A Three-Part Study to Investigate the Incidence and Potential Etiologies of Tadalafil-Associated Back Pain Or Myalgia

A three-part study to investigate the incidence and potential etiologies of tadalafil-associated back pain or myalgia

AD Seftel1*, J Farber2, J Fletcher3, MC Deeley4, A Elion-Mboussa5, A Hoover5,AYu4 and P Fredlund6

1Case Western Reserve University, University Hospitals of Cleveland, Cleveland, Ohio, USA; 2University Hospitals of Cleveland, Case Western Reserve University School of Medicine, Cleveland, Ohio, USA; 3Division of Nuclear Medicine, Department of Radiology, Indiana University School of Medicine, Indianapolis, Indiana, USA; 4ICOS Corporation, Bothell, Washington, USA; 5Lilly Research Laboratories, Indianapolis, Indiana, USA; and 6University of Washington School of Medicine, Seattle, Washington, USA

The potential mechanisms underlying back pain and/or myalgia experienced by men taking tadalafil were investigated. An integrated analysis of 10 placebo-controlled tadalafil clinical trials (N ¼ 1846) showed that the incidence of back pain and/or myalgia was 9.4% in patients receiving tadalafil 10 mg (N ¼ 394), 8.3% in patients receiving tadalafil 20 mg (N ¼ 883) and 3.7% in placebo- treated patients (N ¼ 569). One (0.3%) patient receiving tadalafil 10 mg, six (0.7%) patients receiving tadalafil 20 mg, and no patients receiving placebo discontinued treatment due to back pain and/or myalgia. In a prospective study in healthy volunteers, no substantial changes were observed in laboratory markers indicative of inflammation or muscle damage, and tadalafil did not affect renal plasma flow nor produce lumbar or gluteal myositis by positron emission tomography scan or magnetic resonance imaging. Although the mechanism of back pain and/or myalgia remains unknown, these events appear to be self-limiting and a general effect of phosphodiesterase 5 inhibition. International Journal of Impotence Research (2005) 17, 455–461. doi:10.1038/sj.ijir.3901374; published online 21 July 2005

