Ocular Safety in Patients Using Sildenafil Citrate Therapy for Erectile Dysfunction

Blackwell Science, LtdOxford, UKJSMJournal of Sexual Medicine1743-6095Journal of Sexual Medicine 20052006311227Review ArticleSildenafil Ocular SafetyLaties and Sharlip

12

Ocular Safety in Patients Using Sildenafil Citrate Therapy for Erectile Dysfunction Alan Laties, MD,* and Ira Sharlip, MD† *Scheie Eye Institute, University of Pennsylvania Medical School, Philadelphia, PA, USA; †University of California San Francisco, San Francisco, CA, USA DOI: 10.1111/j.1743-6109.2005.00194.x

ABSTRACT

Sildenafil citrate improves erectile function in men with erectile dysfunction (ED) by selectively inhibiting cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), which is present in all vascular tissue. Sildenafil also has a weaker inhibitory action on PDE6, located in the rod and cone photoreceptors. Modest, transient visual symptoms, typically blue tinge to vision, increased brightness of lights, and blurry vision, have been reported with sildenafil use and occur more frequently at higher doses. Visual function studies in healthy subjects and in patients with eye disease suggest that sildenafil does not affect visual acuity, visual fields, and contrast sensitivity. Transient, mild impairment of color discrimination can occur around the time of peak plasma levels. Spontaneous postmarketing reports of visual adverse events, including nonarteritic anterior ischemic optic neuropathy (NAION), have been reported during the 7 years that sildenafil has been prescribed to more than 27 million men worldwide. However, because men with ED frequently have vascular risk factors that may also put them at increased risk for NAION, a causal relationship is difficult to establish. No consistent pattern has emerged to suggest any long-term effect of sildenafil on the retina or other structures of the eye or on the ocular circulation. Laties A, and Sharlip I. Ocular safety in patients using sildenafil citrate therapy for erectile dysfunction. J Sex Med 2006;3:12–27. Key Words. Sildenafil; Ocular Safety; Erectile Dysfunction

Introduction

S

ildenafil citrate is a potent and selective inhibitor of cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase type 5 (PDE5), an enzyme expressed throughout the smooth muscle of the vasculature, including the arteries and arterioles supplying the erectile tissue of the penis [1,2]. By inhibiting PDE5, sildenafil enhances the nitric oxide–cGMP pathway that mediates smooth muscle relaxation, and in so doing, improves penile blood flow and erectile function [3,4]. Clinical trial experience includes more than 13,000 patient-years of exposure in over 100 manufacturer-sponsored trials, as well as numerous independently conducted studies. Together, these have established sildenafil as an effective treatment for erectile dysfunction (ED). In the 7 years since it was approved, more than 27 milJ Sex Med 2006;3:12–27

lion men worldwide have been prescribed sildenafil. Adverse events have generally been similar to those observed in sildenafil clinical trials. The most common adverse events reported by patients using sildenafil have been predominantly transient and mild to moderate in severity, and have included headache, facial flushing, rhinitis, dyspepsia, and abnormal vision. These effects likely result from sildenafil inhibition of PDE5 in the smooth muscle of the systemic vasculature and the digestive tract and sildenafil inhibition of cGMP-specific PDE6 in the retina [1,5]. Sildenafil has a 10-fold lower affinity for PDE6 compared with PDE5 [4]. PDE6 is present in high concentrations in the rod and cone cells of the retina and is required for the phototransduction process. Occurrences of abnormal vision, which are likely mediated by cross-inhibition of PDE6, are the most common ocular adverse events reported with sildenafil use and are variously described as mild, © 2006 International Society for Sexual Medicine

Sildenafil Ocular Safety transient color tinge to vision; increased sensitivity to light; or blurry vision [6]. The potential effects of sildenafil-induced vasodilation on the ocular circulation and sildenafil inhibition of PDE6 on the visual function have been intensively studied during preclinical development and in clinical trials conducted before and after sildenafil was approved for marketing. A few sporadic postmarketing accounts of more serious visual effects, including decreased vision resulting from nonarteritic anterior ischemic optic neuropathy (NAION), have been reported in patients prescribed sildenafil. Similarly, case reports of NAION in patients prescribed the more recently approved PDE5 inhibitor, tadalafil, have been published [7–9]. This article reviews the reported effects of sildenafil on visual function and ocular blood flow from clinical trials and postmarketing reports and will further explore the potential association between PDE5 inhibitor use and NAION, particularly with regard to shared risk factors, such as cardiovascular disease and diabetes, which may predispose patients to both ED and NAION. To provide as complete a description as possible, we limited inclusion of NAION cases associated with PDE5 inhibitor use to those reported as published case reports.

Effects of Sildenafil on Visual Function

Preclinical Studies Preclinical studies conducted in rats and dogs concluded that continuous high-dose sildenafil (up to 60–150 times the maximum human mg/kg dose) has a pharmacologic effect on phototransduction but does not result in any changes in the structure of the retina following long-term exposure (up to 24 months) [10,11]. Electroretinographic (ERG) recordings, which evaluate the electrical function of the eye by recording the electrical changes in the retina after stimulation by light, were used to assess rod and cone function. Threshold changes in rod and cone function in dogs were observed at a free sildenafil plasma concentration of 51 ng/mL (76.5 nM), corresponding to that produced by a 400 mg dose of sildenafil in humans, but were not observed at a sildenafil-free plasma concentration (16 ng/mL, 24 nM), consistent with mean maximum free plasma concentrations produced by sildenafil therapeutic doses in humans (3.5– 13.5 ng/mL) [12]. ERG effects were transient and fully reversible [13].

13

Clinical Studies In two double-blind, placebo-controlled, crossover trials in healthy male subjects aged 40– 65 years with no baseline visual impairment (N = 16, N = 8), mild, transient, fully reversible impairment of color discrimination (FarnsworthMunsell 100-hue test) in the green-blue to bluepurple range was observed with single doses of 100 and 200 mg sildenafil but not with 50 mg sildenafil (Table 1) [14,15]. Significant (P < 0.01) measurable effects were observed at 1 (100 and 200 mg) and 2 hours (200 mg) postdose and resolved within 5 hours [15]. The relationship between plasma sildenafil concentration and impaired color discrimination (Farnsworth-Munsell 100-hue mean total error scores) was found to be linear by regression analysis [15], with subjects with higher sildenafil plasma concentrations generally experiencing greater difficulty in color discrimination. However, even at 200 mg, twice the recommended therapeutic dose, sildenafil caused no changes from baseline in contrast sensitivity, visual acuity, pupillometry, central vision, photostress tests, intraocular pressure, or ERG recordings [14,15]. In postmarketing reports, alterations in ERG recordings following sildenafil administration have been minor and somewhat inconsistent. Modest, transient depressions of rod (scotopic) but not cone (photopic) responses were reported by Vobig et al. [16] in healthy subjects and by Kretschmann et al. [17] in men with ED following 100 mg sildenafil, whereas Luu et al. [18] observed slight depressions in cone function following a single 200 mg sildenafil dose in 18 healthy subjects. In a double-blind, placebo-controlled study in 20 healthy men, Jägle et al. [19] reported that 100 mg sildenafil (vs. placebo) had little effect on most visual test findings but did produce prolongations in ERG photopic and scotopic implicit times and increased sensitivity during light adaptation as assessed by the transient tritanopia test (a measure of inner retinal processing of cone signals); these acute effects were fully reversible within 24 hours. Although transient ERG changes such as these have been reported with sildenafil, there have been no reports of long-term effects on visual function either in high-dose animal studies (both short- and long-term studies), during sildenafil clinical trials, or from postmarketing registries [20]. Collectively, these data indicate that there is no evidence that repeated intermittent use of sildenafil produces any structural damage or clinically significant functional changes to the retina. To put these J Sex Med 2006;3:12–27

