Chester Clinic

 

Doi:10.1016/s0090-4295(03)00359-5

EFFICACY OF TADALAFIL FOR THE TREATMENT OF ERECTILE DYSFUNCTION AT 24 AND 36 HOURS AFTER DOSING: A RANDOMIZED CONTROLLED TRIAL HARTMUT PORST, HARIN PADMA-NATHAN, FRANC ¸ OIS GIULIANO, GREG ANGLIN, LUCIO VARANESE, AND RAYMOND ROSEN Objectives. To examine the therapeutic effects of tadalafil on erectile dysfunction (ED) at 24 and 36 hours
after dosing.
Methods. A multicenter, randomized, double-blind, placebo-controlled, parallel-group study of 348 men
(mean age 57 years) with ED was conducted in Europe and the United States. Patients were stratified by
baseline severity of ED using the Erectile Function domain score of the International Index of Erectile
Function and then randomly allocated within the severity group to receive tadalafil 20 mg (n ⫽ 175) or
placebo (n ⫽ 173). Subsequently, participants were randomly assigned to two 4-week treatment intervals, during which they were requested to attempt sexual intercourse approximately 24 or 36 hours after tadalafil
or placebo dosing. The primary outcome measure was the proportion of successful sexual intercourse
attempts (completed to ejaculation) according to patient self-report using the Sexual Encounter Profile diary.
Results. Of the 348 patients, 327 (94%) completed the trial (163 of 175 in the tadalafil group and 164 of
173 in the placebo group). Thirty-six hours after tadalafil dosing, 59.2% of intercourse attempts were
successful versus 28.3% in the placebo group (P ⬍0.001). The proportion of successful intercourse attempts
at approximately 24 hours after treatment was also significantly greater with tadalafil (52.9%) than withplacebo (29.1%; P ⬍0.001). Tadalafil was well tolerated. The incidences of four treatment-emergent adverse events were significantly greater in the tadalafil group than in the placebo group (all P ⬍0.05): headache, flushing, dyspepsia, and myalgia.
Conclusions. Tadalafil 20 mg is an effective and well-tolerated treatment for ED that has a period of
responsiveness of up to 36 hours. UROLOGY 62: 121–126, 2003. 2003 Elsevier Inc.
Erectiledysfunction(ED)affectsmorethan150 Americans.1–3 Yet, reviews of published studies4
million men worldwide,1 including approxi- have estimated that 70% of ED goes undiagnosed.
mately 20 million European men and 30 million For the minority of these men who do seek help, therapy with the oral, selective phosphodiesterase5 (PDE5) inhibitor sildenafil largely resolves ED, This study was funded by Lilly ICOS LLC. conferring benefits to both patients and their part- H. Porst, H. Padma-Nathan, F. Giuliano, and R. Rosen are paid ners.5–12 The efficacy of PDE5 inhibitors is ascribed consultants to both the sponsor of this study and competitors, are to their ability to amplify the activity of the nitric study investigators funded by the sponsor, and are members of thespeaker's bureau for the sponsor. G. Anglin and L. Varanese are oxide-3⬘,5⬘-cyclic guanosine monophosphate sig- employees of the sponsor and hold stock in the sponsor. naling pathway and to potentiate the smooth mus- From Private Urological Practice, Hamburg, Germany; Uni- cle-relaxing effects of nitric oxide within the cor- versity of Southern California Keck School of Medicine, Los An- pus cavernosum.13 However, despite its high geles, California; Department of Urology, CHU de Biceˆtre, Le efficacy rates, many men stop using sildenafil. The Kremlin-Biceˆtre, France; Eli Lilly Canada, Toronto, Ontario,Canada; Eli Lilly, Erl Wood, United Kingdom; University of Med- reasons for this include cost, adverse events, and icine and Dentistry of New Jersey, Robert Wood Johnson Medical perceived lack of efficacy.14 In addition, in a survey School, Piscataway, New Jersey. about the importance of different outcome vari- Reprint requests: Hartmut Porst, M.D., Urological Practice, ables when choosing among pharmacotherapies Neuer Jungfernstieg 6a, Hamburg 20354, Germany Submitted: September 5, 2002, accepted (with revisions): for ED, the investigators found that success, avoid- January 27, 2003 ing a negative outcome, and naturalness ranked 2003 ELSEVIER INC.