Keywords: impotence; phosphodiesterase inhibitors; back pain; myositis

Introduction In tadalafil clinical pharmacology trials, back pain or myalgia generally occurred 12–24 h after dosing and typically resolved within 48 h. The back pain Oral phosphodiesterase 5 (PDE5) inhibitors are now and myalgia associated with tadalafil treatment was standard therapeutic options for the treatment of characterized by diffuse bilateral lower lumbar, erectile dysfunction (ED). All three currently mar- gluteal, thigh, or thoracolumbar muscular discom- keted PDE5 inhibitors sildenafil citrate (sildenafil), fort, and was exacerbated by recumbency. In general, tadalafil, and vardenafil hydrochloride (vardenafil), pain was reported as mild or moderate in severity, 1–7 are effective and generally well tolerated. The and resolved with acetaminophen or nonsteroidal most common side effects of this class of medica- anti-inflammatory drugs when necessary. Severe tions include headache, flushing, dyspepsia, and back pain was reported infrequently (o5% of all rhinorrhea, the majority of which may be related to reports). Overall, approximately 0.4% of all tadala- the mild vasodilatory effects associated with PDE5 fil-treated ED patients discontinued treatment 8,9 inhibition. Back pain or myalgia have also been as a consequence of back pain or myalgia, within reported to varying degrees with each of the three the same range as discontinuations for headache 4,10–12 marketed PDE5 inhibitors. (0.8%).4 The origins of lumbar pain in general may be complex, myriad, and include structural, degenera- tive, and inflammatory processes of the spine, as *Correspondence: AD Seftel, Department of Urology, Case well as pain referred from the abdomen, pelvis, and Western Reserve University, University Hospitals of 13,14 Cleveland, Cleveland VA Medical Center, 11100 Euclid urinary tract. HMG-CoA reductase inhibitors Ave., Cleveland, OH 44106-5046, USA. have been reported to induce clinically important E-mail: [email protected] myositis or rhabdomyolysis, which may present Received 7 April 2005; accepted 20 May 2005 with back pain or myalgia.15 Tadalafil and back pain and/or myalgia AD Seftel et al 456 To investigate the nature of back pain associated severe event was counted. Patient discontinuation with tadalafil use, we first conducted a retrospective rates due to back pain and/or myalgia were analysis of the combined incidence of eight adverse summarized descriptively. event terms coded in the databases from 10 placebo- controlled studies of tadalafil for ED and possibly associated with back pain and/or myalgia. In the Part 2: PET, MRI, and radionuclide testing second part of the investigation, we prospectively conducted a clinical pharmacology study in healthy Healthy males, 18–45 y of age, were enrolled into volunteers using three radiologic examinations 18 a double-blind, two-period crossover study compar- ([ F]-fluorodeoxyglucose positron emission tomo- ing a single dose of either placebo and tadalafil graphy scan ([18F]-FDG-PET),16 gadolinium-en- 17 20 mg or placebo and tadalafil 80 mg. The periods hanced magnetic resonance imaging (MRI) scans, were separated by a 10-day washout period. Sub- and technetium mertiatide (Tc99m) scanning) to jects were resident in a Clinical Pharmacology Unit investigate whether there is a pathological process the night before dosing and through 24–30 h post- or venocongestion localized in the lumbar and dose. At 22–30 h after dosing in each period, gluteal muscles, or an underlying abnormality in radionuclide renal scan, bilateral gadolinium- renal plasma flow. In the final part, we conducted a enhanced MRI scans of the lumbar and gluteal prospective laboratory investigation to examine the muscles, and [18F]-FDG-PET scans were per- possible involvement of inflammatory or myolytic formed.20,21 The timing of these assessments corre- processes in the reports of back pain and/or myalgia. sponded to the time of peak incidence of reported The results of this investigation indicated that back pain and/or myalgia following tadalafil dosing back pain or myalgia induced by tadalafil occurs in subjects enrolled in clinical pharmacology stu- with a combined incidence of approximately 9% in dies (12–24 h post dose).10 Effective renal plasma patients with ED, and are not associated with a flow in each kidney (ml/min/1.73 m2) was assessed serious underlying pathology. by determining Tc99m clearance.22 Subjects re- turned approximately 48 h post-dose for clinical laboratory evaluations and physical examination. Patients and methods The outcome measures for the MRI scan were qualitative comparisons for the presence of fasciitis, vasculitis, myositis, abscess and lumbar and gluteal Part 1: Integrated data analysis muscle venocongestion after dosing, relative to the predose assessment. The outcome measure for FDG PET was the standardized uptake value (SUV) of We retrospectively analyzed a large database of radiolabeled glucose. The outcome measure for the patients with ED who had enrolled in one of 10 99mTc mertiatide study was effective renal plasma multicenter, randomized, placebo-controlled, dou- flow. All assessments were made by two treatment- ble-blind, efficacy, and safety studies conducted blinded qualified radiologists or nuclear medicine between November 1999 and September 2002. Nine physicians. of the 10 studies were included in the integrated All subjects who completed at least one study analysis of 11 tadalafil studies previously re- period were included in the analysis. An analysis of ported.18 The remaining study reported here en- 19 covariance (ANCOVA) model that included terms rolled men with diabetes mellitus and ED. for baseline, subject, period, and treatment was used Inclusion and exclusion criteria, study design, and to calculate the least-squares means and residual patient demographics have been described pre- variance to compute 95% confidence intervals for 18,19 Z Z viously. Briefly, men 18 y old with a 3- the post-baseline effective renal plasma flow and month history of ED were randomized to 12 weeks PET scan SUV. Categorical changes from baseline in of treatment with placebo or tadalafil taken as MRI scan data were made (worse, better, or same). needed up to once per day. Symptoms reported by Values of the same or better were pooled together patients during the clinical trials were recorded and McNemar’s test performed to test for treatment verbatim, then classified using the Medical Diction- differences. For blood flow data, values of À1 ary for Regulatory Activities (MedDRA) terminology. (decrease) and 0 (no change) were pooled together, Eight terms including back pain, myalgia, back and the McNemar’s test performed to test for stiffness, buttock pain, coccydynia, loin pain, pain treatment differences. NOS (not otherwise specified), and sacral pain were collectively referred to as ‘back pain and/or myalgia.’ New or worsened reports of back pain and/or Part 3: Tests for inflammatory conditions myalgia reports during the study period were summarized for all randomized patients treated with placebo or tadalafil 10 or 20 mg. When a All subjects enrolled in one of five double-blind, patient reported more than one event, only the most placebo-controlled, crossover-design, clinical phar-