J Sex Med 2006;3:12–27

OL, 3 months, 50 or 100 mg twice weekly

Dundar et al. 2005 [25]

OL, 100 mg

Case series, 100 mg

OL, 200 mg

PC, 100 mg

PC, 200 mg

OL, 50 and 100 mg

OL, 50 or 100 mg

PC, 100 mg

Vobig et al. 1999 [16]

Kretschmann et al. 1999 [17]

Luu et al. 2001 [18]

Jägle et al. 2004 [19]

McCulley et al. 2000 [22]

Ermis et al. 2004 [23]

Öner et al. 2004 [24]

Birch et al. 2002 [44]

31

47

9

18

28

8

20

18

6

5

16

8

14

123

4,274

N

Macular degeneration

Men with ED

Healthy men

Healthy volunteers

Healthy volunteers

Healthy volunteers

Men with ED

Healthy volunteers

Healthy volunteers

Healthy volunteers

Men with ED

66 patients with pre-existing eye disorders Men postprostatectomy

Men with ED

Men with ED

Population

Visual acuity, Amsler grid, color perception, visual field, photostress test

Humphrey visual field (W/W and B/Y)

Humphrey visual field (W/W and B/Y), IOP

Humphrey visual field (W/W and B/Y)

ERG

Color discrimination, ERG

Visual acuity, visual field, color, IOP, ERG Visual acuity, perimetry, color test, full-field ERG

Visual field, visual acuity, photostress, IOP, ERG Color discrimination (FM 100-hue)

Visual acuity, color vision, Humphrey perimetry

Visual AEs

Visual acuity, contrast sensitivity, photostress test, slit lamp, and FM 100-hue Visual acuity, FM 100-hue, contrast sensitivity, photostress test, and slit lamp examination Visual AEs

Assessments

Single supratherapeutic dose of sildenafil produced no clinically significant effects Statistically significant change in FM 100-hue scores 1–2 hours after 100 or 200 mg; reversible and coincided with peak plasma concentrations ERG wave reductions that resolved within 6 hours; no other significant effects Slight changes in stereoscopic vision and in color test errors; ERG implicit times increased; no other changes reported Statistically significant increase in color vision errors compared with no drug; small changes in cone function and ERG parameters were within normal limits Statistically significant increase in implicit time at 100 mg; significant effect on implicit time and wave amplitude at 200 mg; ERG normal within 24 hours Most (80%) subjects had no detectable changes in Humphrey visual field (W/W and B/Y) after 200 mg sildenafil No significant effect of sildenafil on visual field or IOP at 1 hour postdose No significant changes in visual field at 2 hours after sildenafil No acute changes in any visual function test; no visual AEs

No clinically significant changes in examination or FM 100-hue test at 12 or 52 weeks compared with baseline measurements No clinically significant changes after 2 years of sildenafil; no discontinuations due to visual AEs 7/39 sildenafil-treated patients had visual AEs and only 1 discontinued due to visual AE. 2/27 placebo-treated patients had visual AEs An average of 2 mild visual AEs were reported by 4 patients receiving 100 mg and 2 patients receiving 50 mg sildenafil No significant changes from baseline in visual acuity, color vision, or Humphrey perimetry (W/W and B/Y), and no abnormalities noted on anterior segment and fundus examinations

Results

AEs = adverse events; B/Y = blue on yellow; ED = erectile dysfunction; ERG = electroretinogram; FM = Farnsworth-Munsell; IOP = intraocular pressure; OL = open-label; PC = placebo-controlled; W/W = white on white.

PC, 50–200 mg

Laties et al. 1999 [15]

Acute studies Laties et al. 1998 [14]

PC, 200 mg

Subanalysis of 18 phase II/III trials, 25, 50, and 100 mg PC, 36 weeks, 50 and 100 mg

Grunwald et al. 1999 [26]

Laties et al. 2002 [28]

OL, 2 years, 25, 50, and 100 mg

Zrenner et al. 2000 [30]

OL, 40 weeks, 25, 50, and 100 mg

Design + dose

Summary of studies examining the effects of sildenafil on visual function

Long-term studies Laties et al. 1998 [14]

Study

Table 1

14 Laties and Sharlip

15

Sildenafil Ocular Safety results into context, Zrenner stated that the transient minor changes in retinal function after sildenafil as measured by ERG recordings were akin to “the light-absorbing effect of a car windshield” [21]. Several studies have assessed the effects of sildenafil on visual field in healthy subjects [16,22,23] and men with ED [24,25]. An early study of five healthy men found no effects of a single 100 mg dose of sildenafil on visual field [16]. Likewise, no differences in Humphrey visual field testing were observed in a study of 28 healthy male volunteers 1 hour after administration of 50 and 100 mg sildenafil [23]. A transient decrease in Humphrey visual field, both white-on-white and blue-on-yellow score, was noted for one of five healthy subjects receiving 200 mg sildenafil in a single-blind, placebo-controlled study [22]. This subject experienced severe headache, flushing, and abdominal discomfort that may have interfered with testing. In a single-dose (50 or 100 mg) study in 18 men with ED, none of the patients had differences in Humphrey visual field scores at 2 hours after sildenafil dosing compared with before dosing, including three patients who experienced headaches. No changes in visual acuity, color vision, or visual field were observed in 14 patients with ED receiving 50 mg sildenafil twice weekly for 3 months. Occurrence of visual adverse events with sildenafil use was examined in a pooled analysis of 18 placebo-controlled, fixed- and flexible-dose efficacy trials of sildenafil (taken as needed, no more than 1 dose/day) in patients with ED (age range 18–87 years) who took sildenafil (N = 2,722) or placebo (N = 1,552) for up to 6 months [5,6]. One patient from these 18 trials discontinued sildenafil treatment owing to a visual adverse event reported as moderately blurred vision after taking a 10 mg dose [6,26]. In the flexible-dose trials (initial dose 50 mg adjustable to 25 or 100 mg), visual adverse events were reported by 2.7% of sildenafiltreated and 0.4% of placebo-treated patients. An analysis of the fixed-dose trial subset revealed that visual adverse events occurred more frequently at higher sildenafil doses, with 1%, 2%, and 11% of those receiving 25, 50, and 100 mg sildenafil doses, respectively, reporting these adverse events [5]. A larger pooled analysis of 25 double-blind, placebocontrolled trials found a similar occurrence of visual effects, with 5% of sildenafil-treated patients (N = 3,545) and <1% of the placebo-treated patients (N = 2,373) reporting visual adverse