ALL RIGHTS RESERVED highest.15 It is therefore possible that some men ure to achieve erection after radical prostatectomy or pelvic may discontinue sildenafil use because it makes surgery, a history of stroke or spinal cord trauma in the pre- sexual encounters feel less natural.
vious 6 months, unstable cardiac disease, clinically significantrenal insufficiency or hepatobiliary disease, and concomitant On closer examination, the perceived lack of ef- antiandrogen use or chemotherapy.
ficacy of sildenafil can usually be attributed to in- To ensure balanced allocation, patients were stratified by adequate dosing and failure by the physician to baseline ED severity according to their scores on the Erectile give thorough instructions (or of the patient to fol- Function domain of the International Index of Erectile Func- 16 For instance, some patients who are with mild ED characterized by a score of 17 to 25, moderate ED by a score of 11 to 16, and severe ED by a regarded as sildenafil failures may not have re- score of 1 to 10. Although scores of 26 to 30 are indicative of ceived sufficient sexual stimulation before at- no ED,21 those entering the study with scores of 26 or greater tempting intercourse, and others may have at- were added to the mild group for classification purposes. Pa- tempted intercourse too early after dosing or after a tients were randomized to tadalafil or placebo according to a computer-generated randomization table. At the screeningvisit (4 weeks before randomization), patients underwent a Tadalafil (Cialis, Lilly ICOS LLC, Indianapolis, physical examination, 12-lead electrocardiogram, and labora- Ind and Bothell, Wash) is a potent, reversible, and tory tests. Vital signs (blood pressure and heart rate) were selective PDE5 inhibitor for the treatment of ED.17 measured at each visit, and the physical examination was re- Compared with sildenafil (Viagra, Pfizer, New peated at week 8 or at premature discontinuation, if necessary, York, NY), tadalafil has an extended terminal half- at each investigator's discretion.
life, 17.5 hours18 versus 3.7 hours,19 suggesting alengthened period of responsiveness compared with sildenafil.
The proportion of "yes" responses to Sexual Encounter Pro- file (SEP) question 3 (SEP-Q3), "Did your erection last long On the basis of the pharmacokinetic data, as well enough for you to have successful intercourse? [yes/no]," rep- as preliminary clinical evidence suggesting an ex- resented the primary efficacy variable.
tended duration of action, this study was designed Adverse events reported by patients were recorded at each to evaluate the efficacy of tadalafil at 24 and 36 4-week visit, classified by severity, and coded using the hours after dosing in men with ED.
COSTART (Coding Symbols for a Thesaurus of Adverse Reac-tion Terms) dictionary. Investigators also assessed the rela-tionship of each event to the study drug. The safety outcome MATERIAL AND METHODS
measure was the incidence of treatment-emergent adverseevents in the placebo or tadalafil group. Treatment-emergent STUDY DESIGN AND PATIENT POPULATION
adverse events were defined as events that first occurred or This multicenter, randomized, double-blind, placebo-con- worsened after the baseline assessment.
trolled, parallel-group trial was conducted at 36 centers inEurope and the United States from February through April2001. Ethical review boards approved its protocol and in- formed consent documents, and all patients and partners pro- Each randomized patient was eligible for the efficacy anal- vided written informed consent before enrollment. The study ysis. The analysis of safety included all randomized patients.
consisted of a 4-week treatment-free run-in period (during All analyses were performed with the patients included in the which patients qualified for randomization in part by attempt- group to which they were assigned by random allocation. Pa- ing sexual intercourse at least four times), followed by ran- tient baseline characteristics were summarized for each treat- domization in a 1:1 ratio to tadalafil 20 mg or matching pla- cebo for 8 weeks.
For continuous patient characteristics at baseline, the mean The treatment period was divided into two 4-week inter- values by therapy group were compared using analysis of vari- vals, each of which began with the investigator dispensing two ance. The incidence of the categorical variables at baseline was doses of treatment for at-home use. Each man was instructed compared using the Pearson chi-square test.
to take one dose of treatment before sexual activity, with no It was specified a priori that a sexual encounter that was restrictions on alcohol or food intake. During one 4-week recorded ⱖ20 hours or ⱕ30 hours after dosing was considered phase, the patients were to attempt sexual intercourse twice in an eligible 24-hour encounter if it was the first encounter after conjunction with medication use, each time at approximately dosing. Similarly, an encounter that was recorded ⱖ30 hours 24 hours after dosing, with an 8 to 10-day washout period and ⱕ48 hours after dosing was considered an eligible 36- between attempts.