International Journal of Impotence Research Tadalafil and back pain and/or myalgia AD Seftel et al 457 Table 1 Laboratory tests measured tadalafil 20 mg group. Overall, 25.4% of patients were 65 y or older. The patients in these studies Hematology Serum chemistry were Caucasian (76.9%), East or Southeast Asian Erythrocyte count (RBC) Aldolase Erythrocyte sedimentation Alanine aminotransferase (ALT) (15.8%), African American (3.2%), Hispanic (3.1%), rate (ESR) Amyloid or other (0.9%). Patients’ ED had an organic (62.7%), Leukocytes (WBC) Aspartate aminotransferase (AST) psychogenic (10.5%), or mixed (organic/psycho- C-reactive protein (CRP) genic (26.8%)) etiology. Major comorbidities in- Urinalysis Calcium Blood Creatine phosphokinase (CPK) cluded histories of hypertension (30.6%), diabetes Glucose Creatinine mellitus (27.7%), or hyperlipidemia (17.8%). Ketones Lactate dehydrogenase (LDH) The incidence of back pain and/or myalgia was Microscopy (if protein Potassium 3.7% in placebo-treated patients, 9.4% in patients and/or blood detected) Sodium receiving tadalafil 10 mg, and 8.3% in patients Protein Specific gravity receiving tadalafil 20 mg. Patients who discontinued treatment due to back pain and/or myalgia included one (0.3%) receiving tadalafil 10 mg, six (0.7%) receiving tadalafil 20 mg, and none receiving placebo. macology studies conducted between August and December 2002 were categorized as to whether they Part 2: PET, MRI, and radionuclide testing experienced a back pain and/or myalgia event with an onset of 0–48, 448 h after dosing, or not at all. These studies enrolled healthy 18–65 y-old men, [18F]-FDG-PET was used to identify an inflammatory men with diabetes, or men with controlled hyper- process in the region, as increased uptake of glucose tension. Subjects received either a single dose of is associated with an inflammatory process.16 placebo or tadalafil 20, 40, or 80 mg, or placebo or Gadolinium-enhanced MRI scans were used to tadalafil 20 mg daily for 6 days. All study subjects detect evidence of localized inflammation (eg, underwent laboratory evaluations (Table 1) at base- fasciitis, vasculitis, myositis, and abscess) and line and 24–48 h after placebo or tadalafil adminis- lumbar and gluteal venocongestion.17 Finally, renal tration. Prior to receiving the study treatment, plasma flow was assessed using a radionuclide scan subjects were instructed to report any back pain following intravenous injection of Tc99m to primar- and/or myalgia or muscle aches to the investigator. ily test the hypothesis that tadalafil induced renal Subjects who developed back pain and/or myalgia artery vasodilatation, possibly leading to distension during treatment were evaluated clinically and had of the renal capsule and pain. directed physical examinations. If the back pain A total of 20 subjects were enrolled into this and/or myalgia occurred during the follow-up radiographic investigation, 10 each in the tadalafil period (448 h post dose), subjects were required to 20 mg (Group 1) and 80 mg (Group 2) dose levels. In return to the study site within 48 h of symptom all, 17 subjects completed both treatment periods. onset for examinations and evaluations as above, One subject from Group 1 discontinued before including laboratory tests (Table 1). randomization, one subject from Group 2 did not Analysis of the overall treatment effect on the return for the post-dose imaging studies after change of laboratory values from entry at each time receiving placebo during the first treatment period, point was performed using a ranked analysis of and one subject from Group 2 received placebo variance (ranked ANOVA) model that included the during the first treatment period but did not return treatment group, adjusted for pooled site. for the second treatment period. The mean ages (7s.d.) were 2979.7 (N ¼ 9) in Group 1 and 2677.1 (N ¼ 8) in Group 2. No subject discontinued due to Results an adverse event. Back pain and/or myalgia was reported by three subjects following tadalafil 20 mg administration, three subjects following tadalafil Part 1: Integrated data analysis 80 mg administration and two subjects following placebo administration. There were no clinically meaningful or significant The clinical study database comprised 1846 patients differences between the mean effective renal plasma with ED, of whom 569 received placebo, 394 flow rates following tadalafil administration when received tadalafil 10 mg, and 883 received tadalafil compared with placebo (Table 2). None of the 20 mg. The placebo and tadalafil groups were well subjects had a change in tissue inflammation balanced for demographic and baseline disease (fasciitis, vasculitis, myositis, or abscess) or blood characteristics. The mean age (7s.d.) of patients flow in the lower lumbar or gluteal muscles as was 57.4710.3 in the placebo group, 57.8710.1 in assessed by MRI at 24 h postdose compared to the tadalafil 10 mg group, and 57.0710.5 in the predose following any treatment (data not shown).