events [20]. Visual adverse events were most frequently described as transient color tinge to vision, increased sensitivity to light, or blurry vision [6]. Blurry vision may follow increased tear production in response to conjunctival injection (ocular redness, bloodshot appearance), a vascular event thought to stem from PDE5 inhibition [27]. The effect of daily sildenafil dosing on occurrence of visual adverse events was examined in a double-blind, placebo-controlled, postprostatectomy study in which men took sildenafil (50 mg, N = 40; or 100 mg, N = 41) or placebo (N = 42) daily for 9 months [28]. Four patients receiving 100 mg sildenafil and two receiving 50 mg sildenafil, each reported an average of two visual events that were described as blue haze, blue vision, or blurred vision. All visual events were mild in severity, and none resulted in discontinuation. In a long-term, open-label sildenafil study (25, 50, and 100 mg for 9 months), 60 of 435 enrolled patients reported 69 visual adverse events [29]. Modest, transient changes in color discrimination, blue tinge to vision, or an altered perception of brightness of light were most common. Nearly all (86%) visual adverse events occurred within 2 hours of sildenafil dosing and the duration of the visual symptoms was less than 4 hours for 80% of patients. Detailed objective visual function tests were conducted for 31 patients receiving open-label sildenafil for up to 2 years [30]. There were no clinically significant changes from baseline in Farnsworth-Munsell 100-hue color test scores or scores for other visual function tests or abnormalities in eye structures. Retesting of color discriminating ability after long-term sildenafil treatment (1 and 2 years) at least 24 hours after the last sildenafil dose showed no changes from baseline, suggesting there was no cumulative change in visual function. Taken together, the results from the range of visual function tests from multiple studies suggest that visual effects observed with sildenafil appear to be dose dependent, occurring more frequently at the 100 mg maximum recommended or supratherapeutic doses. Acute changes in objective measures of rod and/or cone function reported with sildenafil have been transient and generally have not had substantial effect on visual performance. Ocular Circulation

Because sildenafil is known to produce mild systemic vasodilatory effects, potential effects of J Sex Med 2006;3:12–27

J Sex Med 2006;3:12–27

PC, acute, 100 mg

PC, acute, 100 mg

PC, acute, 100 mg

OL, acute, 50 mg

PC, acute, 100 mg

OL, acute, 50 mg

PC, acute, 100 mg

OL, acute, 100 mg + visual sexual stimulation

Grunwald et al. 2001 [33]

Metelitsina et al. 2005 [34]

Grunwald et al. 2002 [35]

Pache et al. 2002 [36]

Polak et al. 2003 [37]

Dündar and Ozkan 2001 [38]

Koksal et al. 2005 [39]

Kurtulan et al. 2004 [40] 38

30

14

12

10

15

15

15

13

12

6

15

16/48

N

Men with ED

Men with ED

Healthy volunteers

Healthy men

Healthy volunteers

Healthy men

Men with age-related macular degeneration

Healthy men

Healthy subjects

Healthy volunteers

Men with ED and glaucoma

Men with glaucoma

Healthy volunteers

Population

Doppler ultrasonography of penile cavernosal artery and central retinal artery

Blood flow in retinal arteries, IOP, color vision, acuity, funduscopy Ocular blood flow, IOP

Retinal artery and vein diameter, IOP Retinal hemodynamic parameters

Digitized funduscopic photographic assessment of retinal blood vessel diameters

IOP, ocular blood flow, perfusion pressure Choroidal blood velocity, volume, flow; visual acuity, IOP, perfusion pressure

Choroidal congestion (ultrasonography), contrast sensitivity, color vision

Ocular blood flow, contrast sensitivity, pulse amplitude, IOP

Visual acuity, IOP, visual field, perimetry, slit lamp, color vision, funduscopy

IOP

IOP, pupillometry

Assessments

AEs = adverse events; ED = erectile dysfunction; IOP = intraocular pressure; OL = open-label; PC = placebo-controlled.

PC, acute, 200 mg

McCulley et al. 2002 [32]

OL, acute, 50 mg

OL, acute, 50–100 mg

Eke et al. 2001 [43]

Ocular hemodynamics Paris et al. 2001 [31]

PC, acute, 100 mg

PC, 10–150 mg

Grunwald et al. 2001 [42]

Design + dose

Intraocular pressure Yajima et al. 2000 [41]

Summary of studies assessing the effects of sildenafil on intraocular pressure and ocular hemodynamics

Study

Table 2

Significant increases in ocular blood flow (29%), contrast sensitivity (34%), and retinal microcirculation (8%); no changes in pulse amplitude or IOP No significant differences compared with baseline in mean choroidal thickness or contrast sensitivity. Color discrimination errors increased with sildenafil but did not correlate with choroidal thickness No significant acute change in sildenafil-treated patients compared with placebo-treated patients With sildenafil, no significant changes in choroidal volume, velocity, and flow; visual acuity, heart rate, and IOP; mean arterial pressure and perfusion pressure significantly decreased at 30 minutes No significant differences in percent change from baseline for average diameter of superior and inferior temporal retinal veins and retinal temporal artery (sildenafil vs. placebo) Increase in retinal arterial (6%) and venous (6%) diameters at 1 hour postdose; no change in IOP Increase in retinal venous diameters (5%) and retinal blood flow (16%) at 80 minutes postdose; no change in retinal arterial diameter or blood velocity, IOP, mean arterial pressure, or pulse rate Increased blood flow velocity in ophthalmic artery; no other changes Ophthalmic and short posterior ciliary artery peak systolic, end diastolic, and mean velocities significantly increased at 1 hour after sildenafil; no changes in central retinal artery velocities Significant increase in mean cavernosal peak systolic velocity, but no significant changes in central retinal artery flow parameters (overall and in 5 patients with ocular AEs)

No effect on IOP or pupillometry in subjects receiving sildenafil or placebo No significant acute change in sildenafil-treated patients compared with placebo-treated patients No clinically significant ocular effects of sildenafil compared with baseline