hour encounter if it was the first encounter after dosing. How- In the other 4-week interval, men were instructed to at- ever, the data presented herein are for encounters made ⱖ22 tempt intercourse at approximately 36 hours after dosing, and hours or ⱕ26 hours after dosing for the 24-hour time point then repeat after another 8 to 10-day washout period. Patients and for encounters made ⱖ34 hours or ⱕ38 hours after dosing were also randomized into two order groups, with intercourse for the 36-hour time point.
requested either 36 hours after dosing for the first 4-week Two null hypotheses were tested in a sequential fashion.
interval, and then 24 hours after dosing for the second, or vice The first was that there was no difference between tadalafil 20 mg and placebo in terms of the proportion of successful inter- Men aged 18 years or older with a minimum 3-month his- course attempts at 24 hours after dosing, as measured by SEP- tory of ED who were in a stable, monogamous relationship Q3. To reject this null hypothesis, significance at the 0.05 level with a female partner were eligible for enrollment. ED was was required. A second null hypothesis was tested only be- defined as a consistent change in the quality of erection that cause the first null hypothesis was rejected with P ⬍0.05: that adversely affected the patient's satisfaction with sexual inter- there was no difference between tadalafil 20 mg and placebo in course. Patient exclusion criteria included the presence of pe- terms of the proportion of successful intercourse attempts at nile implants or clinically significant penile deformities, fail- 36 hours after dosing, as measured by SEP-Q3. To reject this UROLOGY 62 (1), 2003
signed to placebo (P ⬍0.001; Table II). On the TABLE I. Baseline demographic
basis of positive responses to SEP-Q3, 120 (53%) of 227 intercourse attempts at 24 hours were suc- cessfully completed in the tadalafil group com- (n ⴝ 173)
(n ⴝ 175)
pared with 72 (29%) of 247 in the placebo control group (P ⬍0.001). Of the patients randomized to placebo (n ⫽ 173), 144 had a sexual attempt at 24 hours and 128 at 36 hours. Approximately 37% and 35% of these patients had a successful attempt at 24 and 36 hours after dosing, respectively.
Among those randomized to tadalafil (n ⫽ 175), 138 and 131 patients had eligible encounters at 24 Severity of ED* (n) and 36 hours after dosing, respectively. Of those, 61% had a successful intercourse attempt at 24 hours and 64% had a successful intercourse at- tempt at 36 hours (P ⬍0.001).
Treatment with tadalafil was well tolerated. The Current smoker (n) incidences of treatment-emergent headache, flush- Current alcohol use (n) ing, dyspepsia, and myalgia were significantlygreater in the active-treatment arm compared KEY: ED ⫽ erectile dysfunction.
Numbers in parentheses are percentages. with the placebo group (Table III). Notably, there *Based on Erectile Function domain scores on the International Index of Erectile were no visual-perceptual changes, cardiovascular Function (mild, 17–30 [includes men with no ED, scores of 26 –30]; moderate,11–16; severe, 1–10). events, or any clinically significant effects oftadalafil on electrocardiographic findings, heartrate, or blood pressure.
null hypothesis, significance at the 0.05 level was required.
The majority of adverse events were mild or Each test was two-tailed.
moderate in severity. A total of 4 patients discon- For primary efficacy analyses of SEP-Q3, the "yes"/"no" tinued the study prematurely because of adverse responses were considered in a categorical repeated-measures events: 3 (2%) in the tadalafil group and 1 (0.5%) model. The model included terms for treatment group, inves-tigative site, patient's baseline percentage "yes" responses to in the placebo group. Of the 3 patients taking SEP-Q3, and the baseline value of the Erectile Function do- tadalafil who withdrew, 1 each experienced myal- main of the International Index of Erectile Function. One gia (with lethargy) after two doses; dyspepsia after model was fitted for the responses for the 24-hour time point, one dose; or abdominal pain (with nausea) after and a separate model was fitted for the responses for the 36- one dose. One placebo recipient experienced diz- hour time point.