International Journal of Impotence Research Tadalafil and back pain and/or myalgia AD Seftel et al 458 Table 2 Mean effective renal plasma flow selected laboratory evaluation, mean values ob- tained at baseline and during pain (onset 0–48 or Effective renal plasma flow Placebo Tadalafil Difference a 2 b 448 h after dosing) were comparable (Figure 1). mean (ml/min/1.73 m ) (95% CI) Mean changes from baseline between treatment groups for three of the five tests were not signifi- Tadalafil 20 mg treatment group (N ¼ 9) Right kidney 271 279 8.5 (À8.2–25.2) cantly different (all p40.05). Leukocyte counts were Left kidney 281 297 16.3 (À5.8–38.3) lower 0–48 h post treatment in the tadalafil group experiencing back pain and/or myalgia compared Tadalafil 80 mg treatment group (N ¼ 8) with placebo (p ¼ 0.028), and the mean ESR in the Right kidney 263 261 À2.4 (À19.4–14.7) Left kidney 276 285 9.4 (À12.9–31.6) tadalafil-treated subjects 0–48 h post-treatment was greater than that for placebo (p ¼ 0.04). The magni- a Baseline-adjusted least-squares means. tudes of the differences between treatment groups b CI, confidence interval for the difference between tadalafil and for both parameters were small and not clinically placebo; there were no significant differences between placebo meaningful. No tadalafil-treated subjects experien- and tadalafil. cing back pain and/or myalgia exhibited a CRP level (Z5 mg/dl) or ESR value suggestive of an inflammatory response (Z100 mm/h).23,25 No tadalafil-treated No subject exhibited a change in distribution of subject had a post-dose absolute eosinophil count renal perfusion and/or function that could be Z1000 cells/ml, a level associated with eosinophi- ascertained by visual inspection of the flow images lia–myalgia syndrome.26 No tadalafil-treated subject during the initial phase of radiopharmaceutical had a CPK or aldolase level in an abnormal range distribution or during the renogram (renal uptake, that may be indicative of myopathy or rhabdomyo- excretion and clearance) component of the study. lysis.15,27 There were no significant differences in [18F]-FDG Laboratory parameters were also compared be- SUV for the right and left lumbar and gluteal tween all placebo-treatment periods and tadalafil- muscles between tadalafil 20 mg and 80 mg and treatment periods, regardless of back pain and/or corresponding placebo treatments (Table 3). There myalgia symptoms (N ¼ 541). This analysis did not were no subjects with an abnormal focal or diffuse indicate any clinically relevant differences between localization of the FDG radiopharmaceutical agent. tadalafil and placebo for any parameter (data not shown). When a similar analysis was performed comparing tadalafil-treated subjects with back pain Part 3: Tests for inflammatory conditions and/or myalgia to those that did not have these symptoms (N ¼ 268), no clinically relevant difference was found for any laboratory parameter (data A total of 283 subjects entered the five clinical not shown). pharmacology crossover studies. Of these, 273 subjects were exposed to placebo, and 195 subjects were exposed to 20 mg tadalafil, 60 to tadalafil 40 mg Comment and eight to tadalafil 80 mg. Back pain and/or myalgia were reported by 26 and 146 subjects during placebo and tadalafil treatments, respec- Part 1 of this article was a retrospective, integrated tively. Of the total back pain and/or myalgia adverse analysis of the tadalafil clinical trial database of events reported by tadalafil-treated subjects, 95.6% 10 placebo-controlled efficacy and safety studies of were mild or moderate in severity, with two (1.5%) tadalafil. This analysis showed that 8.3–9.4% of ED leading to discontinuation from the study. Each patients treated with tadalafil developed back pain subject experiencing back pain and/or myalgia and/or myalgia compared with 3.7% in placebo- was evaluated clinically, and their laboratory test re- treated patients, with o1% of patients discontinu- sults were reviewed by the investigator. No subject ing from studies because of these adverse events. was deemed medically to have developed muscle In part 2, radiologic studies with gadolinium- damage or an inflammatory process accounting for enhanced MRI and [18F]-FDG-PET in healthy volun- the symptoms. teers showed that tadalafil treatment was not Laboratory data were collected for 273 (96.5%) associated with changes indicative of an underlying during placebo treatment and 268 (94.7%) during inflammatory condition or muscle injury. The MRI tadalafil treatment. All of the laboratory parameters scans also failed to show evidence for venoconges- listed in Table 1 were analyzed. Five representative tion in the lumbar or gluteal muscles following laboratory parameters potentially indicative of an tadalafil treatment. These radiographic techniques inflammatory process or muscle damage are pre- may not be sufficiently sensitive to detect subtle sented: creatine phosphokinase (CPK), C-reactive changes in pooling of venous blood in the large protein (CRP), leukocyte counts, erythrocyte sedi- muscle groups of the lower back and gluteal region, mentation rate (ESR), and aldolase.23,24 For each however. Renal radionuclide scans showed that