Results

16 Laties and Sharlip

Sildenafil Ocular Safety sildenafil on ocular circulation have been the focus of several studies in healthy subjects and patients with ED (Table 2). Overall, reported effects have been minor and inconsistent; inconsistencies in reported changes may reflect the difficulty in measuring relatively small changes. For example, an increase in pulsatile ocular blood flow, which predominantly arises from pulsatile choroidal blood flow, was observed 2 hours after administration of 50 mg sildenafil in a study of 12 healthy adults [31], whereas no differences in changes from baseline in mean choroidal thickness were observed in seven healthy subjects receiving 200 mg sildenafil compared with six healthy subjects receiving no drug [32]. In the latter study, McCulley et al. reported an increase in choroidal thickness at 90 minutes postdose in one of seven healthy subjects receiving 200 mg sildenafil; no correlation between errors in color discrimination and choroidal thickness was found. No changes in mean foveolar choroidal or optic nerve blood flow measurements, mean arterial blood pressure, intraocular pressure, or perfusion pressure were observed at 1 and 5 hours after ingestion of 100 mg sildenafil compared with placebo in a double-blind, placebo-controlled crossover study of 15 healthy volunteers [33]. Administration of 100 mg sildenafil in 15 patients with age-related macular degeneration was also found to produce no changes in mean choroidal blood velocity, volume, and flow in the 5 hours after administration compared with placebo [34]. There were no changes in contrast sensitivity, visual acuity, intraocular pressure, and heart rate with sildenafil, but a decrease in mean brachial artery pressure and ocular perfusion pressure was noted at 30 minutes after sildenafil dosing. Interestingly, in these two studies significant inverse correlations were determined between mean arterial pressure or perfusion pressure and superotemporal optic nerve blood flow (R = −0.87, P = 0.003 and R = −0.83, P = 0.0001, respectively) [33] or choroidal blood velocity (R = −0.56, P = 0.03 and R = −0.59, P = 0.02, respectively) [34] after sildenafil dosing. Inconsistent and minor findings have also been reported concerning the vasodilatory effects of sildenafil on ocular vessels. Using digitized fundus photographs, Grunwald et al. [35] noted no change in average diameter for the superior and inferior temporal veins and the retinal temporal artery at 1 and 5 hours following 100 mg sildenafil compared with placebo in 15 healthy volunteers. Using a retinal vessel analyzer, Pache et al. [36]

17 reported a minor increase of 5.8% in both retinal arterial and venous diameters at 30 minutes after administration of 50 mg sildenafil; diameters returned to baseline values within 120 minutes. Mild decreases in systolic and diastolic blood pressure and an increase in heart rate were also noted at 30 minutes; the intraocular pressure did not change during the study. Compared with placebo, minor increases in retinal venous diameter (maximum effect, 4.7 ± 3.2% at 80 minutes) and in retinal blood flow (maximum effect, 15.7 ± 18.0% at 80 minutes) were reported by Polak et al. [37] following 100 mg sildenafil in 12 healthy subjects. No effects of sildenafil on flicker-induced vasodilation in retinal arteries or veins, mean arterial pressure, pulse rate intraocular pressure, retinal blood velocity, or retinal artery diameter were observed. In a study of 14 healthy men given 50 mg sildenafil, increases in peak systolic, end diastolic, and mean velocities measured by color Doppler ultrasonography were observed in the ophthalmic artery, but not in the central retinal or short temporal posterior ciliary arteries, at 1 hour after sildenafil dosing [38]. Heart rate also increased, but there were no changes in systolic or diastolic blood pressure, intraocular pressure, color vision, or visual acuity. Color Doppler ultrasonography findings from a double-blind, placebo-controlled study in patients with ED reported increases in peak systolic, end diastolic, and mean velocities in the ophthalmic and short posterior ciliary arteries but not the central retinal artery at 1 hour postdose in patients receiving 100 mg sildenafil (N = 20) compared with those receiving placebo (N = 10) [39]. There were no differences in systolic or diastolic blood pressure or intraocular pressure compared with baseline in the sildenafil group and no differences in changes from baseline for these parameters for sildenafil compared with placebo. In 38 men with ED, no changes in color Doppler measurements of central retinal artery peak systolic and end diastolic flow velocities, volume, and diameter were observed at 60 and 75 minutes after 100 mg sildenafil dosing and audiovisual sexual stimulation [40]; mean cavernosal arterial peak systolic velocity increased significantly at these time points. Two single-blind, placebo-controlled studies specifically assessed the effects of sildenafil on intraocular pressure at doses up to 150 mg in 16 and 48 healthy volunteers [41]. No effects on intraocular pressure or pupil diameter were observed in subjects receiving sildenafil or placebo. J Sex Med 2006;3:12–27

18 Although reports on blood flow effects are not uniform, there are no reports that sildenafil treatment causes a decrease in retinal, optic nervehead, or choroidal blood flow. In fact, in two studies, changes in mean arterial pressure or perfusion pressure were shown to inversely correlate with changes in superotemporal optic nerve blood flow [33] or choroidal blood velocity [34] after sildenafil dosing, suggesting that optic nervehead and choroidal blood flow is maintained or even enhanced after treatment with sildenafil. This occurred even if perfusion pressure or systemic blood pressure was reduced and would seem to indicate a protective effect through autoregulation of blood flow in these vessels. Patients with Pre-Existing Eye Disorders

An analysis of combined data from 18 phase II and III clinical trials identified 66 patients with ED and a pre-existing eye disorder, including glaucoma (N = 34), diabetic retinopathy (N = 16), and macular degeneration (N = 16), who received fixed or flexible doses (5–200 mg) of sildenafil or placebo for 4–26 weeks [26]. Sildenafil was generally well tolerated in patients with these pre-existing eye disorders. Visual adverse events were similar in sildenafil-treated and placebo-treated patients. As discussed previously, no clinically important changes in intraocular pressure were noted in studies in which this was assessed in healthy subjects administered sildenafil. In a double-blind, randomized, placebo-controlled, crossover study of 15 patients with bilateral chronic open-angle glaucoma and a history of elevated intraocular pressure, no statistically or clinically significant change in intraocular pressure was detected in either eye at 1–5 hours after administration of 100 mg sildenafil compared with placebo [42]. No clinically significant adverse ocular effects of sildenafil (50–100 mg) were reported in a group of six patients with glaucoma and concomitant ED [43]. Changes in intraocular pressure were limited to decreases of 1.5–3.5 mm Hg from baseline in four patients and increases of 3–6 mm Hg in two patients at 1–2 hours after taking sildenafil; no clinically significant changes were observed in visual acuity, color vision, slit lamp findings, or visual field testing. In a similar vein, Metelitsina et al. [34] concluded that sildenafil (100 mg) produced no changes (compared with placebo) in mean choroidal blood velocity, volume, and flow in 15 patients with age-related macular degeneration. No acute J Sex Med 2006;3:12–27