Safety was assessed by evaluating all reported adverse ziness and headache.
events, vital signs, and physical examination results. Treat-ment-emergent adverse events were summarized by the COSTART preferred term for severity and relationship tostudy drug. The analysis comparing the incidence of treat- Because of their relatively short half-lives, phar- ment-emergent adverse events among treatment groups was macologic agents for ED have historically been performed using Fisher's exact test.
used just before a couple engages in sexual activity,inextricably linking the medication with a man's sexual performance. For example, with alprostadil Of 348 men enrolled, 327 (94%) completed injection (Caverject, Pharmacia & Upjohn, Pea- treatment. The baseline characteristics were well pack, NJ), erection is expected to occur within 5 to balanced in the two treatment groups (Table I).
20 minutes after dosing and to last up to 1 hour, The mean age in each group was 57 years, and most regardless of sexual stimulation.22 With the alpros- patients had ED for more than 1 year. On the basis tadil urethral suppository (MUSE, Vivus, Moun- of previously established Erectile Function domain tain View, Calif), erection is expected to occur categories of the International Index of Erectile within 10 minutes of administration and to last for Function, about 40% of men had mild ED, 35% had 30 to 60 minutes, with or without sexual stimula- severe ED, and 25% had moderate ED.
tion.23 With sildenafil (Viagra, Pfizer, New York, Tadalafil was effective for 36 hours, with 132 NY), men may experience erection between 30 (59%) of 223 intercourse attempts successfully minutes and 4 hours after ingestion, and sexual completed in patients randomized to the 20-mg stimulation is required.24 For apomorphine dose compared with 60 (28%) of 212 in those as- (Ixense, Takeda Europe Research & Development UROLOGY 62 (1), 2003
TABLE II. Effects of tadalafil on successful intercourse completion over time*
Placebo (n ⴝ 173)
Tadalafil (n ⴝ 175)
Time Point
Attempts (n)
Attempts (n)
Attempts (n)
Attempts (n)
Numbers in parentheses are percentages.
*Proportion of successful intercourse attempts according to Sexual Encounter Profile Question 3 (SEP-Q3). For the requested 24-hr time point, first attempts made ⱖ22 hr and ⱕ26 hr after dosing were included; for the requested 36-hr time point, first attempts made ⱖ34 hr and ⱕ38 hr after dosing were included. †P ⬍0.001 for comparison (tadalafil vs. placebo) from a repeated-measures logistic regression model of yes/no responses to SEP-Q3 for requested encounter. tivity, causing them to plan their sexual encounters TABLE III. Incidence of adverse events*
rather than allowing them to occur spontaneously.
Prior studies18 using successful intercourse com- (n ⴝ 173)
(n ⴝ 175)
pletion (SEP-Q3) as the primary outcome measure demonstrated that the earliest time to the onset of significant effects for tadalafil 20 mg was 16 min- utes after dosing (32% success rate versus 15% with placebo; P ⬍0.05). At 30 minutes after dos- Data presented as number of patients, with the percentage in parentheses. ing, 52% of men were considered responders to *Treatment-emergent adverse events of all causes either occurring in at least 3% ofeach treatment group or exhibiting a significant difference across treatment arms. treatment versus 35% in the placebo group(P ⬍0.05).
The extended period of responsiveness afforded Centre, London, United Kingdom), men may ex- by tadalafil, which has a terminal half-life of 17.5 perience erection 20 minutes after sublingual ad- hours, may begin to change the treatment para- ministration, provided they have adequate sexual digm for men with ED. Unlike currently available stimulation, and can take a subsequent dose 8 treatments, tadalafil may, for example, enable a pa- tient to take a pill on a Friday evening and have In this trial, the ability of tadalafil to significantly intercourse with his partner on Saturday night or increase the percentage of successful intercourse Sunday morning. The broad therapeutic coverage attempts was still evident 36 hours after dosing, conferred by tadalafil, which can be taken without with approximately 60% of intercourse attempts restrictions on alcohol or food intake, might trans- successfully completed at this time point versus late to enhanced convenience and simplicity of ad- 28% with placebo (P ⬍0.001). Tadalafil was well ministration, traits that are valued by men with tolerated and exhibited a tolerability profile consis- tent with previously published data.17 This was not a study of efficacy per se or the time of maximum efficacy; rather, it was designed todetermine whether tadalafil was associated with a The advent of a pharmacologic agent such as treatment effect that could be discriminated from tadalafil, with a period of responsiveness that be- the effect of placebo for at least 24 and 36 hours.
gins soon after dosing and lasts up to 36 hours, may Standardized efficacy trials showed that approxi- allow men and their partners more freedom in the mately 75% of intercourse attempts were success- timing of their sexual activity.
