International Journal of Impotence Research (2005) 17, 455–461 & 2005 Nature Publishing Group All rights reserved 0955-9930/05 $30.00 www.nature.com/ijir 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 myal- gia.’ 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