International Journal of Impotence Research Tadalafil and back pain and/or myalgia AD Seftel et al 459 ab500 500 5 5

400 400 4 4

300 300 3 3

2 CPK (U/l) 200 200 2 CRP mg/dl

100 100 1 1

0 0 0 0 Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil BaselinePain at 48 hrs Pain at >48 hrs BaselinePain at 48 hrs Pain at >48 hrs

cd20 20 60 60

15 15 45 45 /l) 9

10 10 30 30 ESR (mm/hr)

Leukocytes (x10 5 5 15 15

0 0 0 0 Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil BaselinePain at 48 hrs Pain at >48 hrs BaselinePain at 48 hrs Pain at >48 hrs

e 15 15

10 10

Aldolase (U/l) 5 5

0 0 Placebo Tadalafil Placebo Tadalafil Placebo Tadalafil BaselinePain at 48 hrs Pain at >48 hrs Figure 1 Clinical laboratory parameters. Baseline and post-baseline measurements for subjects who developed back pain and/or myalgia during placebo (n ¼ 26) or tadalafil (n ¼ 146) treatment. (a) CPK, upper limit 198 U/l. (b) CRP, upper limit 0.287 mg/dl. (c) Leukocytes, normal range 3.8–10.7 Â 109/l. (d) ESR, upper limit 16 mm/h. (e) Aldolase, normal range 1.2–7.6 U/l. Key: B, mean; —, median; and K, the maximum value for all subjects, if above bars; box, the 25–75% range; bars, the maximum subject value within 1.5 Â of the interquartile range; mg/dl, milligrams per deciliter; mm/h, millimeters per hour; U/l, units per liter. effective renal plasma flow was unaffected by develop back pain and/or myalgia consistent with tadalafil treatment. No anatomic or functional the pattern of back pain and/or myalgia seen in other abnormality was noted on renal scan. In order to tadalafil clinical pharmacology studies. Thus, the increase the opportunity to observe tadalafil-related lack of radiologic findings supports the conclusion effects in the radiologic study, tadalafil was admi- that gross renal or muscular damage did not under- nistered at the 80-mg dose, four times the maximum lie the back pain and/or myalgia. marketed dose. No diagnostic changes were seen In Part 3, a prospective study of 268 tadalafil- even though participants in the radiologic study did treated subjects during clinical pharmacology