ful (as measured by SEP-Q3) among men treatedwith tadalafil 20 mg (P ⬍0.001 versus placebo), with 80% success for attempts undertaken up to 24 1. McKinlay JB: The worldwide prevalence and epidemi- hours after dosing.18 Differences among the rates ology of erectile dysfunction. Int J Impot Res 12(suppl 4):
S6 –S11, 2000.
of successful sexual intercourse with tadalafil in 2. Phillips P: Reports at European Urology Congress re- this study compared with standardized efficacy flect issues of interest to aging men. JAMA 279: 1333–1335,
trials are likely related to the study's design. In the standardized efficacy trials, men were allowed to 3. NIH Consensus Conference. Impotence. NIH Consen- take tadalafil at any time of their choosing before sus Development Panel on Impotence. JAMA 270: 83–90,
1993.
engaging in sexual activity. In this trial, patients 4. Chun J, and Carson CC: Physician-patient dialogue and and their partners were required to wait a prespeci- clinical evaluation of erectile dysfunction. Urol Clin North Am fied amount of time before engaging in sexual ac- 28: 249 –258, 2001.
UROLOGY 62 (1), 2003
5. Goldstein I, Lue TF, Padma-Nathan H, et al, for the 25. Ixense威 (apomorphine hydrochloride) prescribing in- Sildenafil Study Group: Oral sildenafil in the treatment of formation. London, United Kingdom, Takeda Europe Re- erectile dysfunction. N Engl J Med 338: 1397–1404, 1998.
search & Development Centre, 2001.
6. Dinsmore WW, Hodges M, Hargreaves C, et al: Silden- afil citrate (Viagra) in erectile dysfunction: near normalisationin men with broad-spectrum erectile dysfunction compared EDITORIAL COMMENT 1 with age-matched healthy control subjects. Urology 53: 800 –
The world of ED changed forever at the 1983 American Urological Association meeting in Las Vegas, when a British 7. McMahon CG, Samali R, and Johnson H: Efficacy, physiologist named Giles Brindley stepped from behind the safety and patient acceptance of sildenafil citrate as treatment podium and lowered his pants, revealing to colleagues his for erectile dysfunction. J Urol 164: 1192–1196, 2000.
phentolamine-induced erection. Said one pundit of this water- 8. Rendell MS, Rajfer J, Wicker PA, et al, for the Sildenafil shed event, "Farther down the Strip, Siegfried and Roy were Diabetes Study Group: Sildenafil for treatment of erectile dys- making a white Bengal tiger disappear, and two circus aerial- function in men with diabetes: a randomized controlled trial.
ists— one sitting on the other's shoulders—were traversing a JAMA 281: 421–426, 1999.
tightrope without a net. But even in Vegas they'd never seen a 9. Guay AT, Perez JB, Jacobson J, et al: Efficacy and safety show like this." Thus was crystallized the enduring principle of sildenafil citrate for treatment of erectile dysfunction in a that penile erection is caused by smooth muscle relaxation in population with associated organic risk factors. J Androl 22:
the corpora cavernosa. Few breakthroughs in medical history 793–797, 2001.
have been heralded with the dramatic impact of Brindley's 10. Hultling C, Giuliano F, Quirk F, et al: Quality of life in moment in Nevada.
patients with spinal cord injury receiving Viagra (sildenafil Tadalafil (Cialis, Lilly ICOS LLC), along with sildenafil (Vi- citrate) for the treatment of erectile dysfunction. Spinal Cord agra, Pfizer) and vardenafil (Levitra, Bayer), belong to an 38: 363–370, 2000.
orally effective class of smooth muscle relaxants called phos- 11. Weber DC, Bieri S, Kurtz JM, et al: Prospective pilot phodiesterase (PDE) inhibitors. Unlike Brindley's direct-act- study of sildenafil for treatment of postradiotherapy erectile ing phentolamine, PDE5 (penile) inhibitors produce erections dysfunction in patients with prostate cancer. J Clin Oncol 17:
indirectly, by inhibiting breakdown of cyclic guanosine mono- 3444 –3449, 1999.
phosphate, the neurotransmitter for corporal smooth muscle 12. Lewis R, Bennett CJ, Borkon WD, et al: Patient and relaxation. Thus, with PDE5 inhibitors, erection develops in a partner satisfaction with Viagra (sildenafil citrate) treatment physiologic manner by amplification of the nitric oxide path- as determined by the Erectile Dysfunction Inventory of Treat- way and only with sexual stimulation. Sildenafil, the sole ment Satisfaction Questionnaire. Urology 57: 960 –965, 2001.