Laties and Sharlip visual effects or worsening of pre-existing visual impairment were reported following a single 100 mg dose of sildenafil in a randomized, doubleblind, placebo-controlled clinical trial of nine men aged 50–85 years with early-stage (minimal visual impairment and multiple drusen in the macula), age-related macular degeneration [44]. During the 8-hour period following dosing, no clinically relevant changes from baseline in repeated measurement of visual acuity, visual field, color discrimination, photostress, central vision, or traffic light tests were reported. Nonarteritic Anterior Ischemic Optic Neuropathy (NAION)

There have been a small number of spontaneous postmarketing reports of patients developing NAION after taking a PDE5 inhibitor for ED (Tables 3 and 4). NAION is the most common cause of acute optic neuropathy in adults aged 50 years or older [45–47]. The estimated annual incidence of NAION is between 2.3 and 10.2 cases per 100,000 people aged ≥50 years [45,46]. Most frequently, the patient reports a sudden painless decrease in vision, typically in one eye only. On evaluation, an afferent pupillary defect, pale swollen optic disc with nerve fiber layer hemorrhages, and loss of visual acuity and/or visual field in the affected eye is noted [48]. In contrast to the arteritic form caused by giant cell arteritis, a definitive cause of NAION has not been established. NAION is generally thought to result from circulatory insufficiency to the optic nervehead, which is supplied by para-optic branches of the posterior ciliary arteries [49]. Cross-inhibition of PDE6 by PDE5 inhibitors, which is believed to produce visual effects, including transient color tinges, increased sensitivity to light, and blurry vision, is not believed to play a role in NAION because PDE6 is not found in the vasculature. Despite intensive study, the true nature of NAION has remained elusive. A “disc at risk” or “crowded disc” (small cup to disc ratio), an anatomic variant of the optic disc (Figure 1) in which the optic nervehead either has an absent or small physiologic cup, is a well-recognized risk factor [50,51]. Other established risk factors include increasing age [52], hypertension [52,53], and diabetes [52,53]. In addition, smoking [53], nocturnal hypotension [54], hypercholesterolemia, ischemic heart disease, stroke, prothrombotic factors [55], sleep apnea [56], and elevated homocysteine [57]

Pomeranz et al. 2002 [75]

Cunningham and Smith 2001 [76]; Pomeranz et al. 2002 [75]

Pomeranz et al. 2002 [75]

Pomeranz et al. 2002 [75]

Pomeranz and Bhavsar 2005 [77]

2

3

4

5

6

59

59

62

42

69

52

Age

25

25

50

Yes

Yes

Yes

Unk

No

50

50

Unk

Unk

No

Sexual activity

50

50 or 100

50

SIL dose (mg)

Few hours

24 hours

Several hours

Left eye, color changes, LV

Both eyes, saw bright colors; right eye, LV, RAPD, soreness

Right eye, inferior VFD

Right eye, inferior VFD

Right eye, blurred vision, inferior VFD

∼8 hours

Unk

Right eye, eye pain (retroorbital and with movement)

Left eye, painless LV

Both eyes, blue “lightning bolts,” blurry vision

Symptoms

12 hours

45 minutes

1 hour

Latency (postdose)

Left eye, ODS, VF severely constricted

Right eye, ODS, inferior VFD extending to superior; subsequent inferior VFD left eye

Right eye, ODS with hemorrhages, inferior VFD, RAPD

Right eye, mild ODS with hemorrhages, inferior VFD; left eye, disc pallor, superior VFD

Right eye, ODS with hemorrhages, inferior VFD, RAPD

Right eye, ODS with hemorrhages, inferonasal VFD, RAPD

Left eye, ODS, inferior VFD

Signs

Left eye, 20/100 progressing to CF and then HM

Both eyes, initially 20/20, reduced to 20/70, then LP (right) and to 20/60 (left)

Both eyes, 20/25

Right eye, 20/50; left eye, 20/80

Right eye, 20/20 reduced to 20/200; left eye, 20/20

Both eyes, 20/20

Right eye, 20/80; left eye, 20/20

20/20 corrected both eyes

Visual acuity

ESR = 7 mm/hour, 6 mm/hour after methylprednisolone

ESR = 72 mm/hour, chol 246 mg/dL, trig 236 mg/dL, ANA and TAB negative, MRI of brain and orbits normal, ESR = 3 mm/hour after methylprednisolone and prednisone

ESR = 10, ANA normal, MRI normal

Lab values

Right eye, NAION (4 months prior)

Headaches, depression, GERD, skin cancer

Left eye, cup : disc = 0.1; CAD, DM, smoking

Left eye, NAION (2 years prior)

Left eye, cup : disc = 0.1

Color blindness, depression

HC

Cup : disc = 0.1, Crohn’s disease, TURP, ADD

Risk factors, medical history

Sertraline, omeprazole

Sertraline, omeprazole

Insulin, metformin, bisoprolol

Aspirin daily

Sertraline

Atorvastatin, aspirin daily

Methylphenidate (bid)

Medications

ADD = attention deficit disorder; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; BP = blood pressure; BPH = benign prostatic hypertrophy; BT = brachytherapy for prostate cancer; BUN = blood urea nitrogen; CAD = coronary artery disease; CF = count fingers; chol = cholesterol; CRP = C-reactive protein; CT = computerized tomography; DM = diabetes mellitus; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FC = counting fingers; GERD = gastroesophageal reflux disease; HC = high cholesterol; HM = hand motion; HTN = hypertension; IHD = ischemic heart disease; LP = light perception; LV = loss of vision; MI = myocardial infarction; MRA = magnetic resonance angiogram; MRI = magnetic resonance imaging; NLP = no light perception; OD = optic disc; ODS = optic disc swelling; RAPD = relative afferent pupillary defect; RD = retinal detachment; SIL = sildenafil; STS = syphilis screening test; TAB = temporal artery biopsy; trig = triglyceride; TSH = thyroid-stimulating hormone; TURP = transurethral resection of prostate; Unk = unknown; VF = visual field; VFD = visual field defect.

Egan and Pomeranz 2000 [74]; Pomeranz et al. 2002 [75]

Source

Clinical data for suspected nonarteritic anterior ischemic optic neuropathy (NAION) in patients prescribed sildenafil

1

Patient No.

