication for menwith ED, very well tolerated and safe. Moreover,it has opened the eyes of society regarding aserious disease affecting millions of couples.

Eduardo Bertero, MD

Sildenafil citrate (Viagra), the “mighty blue pill,”was the first PDE5 inhibitor approved by the U.S.Food and Drug Administration in March 1998and by the European Medicines Agency in Sep-tember 1998 for the on-demand treatment of ED.

Several clinical trials have been carried out toprove the efficacy of this drug, and its safety hasbeen challenged in every way for long time.Treatment-related adverse events have beenclearly demonstrated to be generally mild to mod-erate and represented primarily by headache,facial flushing, nasal congestion, and dyspepsia. Inthis review, based on 67 DBPC trials and on themanufacturer’s postmarketing safety database,Giuliano et al. confirmed this excellent safetyprofile, showing that sildenafil was well toleratedat 50 and 100 mg in men with broad spectrumetiology ED, even in those aged ≥65 and ≥75years. Likewise, no causal link between sildenafiland either cardiovascular events or any new safetyrisks relating to cardiovascular events, priapism,nonarteritic anterior ischemic optic neuropathy,hearing loss, or drug interactions was reported.Moreover, the safety profile in men with moderateimpairment of either renal or hepatic function wassimilar to that of men without these problems.Additionally, there were not safety issues in con-junction with overdose, dependence, abuse, ormisuse of sildenafil. Based on the facts, this reviewconfirmed the significant efficacy, tolerability, andsafety of this drug, allowing sildenafil to beapproved and used worldwide.

These first observations are linked with anumber of important aspects in everyday clinicalpractice: (i) The European Association ofUrology (EAU) guidelines on male sexual dys-function [6] suggest the “classic” use of sildenafilas first-line oral therapy for ED of any origin.Being urologists, it has been even more excitingto deal with its effectiveness in men undergoingradical prostatectomy as it was initially empha-sized by the historical paper of Zippe et al. in1998 [7]. Since then, an impressive number ofstudies and papers have helped both researchersand physicians in everyday clinical practice tohighlight the importance of physiology andpathophysiology of erections in men who havebeen and keep being treated with Viagra to rees-tablish their own spontaneous or pill-assistederections after surgery [8]. The use of sildenafilsince 1998 is extraordinary. Both the AmericanUrology Association guidelines [9] and those ofthe International Society for Sexual Medicine [10]basically confirm EAU indications for sildenafil.Therefore, sildenafil is a proven drug, with offi-cial guideline indications for its use and, becauseof this, widely prescribed by clinicians.

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(ii) Viagra is not just a drug, but it is also a symbolof the “andrology world” rebirth, along with thedevelopment of the novel concept of Sexual Medi-cine. In this context, how lucky we have been livingin the real “Viagra era” that has certainly hugelycontributed to our scientific and clinical growth inthe field of sexual health and human well-being.Indeed, Viagra represents the first and only medi-cation for ED which has made a clear change in theworld culture: It represents a highly publicizedmass media topic. Just to get an idea, simply enter-ing sildenafil as a text word for a Google search, youwill get about 39,400,000 results in 0.15 seconds. Itsname, shape, and blue color are familiar to billionsof people of different race, social class, and age. It isthe subject of many jokes and movie scenes, and it isamazing how other PDE5 inhibitors or prostaglan-dins are described to patients in this way: “It is likeViagra but . . .”

Viagra has been, is, and will be for many yearsthe best-known little blue diamond pill, and it isclearly safe!

Francesco Montorsi, MD

References

1 Giuliano F, Jackson G, Montorsi F, Martin-Morales A,Raillard P. Safety of sildenafil citrate: Review of 67 double-blind placebo-controlled trials and the postmarketing safetydatabase. Int J Clin Pract 2010;64:240–55.

2 Glina S, Bertero E, Claro J, Damião R, Faria G, Fregonesi A,Jaspersen J, Mendoza A, Mattos D Jr, Rocha LC, SotomayorM, Telöken C, Ureta S, Zonana E, Ugarte F. Efficacy andsafety of flexible-dose oral sildenafil citrate (Viagra) in the

treatment of erectile dysfunction in Brazilian and Mexicanmen. Int J Impot Res 2002;14:S27–32.

3 Bechara A, Casabé A, De Bonis W, Helien A, Bertolino MV.Recreational use of phosphodiesterase type 5 inhibitors byhealthy young men. J Sex Med 2010;7:3736–42.

4 Campbell N, Clark JP, Stecher VJ, Goldstein I. Internet-ordered viagra (sildenafil citrate) is rarely genuine. J Sex Med2012;9:2943–51.

5 Dachille G, Lamuraglia M, Leone M, Pagliarulo A, PalascianoG, Salerno MT, Ludovico GM. Erectile dysfunction andalcohol intake. Urologia 2008;75:170–6.

6 Hatzimouratidis K, Amar E, Eardley I, Giuliano F,Hatzichristou D, Montorsi F, Vardi Y, Wespes E; EuropeanAssociation of Urology. Guidelines on male sexual dysfunc-tion: Erectile dysfunction and premature ejaculation. Eur Urol2010;57:804–14.

7 Zippe C, Kedia AW, Kedia K, Nelson DR, Agarwal A. Treat-ment of erectile dysfunction after radical prostatectomy withsildenafil citrate (Viagra). Urology 1998;52:963–6.

8 Padma-Nathan H, McCullough AR, Levine LA, Lipshultz LI,Siegel R, Montorsi F, Giuliano F, Brock G; Study Group.Randomized, double-blind, placebo-controlled study of post-operative nightly sildenafil citrate for the prevention of erectiledysfunction after bilateral nerve-sparing radical prostatectomy.Int J Impot Res 2008;20:479–86.

9 Montague DK, Jarow JP, Broderick GA, Dmochowski RR,Heaton JP, Lue TF, Milbank AJ, Nehra A, Sharlip ID; ErectileDysfunction Guideline Update Panel. Chapter 1: The man-agement of erectile dysfunction: An AUA update. J Urol2005;174:230–9

10 Montorsi F, Adaikan G, Becher E, Giuliano F, Khoury S,Lue TF, Sharlip I, Althof SE, Andersson KE, Brock G,Broderick G, Burnett A, Buvat J, Dean J, Donatucci C,Eardley I, Fugl-Meyer KS, Goldstein I, Hackett G,Hatzichristou D, Hellstrom W, Incrocci L, Jackson G,Kadioglu A, Levine L, Lewis RW, Maggi M, McCabe M,McMahon CG, Montague D, Montorsi P, Mulhall J, Pfaus J,Porst H, Ralph D, Rosen R, Rowland D, Sadeghi-Nejad H,Shabsigh R, Stief C, Vardi Y, Wallen K, Wasserman M.Summary of the recommendations on sexual dysfunctions inmen. J Sex Med 2010;7:3572–88.

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