PDE5 inhibitor currently approved in the United States, has 13. Ignarro LJ, Bush PA, Buga GM, et al: Nitric oxide and enjoyed enormous success because of its specificity, effective- cyclic GMP formation upon electrical field stimulation cause ness, convenience, and safety; according to Pfizer, more than relaxation of corpus cavernosum smooth muscle. Biochem 20 million men in 110 countries have used the drug.
Biophys Res Commun 170: 843–850, 1990.
In the present report of Phase III tadalafil data, 348 men 14. Madduri SD: After two years, did Viagra live up to its with organic and/or psychogenic ED were given the drug (20 expectations? Missouri Med 98: 243–245, 2001.
mg) or placebo in an 8-week randomized, multicenter trial.
15. Hanson-Divers C, Jackson SE, Lue TF, et al: Health The trial was designed specifically to test the duration of ac- outcomes variables important to patients in the treatment of tion of the drug. Thirty-six hours after dosing, approximately erectile dysfunction. J Urol 159: 1541–1547, 1998.
two thirds of tadalafil patients, but only one third of placebo 16. El-Galley R, Rutland H, Talic R, et al: Long-term effi- patients, were able to have successful intercourse (P ⬍0.001).
cacy of sildenafil and tachyphylaxis effect. J Urol 166: 927–
Side effects were uncommon and not severe, including mostly the now-familiar headache, flushing, and dyspepsia. A fewpatients also reported myalgias, possibly because of skeletal 17. Brock G, McMahon CG, Chen KK, et al: Efficacy and muscle PDE inhibition. Only 3 of 175 tadalafil patients discon- safety of tadalafil in the treatment of erectile dysfunction: re- tinued the trial prematurely because of adverse events. Thus, sults of integrated analyses. J Urol 168: 1332–1336, 2002.
the data support the authors' statement that tadalafil is effec- 18. Rosen RC, Padma-Nathan H, Shabsigh R: Cialis tive and well tolerated.
(IC351) provides prompt response and extended period of What distinguishes tadalafil pharmacologically is its long responsiveness for the treatment of men with erectile dysfunc- duration of action, relative selectivity for PDE5, and bioavail- tion (ED). Program and abstracts of the 96th Annual Meeting ability independent of food intake. The drug has a half-life of of the American Urological Association, June 2–7, 2001, Ana- 17.5 hours compared with 4 hours for sildenafil, earning heim, California.
tadalafil the nickname "weekender." Clearly, tadalafil could be 19. Walker DK, Ackland MJ, James GC, et al: Pharmacoki- taken on Friday and continue to enhance erectile function for netics and metabolism of sildenafil in mouse, rat, rabbit, dog, at least the next several days without redosing. This conve- and man. Xenobiotica 29: 297–310, 1999.
nience must be weighed against the possibility of a lingering 20. Rosen RC, Riley A, Wagner G, et al: The International undesirable effect in some men. In Europe, where the drug Index of Erectile Function (IIEF): a multidimensional scale was approved in November 2002, the package leaflet carries a for assessment of erectile dysfunction. Urology 49: 822–830,
stern warning ("Do not take Cialis") not only for men using organic nitrates and nitric oxide donors, but also men with 21. Cappelleri JC, Rosen RC, Smith MD, et al: Diagnostic serious heart disease, recent stroke or myocardial infarction, evaluation of the Erectile Function domain of the Interna- and uncontrolled blood pressure (high or low). The Viagra tional Index of Erectile Function. Urology 54: 346 –351, 1999.
warning is similar.
22. Caverject威 (alprostadil injection) prescribing informa- Just how tadalafil will fit into our therapeutic armamentar- tion. Kalamazoo, Michigan, Pharmacia & Upjohn, 1999.
ium vis-a -vis other PDE5 inhibitors (and future remedies un- 23. MUSE威 (alprostadil urethral suppository) patient in- known) will not become clear until the widespread use ex- formation. Mountain View, California, Vivus, 1998.
pected after Food and Drug Administration approval. What is 24. Viagra威 (sildenafil citrate) prescribing information.
clear, however, is that the pre-Brindley world of ED—a world New York, New York, Pfizer, 2000.
largely consisting of testosterone injections, psychotherapy, UROLOGY 62 (1), 2003

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