Table 3

Sildenafil Ocular Safety 19

J Sex Med 2006;3:12–27

J Sex Med 2006;3:12–27

Pomeranz and Bhavsar 2005 [77]

Pomeranz and Bhavsar 2005 [77]

Pomeranz and Bhavsar 2005 [77]

Pomeranz and Bhavsar 2005 [77]

Pomeranz and Bhavsar 2005 [77]

8

9

10

11

12

60

66

69

50

67

58

Age

Unk

Unk

50

100

50

50

SIL dose (mg)

Unk

Unk

Unk

Unk

Unk

Yes

Sexual activity

8 hours

36 hours

24 hours

8 hours

24 hours

1 hour

Latency (postdose)

Right eye, acute LV upon awakening

Right eye, acute LV while exercising

Left eye, acute LV

Both eyes, “flashbulb” and glare; left eye, LV at 30 hours

Right eye, LV upon awakening

Right eye, LV

Symptoms

Right eye, ODS with hemorrhages, RAPD, superior VFD; inferior VFD 2 weeks later

Right eye, ODS; left eye, OD pale

Left eye, ODS with hemorrhages

Right eye, hypoplastic optic nerve; left eye, ODS, inferior and central VFD

Right eye, ODS, RAPD, superior VFD

Right eye, ODS with hemorrhages, inferior VFD, RAPD

Signs

Both eyes, 20/20

Right eye, 20/25; left eye, NLP

Right eye, 20/32; left eye, 20/100 progressing to 20/200 and then 20/125

Right eye, FC; left eye, 20/70 reduced to FC

Right eye, 20/200 corrected; left eye, 20/25 corrected

Right eye, HM; left eye, 20/40

Visual acuity

BUN 21 mg/dL, creatinine 1.5 mg/dL, chol 286 mg/dL, trig 624 mg/dL; ESR, blood count, TSH, CRP, and carotid ultrasound all normal

ESR, blood count, serum protein, electrophoresis, carotid ultrasound normal

ESR = 1, lipids, rheumatoid factor, ANA, glucose, BP, carotid and vertebral ultrasound, MRA, MRI all normal

HC, epistaxis subsequent to mucosistis, left eye amblyopia

ESR = 43 mm/hour, TAB and carotid and vertebral artery ultrasounds negative

HC, obesity, cardiac dysrhythmia

DM, HTN, HC, left eye RD

HTN, atrial flutter, BT, left eye retinal buckle surgery (3 months prior)

Renal stones, BPH, arthritis, right eye optic nerve hypoplasia (9 years prior)

HTN, seizure disorder

Risk factors, medical history

Lab values

Metoprolol, simvastatin, aspirin

Glipizide, metformin, lisinopril, furosimide, amlodipine, fluvastatin

Chlorthalidone, warfarin, digoxin, diltiazem

Terazosin, gabapentin, metaxalone

Metoprolol, enalapril, sertraline, bisoprolol, nifedipine, nortriptyline, doxazosin, phenobarbital, dicloflenac

Aspirin, pravastatin

Medications

ADD = attention deficit disorder; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; BP = blood pressure; BPH = benign prostatic hypertrophy; BT = brachytherapy for prostate cancer; BUN = blood urea nitrogen; CAD = coronary artery disease; CF = count fingers; chol = cholesterol; CRP = C-reactive protein; CT = computerized tomography; DM = diabetes mellitus; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FC = counting fingers; GERD = gastroesophageal reflux disease; HC = high cholesterol; HM = hand motion; HTN = hypertension; IHD = ischemic heart disease; LP = light perception; LV = loss of vision; MI = myocardial infarction; MRA = magnetic resonance angiogram; MRI = magnetic resonance imaging; NLP = no light perception; OD = optic disc; ODS = optic disc swelling; RAPD = relative afferent pupillary defect; RD = retinal detachment; SIL = sildenafil; STS = syphilis screening test; TAB = temporal artery biopsy; trig = triglyceride; TSH = thyroid-stimulating hormone; TURP = transurethral resection of prostate; Unk = unknown; VF = visual field; VFD = visual field defect.

Pomeranz and Bhavsar 2005 [77]

Source

Continued

7

Patient No.

Table 3

20 Laties and Sharlip

Dheer et al. 2002 [78]

Cockerham 2003 [79]

Gruhn and Fledelius 2005 [80]

Sinha et al. 2004 [81]

14

15

16

17

61

69

50

48

61

Age

100

50

Unk

100

100

SIL dose (mg)

Unk

Unk

Unk

No

Unk

Sexual activity

Unk

∼18 hours

1.5 hours

Unk

Latency (postdose)

Right eye, LV

Right eye, inferior VFD

Left eye, LV upon awakening, color deficit

Both eyes, blue flashes, blurred vision

Right eye, painless LV, “vertical red bar in VF”

Symptoms

Right eye, no ODS; faint focal cloudy swelling of retinal nerve layer along inferotemporal retinal artery evolving to cotton wool spots

Right eye, choked disc, inferior VFD

Left eye, ODS, RAPD

Left eye, superior VFD

Right eye, ODS

Signs

Right eye, CF improved to 6/6; left eye, 6/12

Both eyes, 1.0

Right eye, normal; left eye, 20/400

Both eyes, 20/20 corrected

Right eye, CF; left eye, 6/9 progressing to 6/12

Visual acuity

Vague visual disturbance (1/2 day prior to sildenafil use)

Disc at risk, smoking, hyperopia, amblyopic left eye, severe frontal headaches, suspected sinusitis

ESR = 30 mm/hour, CRP = 96 mg/L, TAB negative; treated with prednisolone with decline in CRP, resolution of headache

HTN, IHD with MI, smoking

Risk factors, medical history

BP, ECG, brain CT normal, ESR = 2 mm/hour, no giant cells, STS, ANA, ANCA, and carotid arteries all normal

ESR = 18 mm/hour

Lab values

Oral penicillin

Atorvastatin, amlodipine, diltiazem, atenolol, omeprazole, transdermal andropatch, aspirin

Medications

ADD = attention deficit disorder; ANA = antinuclear antibody; ANCA = antineutrophil cytoplasmic antibody; BP = blood pressure; BPH = benign prostatic hypertrophy; BT = brachytherapy for prostate cancer; BUN = blood urea nitrogen; CAD = coronary artery disease; CF = count fingers; chol = cholesterol; CRP = C-reactive protein; CT = computerized tomography; DM = diabetes mellitus; ECG = electrocardiogram; ESR = erythrocyte sedimentation rate; FC = counting fingers; GERD = gastroesophageal reflux disease; HC = high cholesterol; HM = hand motion; HTN = hypertension; IHD = ischemic heart disease; LP = light perception; LV = loss of vision; MI = myocardial infarction; MRA = magnetic resonance angiogram; MRI = magnetic resonance imaging; NLP = no light perception; OD = optic disc; ODS = optic disc swelling; RAPD = relative afferent pupillary defect; RD = retinal detachment; SIL = sildenafil; STS = syphilis screening test; TAB = temporal artery biopsy; trig = triglyceride; TSH = thyroid-stimulating hormone; TURP = transurethral resection of prostate; Unk = unknown; VF = visual field; VFD = visual field defect.

Boshier et al. 2002 [68]

Source

13

Patient No.