International Journal of Impotence Research Tadalafil and back pain and/or myalgia AD Seftel et al 460 Table 3 [18F]-FDG-PET mean SUV to tadalafil, the mechanism is likely to be associated with PDE5 inhibition and unlikely to be related to a b SUV, LS mean Placebo Tadalafil Difference (95% CI ) tadalafil’s modest inhibition of PDE11A. Tadalafil is 40-fold less inhibitory of PDE11A compared with Tadalafil 20 mg treatment group (N ¼ 9) PDE5 in vitro.33 Right lumbar 0.69 0.65 À0.040 (À0.136–0.056) Left lumbar 0.66 0.67 0.017 (À0.088–0.122) These studies explored the potential serious Right gluteal 0.63 0.57 À0.066 (À0.160–0.028) causes for back pain and/or myalgia, including Left gluteal 0.65 0.58 À0.075 (À0.188–0.039) muscular trauma/damage, abscess, inflammatory processes, myositis, vasculitis, fasciitis, rhabdomyo- Tadalafil 80 mg treatment group (N ¼ 8) 13–15 Right lumbar 0.71 0.68 À0.033 (À0.133–0.067) lysis, venocongestion, or kidney pathology. Left lumbar 0.70 0.69 À0.011 (À0.119–0.097) None of these serious mechanisms were supported Right gluteal 0.58 0.62 0.033 (À0.064–0.129) by these results. Thus, the mechanism underlying Left gluteal 0.60 0.58 À0.017 (À0.131–0.097) this phenomenon remains unknown, but the symptoms are self-limited and we found no evidence of a Baseline-adjusted least-squares means. injury to the muscles or kidneys. b CI, confidence interval for the difference between tadalafil and placebo; there were no significant differences between placebo and tadalafil. Conclusion

Back pain and/or myalgia events in tadalafil-treated studies showed that back pain and/or myalgia were subjects appear indistinguishable from idiopathic not associated with laboratory evidence of inflam- back pain and/or myalgia associated with placebo mation, vasculitis, renal injury, or muscle injury. treatment using the measurements and laboratory Specifically, normal BUN, serum creatine, serum tests employed in this study. Although the patho- potassium concentrations, and urinalyses argue physiological mechanisms leading to back pain and/ against major renal parenchymal damage. Normal or myalgia in association with tadalafil treatment serum LDH, SGOT, and SGPT argue against infarc- remain unknown, these findings identify no serious tion of kidney, liver, or muscle. Serum CPK and underlying medical pathology. As these events are aldolase measurements indicate the absence of also associated with sildenafil and vardenafil, back rhabdomyolysis. Finally, normal ESR, white blood pain and/or myalgia may be a class effect of PDE5 cell counts, and serum CRP concentration indicate inhibition. the absence of vasculitis. It is notable that the incidence of back pain and/or myalgia was higher in clinical pharmacology studies than in the much longer, ambulatory ED patient Acknowledgements clinical studies. There may be several reasons for the higher incidence reported in clinical pharmacology studies. (1) Subjects were housed in a Clinical Unit Funding for this and the parent studies was and restricted in their physical activities per proto- provided by Lilly ICOS LLC. We wish to thank col. Sitting and lying in the recumbent position may Chris Fischer of ICOS Corporation for his assistance predispose to the development of back pain and/or in the preparation of the manuscript. myalgia.10 (2) Subjects participating in clinical pharmacology studies were typically younger than patients with ED, and it is possible that the younger References age may be a risk factor for PDE5 inhibitor- associated back pain and/or myalgia. (3) Higher doses of tadalafil were administered than the 1 Sadovsky R, Miller T, Moskowitz M, Hackett G. Three-year update of sildenafil citrate (Viagras) efficacy and safety. Int J maximum marketed dose of 20 mg. (4) As subjects Clin Pract 2001; 55: 115–128. were frequently asked about the occurrence of 2 Cheitlin MD et al. Use of sildenafil (Viagras) in patients with adverse events during their stay in the Clinical cardiovascular disease. ACC/AHA Expert Consensus Docu- Unit, and specifically about back pain and/or ment. J Am Coll Cardiol 1999; 33: 273–282. myalgia, there may have been a reporting bias in 3 Hellstrom WJG et al. Vardenafil for treatment of men with erectile dysfunction: efficacy and safety in a randomized, the clinical pharmacologic studies. double-blind, placebo-controlled trial. J Androl 2002; 23: Back pain and myalgia have been reported with 763–771. other PDE5 inhibitors.11,26,28–32 For example, myal- 4 Montorsi F et al. Long-term safety and tolerability of tadalafil gia was reported in 7.4% of patients administered in the treatment of erectile dysfunction. Eur Urol 2004; 45: 339–345. sildenafil 50 mg twice daily, and in 10% of patients 5 Basu A, Ryder REJ. New treatment options for erectile administered sildenafil 50 mg thrice daily. Since dysfunction in patients with diabetes mellitus. Drugs 2004; back pain and myalgia adverse events are not unique 64: 2667–2688.

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International Journal of Impotence Research