Sildenafil Ocular Safety 21

J Sex Med 2006;3:12–27

22

Echocardiogram: dilated left atrium and ventricle, mild mitral and tricuspid regurgitation, but normal function. Doppler: elevated left carotid velocity (arteriosclerotic plaque)

J Sex Med 2006;3:12–27

HTN = hypertension; LV = loss of vision; RAPD = relative afferent pupillary defect; SIL = sildenafil; VFD = visual field defect.

Both eyes, 20/30 Left eye, whitened, swollen inner retina with intraluminal refractile embolus in disc; superior VFD Left eye, sudden painless, superior hemifield LV, red eyes 4 hours Yes 51 Bertolucci et al. 2003 [69] 2

100

69 Tripathi and O’Donnell 2000 [70] 1

100

Unknown

Few hours

Left eye, sudden painless LV

Left eye, superotemporal branch artery occlusion, RAPD

Right eye, 6/6; left eye, 6/24

All labs normal

HTN

Risk factors, medical history Lab values Visual acuity Signs Symptoms Latency (postdose) Sexual activity SIL dose (mg) Age Source Patient No.

Clinical data for patients with branched retinal artery occlusion in patients prescribed sildenafil Table 4

have been reported to be associated with NAION [48,52,53,58]. Many of the vascular risk factors for developing NAION also predict the occurrence of ED, such as hypertension, diabetes, hyperlipidemia, and smoking [57,59–61]. The prevalence of hypertension, diabetes, and hyperlipidemia was recently reported to be 42%, 20%, 42%, respectively, in a large population of ED patients (N = 272,325) [62]. Prevalence of hypertension (47%) and diabetes (24%) in the 420 patients with NAION eligible for the 26-center Ischemic Optic Neuropathy Decompression Trial was similar to that reported for ED [53]. In contrast, the prevalence of hypertension and of diabetes in the U.S. adult population estimated from the National Health And Nutrition Examination Surveys (NHANES) for 1999–2002 is 29% [63] and 7% [64], respectively. Considering that ED and NAION share risk factors, it is likely that some men being treated for ED would coincidentally experience NAION.

Verapamil

Medications

Laties and Sharlip

Figure 1 Diagram of the anatomy and vasculature of the eye. The central retinal artery travels through the optic nerve, which attaches to the back of the eye at a region called the optic disc. An anatomically crowded disc, or disc at risk, may impinge on vessels that supply the optic nerve fibers and increase the risk of an ischemic event.

23

Sildenafil Ocular Safety NAION Incidence in Sildenafil Clinical Trials and Monitored Postmarketing Studies

Safety data from clinical trials and observational studies were examined to ascertain the incidence of NAION in men receiving sildenafil treatment for ED. Both clinical trial data and epidemiologic data are crucial for evaluating a drug’s safety profile, and both have methods to reliably record the occurrence of serious adverse events, including cases of NAION. Clinical trials generally include more frequent and more thorough patient assessments than observational epidemiologic studies, whereas observational studies follow a greater number of patients for longer periods of time, and thus more closely resemble “real-world” usage. A review of the collective database maintained by Pfizer of 103 clinical trials of sildenafil in 13,400 men with ED revealed no cases of reported or observed NAION in more than 13,300 patientyears of observation [27]. Likewise, no cases of NAION were observed during 2,935 patient-years of observation in the International Men’s Health Study, a prospective cohort study conducted between 2001 and 2004 of 3,813 men who received a sildenafil prescription in Germany, France, Spain, or Sweden [27,65]. A Prescription Event Monitoring (PEM) study of patients who received sildenafil from the U.K. National Health Service was independently conducted by the Drug Safety Research Unit at the University of Southampton between 1998 and 2001 [66–68]. During 35,500 patient-years of observation of more than 28,000 patients, one case of NAION was reported to the Drug Safety Research Unit [68]. This patient, a 61-year-old man, had predisposing factors for NAION, including a history of smoking, hypertension, and ischemic heart disease diagnosed following myocardial infarction. The NAION event occurred more than 1 year (368 days) after the patient was first prescribed sildenafil. Based on this one case of NAION in 35,500 patient-years of observation from the PEM, the unadjusted incidence rate of NAION in patients prescribed sildenafil was 2.8 per 100,000 patient-years, suggesting that, in this study, the incidence of NAION due to sildenafil use was not greater than the baseline incidence of NAION. Moreover, in the other studies, the incidence rate of NAION was zero. Case Reports of Vision Loss in PDE5 Inhibitor Users

Spontaneous postmarketing reports of adverse events may be useful for identifying adverse events

that occur once the drug is available to the general public, that were not reported in clinical trials, or that occur at a higher rate than would be expected in the population using the drug. Spontaneous events are less reliable than controlled clinical trial and observational epidemiologic study data because of the voluntary nature of event reporting systems and the influence of factors, such as media attention, the drug’s popularity and time on the market, and the severity of the event, on event reporting. Consequently, events may be either over- or under-reported, may lack medical confirmation, and cannot be used to determine incidence rates for adverse events. A total of 17 case reports of NAION among patients using sildenafil have been published (Table 3). Patient ages ranged from 42 to 69 years. Time to onset (relative to sildenafil dose) was ≤36 hours in cases in which time was recorded. The reported sildenafil dose was 25 mg (1), 50 mg (9), 100 mg (4), unknown/not reported (3). Comorbidities and risk factors reported most frequently included a low cup to disc ratio or crowded disc, history of hypertension, hyperlipidemia, diabetes, coronary artery disease, smoking, and a history of NAION in the other eye. Two cases of vision loss resulting from branch retinal artery occlusions in patients who took sildenafil have been reported (Table 4) [69,70]. Vision loss occurred within a few hours of taking sildenafil in both patients. The first patient, a 69year-old man, had no risk factors predisposing to arterial occlusion other than age, whereas the second patient, a 51-year-old man, had essential hypertension.

Case Reports of Vision Loss in Tadalafil Users

Three cases of NAION have been reported in users of tadalafil (Table 5) [7–9]. All reported accompanying vision loss, all had a temporal association with tadalafil use, and two of three cases had low cup to disc ratio and/or vascular risk factors.

New U.S. Food and Drug Administration-Approved NAION Labeling for PDE5 Inhibitors

At the request of the U.S. Food and Drug Administration, the manufacturers of the three currently marketed PDE5 inhibitors have updated their prescribing information [71–73] as follows: J Sex Med 2006;3:12–27

24

Left eye, small cup : disc ratio, HC

Right eye, inferior VFD 2 hours 20

Yes

Right eye, ODS, inferior VFD, RAPD 4 episodes of right eye inferior VFD after TAD, each resolved within 24 hours 2 hours 3 of 4 times 20 67 Bollinger and Lee 2005 [7] 3

J Sex Med 2006;3:12–27

BP = blood pressure; CRP = C-reactive protein; ESR = erythrocyte sedimentation rate; HC = high cholesterol; ODS = optic disc swelling; RAPD = relative afferent pupillary defect; TAD = tadalafil; VF = visual field; VFD = visual field defect.

Atorvastatin, aspirin, folate

Right eye, crowded disc, laparoscopic prostatectomy, depression ESR and CRP normal Right eye, 2 cotton wool spots in macula; left eye, ODS with hemorrhages, inferior VFD, RAPD Dizziness, BP 162/61 mm Hg; left eye, graying of inferior VF 15 hours, dizziness 45 hours, VFD Escaravage et al. 2005 [8] 2

59

20

No

Both eyes, 20/20

Right eye, 20/30; left eye, 20/40

Bupropion Radical prostatectomy Right eye, 6/6; left eye, 6/9 Left eye, ODS, global reduction in VF, RAPD, decreased color vision (Ishihara test) Left eye, blue areas, flashing lights, blurry vision Peter et al. 2005 [9] 1

59

20

Unknown

7 days

Visual acuity Signs Symptoms Latency (postdose) Sexual activity TAD dose (mg) Age Source Patient No.

Table 5

Clinical data for suspected nonarteritic anterior ischemic optic neuropathy (NAION) in patients prescribed tadalafil

Lab values

Risk factors, medical history

Medications ESR = 7 mm/hour

Laties and Sharlip Non-arteritic anterior ischemic optic neuropathy (NAION), a cause of decreased vision including permanent loss of vision, has been reported rarely postmarketing in temporal association with the use of phosphodiesterase type 5 (PDE5) inhibitors. Most, but not all, of these patients had underlying anatomic or vascular risk factors for developing NAION, including but not necessarily limited to: low cup to disc ratio (“crowded disc”), age over 50, diabetes, hypertension, coronary artery disease, hyperlipidemia and smoking. It is not possible to determine whether these events are related directly to the use of PDE5 inhibitors, to the patient’s underlying vascular risk factors or anatomical defects, to a combination of these factors, or to other factors.

Conclusions

Visual function studies suggest that sildenafil does not affect visual acuity, visual fields, and contrast sensitivity. Minor, transient visual symptoms, reported as blue tinge to vision, increased brightness of lights, and blurry vision, have been reported with sildenafil use and occur more frequently at higher doses, particularly at the time of peak plasma levels. No consistent pattern of effects on the ocular circulation or on the retina or other structures of the eye has been reported with sildenafil use. Based on analysis of carefully monitored sildenafil postmarketing studies and extensive clinical trial experience, the expected number of cases of NAION was not exceeded, suggesting that there is no statistical evidence that NAION is more common in users of PDE5 inhibitors than in men of similar age and health who are not using PDE5 inhibitors. Corresponding Author: Alan Laties, MD, Scheie Eye Institute, University of Pennsylvania Medical School— Department of Ophthalmology, Myrin Circle 51 N. 39th St., Philadelphia, PA 19104, USA. Tel: (215) 8986508; Fax: (215) 898-0528; E-mail: [email protected]. upenn.edu Conflict of Interest: Dr. Laties is a consultant for Pfizer, Inc. References

1 Beavo JA. Cyclic nucleotide phosphodiesterases: Functional implications of multiple isoforms. Physiol Rev 1995;75:725–48. 2 Moreland RB, Goldstein I, Traish A. Sildenafil, a novel inhibitor of phosphodiesterase type 5 in human corpus cavernosum smooth muscle cells. Life Sci 1998;62:309–18. 3 Boolell M, Allen MJ, Ballard SA, Gepi-Attee S, Muirhead GJ, Naylor AM, Osterloh IH, Gingell C. Sildenafil: An orally active type 5 cyclic GMPspecific phosphodiesterase inhibitor for the

Sildenafil Ocular Safety

4

5

6

7

8 9 10

11

12

13 14

15

16 17

18

treatment of penile erectile dysfunction. Int J Impot Res 1996;8:47–52. Ballard SA, Gingell CJ, Tang K, Turner LA, Price ME, Naylor AM. Effects of sildenafil on the relaxation of human corpus cavernosum tissue in vitro and on the activities of cyclic nucleotide phosphodiesterase isozymes. J Urol 1998;159:2164–71. Padma-Nathan H, Eardley I, Kloner RA, Laties AM, Montorsi F. A 4-year update on the safety of sildenafil citrate (Viagra®). Urology 2002;60(suppl 2B):67–90. Morales A, Gingell C, Collins M, Wicker PA, Osterloh IH. Clinical safety of oral sildenafil citrate (VIAGRA) in the treatment of erectile dysfunction. Int J Impot Res 1998;10:69–74. Bollinger K, Lee MS. Recurrent visual field defect and ischemic optic neuropathy associated with tadalafil rechallenge. Arch Ophthalmol 2005;123:400– 1. Escaravage GK Jr, Wright JD Jr, Givre SJ. Tadalafil associated with anterior ischemic optic neuropathy. Arch Ophthalmol 2005;123:399–400. Peter NM, Singh MV, Fox PD. Tadalafil-associated anterior ischaemic optic neuropathy. Eye 2005; 19:715–7. Wallis RM, Casey J, Howe L, Leishman D, Napier CM. Characterisation of retinal phosphodiesterase (PDE) isozymes and the effects of sildenafil in vitro. Ophthalmic Res 1998;30:111. Wallis R, Leishman DJ, Pullman L, Graepel P, Heywood R. Effects of sildenafil on electroretinograms in dogs and retinal histopathology in rats and dogs. Ophthalmic Res 1998;30:68. Milligan PA, Marshall SF, Karlsson MO. A population pharmacokinetic analysis of sildenafil citrate in patients with erectile dysfunction. Br J Clin Pharmacol 2002;53:45S–52S. Laties AM, Fraunfelder FT. Ocular safety of Viagra (sildenafil citrate). Trans Am Ophthalmol Soc 1999;97:115–25. Laties A, Ellis P, Koppiker N, Patat A, Stuckey B. Visual function testing in patients and healthy volunteers receiving VIAGRA. Ophthalmic Res 1998;30(suppl 1):177. Laties A, Ellis P, Mollon JD. The effects of sildenafil citrate (VIAGRA) on color discrimination in volunteers and patients with erectile dysfunction. Invest Ophthalmol Vis Sci 1999;40(4 suppl):S693. Vobig MA, Klotz T, Staak M, Bartz-Schmidt KU, Engelmann U, Walter P. Retinal side-effects of sildenafil. Lancet 1999;353:375. Kretschmann C, Gockein R, Meschi M, Stief CG, Winter R. Short time influences of sildenafil on visual function. Invest Ophthalmol Vis Sci 1999;40(4 suppl):S766. Luu JK, Chappelow AV, Mcculley TJ, Marmor MF. Acute effects of sildenafil on the electroretinogram and multifocal electroretinogram. Am J Ophthalmol 2001;132:388–94.

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